S.H.

Ralston
I.B. McInnes

25
Rheumatology and
bone disease
Clinical examination of the musculoskeletal Fibromyalgia 1092 Diseases of bone 1120
system 1058 Osteoporosis 1120
Bone and joint infection 1094
Functional anatomy and physiology 1060 Septic arthritis 1094 Osteomalacia and rickets 1125
Viral arthritis 1095 Paget’s disease of bone 1128
Investigation of musculoskeletal
disease 1064 Osteomyelitis 1095 Other bone diseases 1130
Joint aspiration 1064 Tuberculosis 1096 Reflex sympathetic dystrophy
syndrome 1130
Imaging 1064 Rheumatoid arthritis 1096 Osteonecrosis 1130
Blood tests 1066
Pathophysiology 1096 Scheuermann’s osteochondritis 1130
Tissue biopsy 1068
Clinical features 1097 Polyostotic fibrous dysplasia 1131
Electromyography 1068
Investigations 1100 Osteogenesis imperfecta 1131
Presenting problems in musculoskeletal Management 1100 Osteopetrosis 1131
disease 1069
Juvenile idiopathic arthritis 1103 Sclerosing bone dysplasias 1131
Acute monoarthritis 1069
Polyarthritis 1069 Seronegative spondyloarthropathies 1104 Bone and joint tumours 1131
Fracture 1071 Ankylosing spondylitis 1105 Osteosarcoma 1132
Generalised musculoskeletal pain 1071 Reactive arthritis 1107 Metastatic bone disease 1132
Back pain 1072 Psoriatic arthritis 1108 Rheumatological involvement in other
Regional musculoskeletal pain 1074 Enteropathic arthritis 1109 diseases 1132
Neck pain 1074 Connective tissue diseases 1109 Malignant disease 1132
Shoulder pain 1074 Endocrine disease 1132
Systemic lupus erythematosus 1109
Elbow pain 1075 Haematological disease 1133
Systemic sclerosis 1112
Hand and wrist pain 1075 Neurological disease 1133
Mixed connective tissue disease 1113
Hip pain 1075 Sjögren’s syndrome 1114 Miscellaneous conditions 1133
Knee pain 1075 Polymyositis and dermatomyositis 1114 Spondylolisis and spondylolisthesis 1133
Ankle and foot pain 1076 Inclusion body myositis 1115 Diffuse idiopathic skeletal hyperostosis 1133
Muscle pain and weakness 1076 Pigmented villonodular synovitis 1134
Vasculitis 1115
Principles of management of Takayasu’s disease 1116 Joint hypermobility 1134
musculoskeletal disorders 1077 Dupuytren’s contracture 1134
Kawasaki disease 1116
Education and lifestyle interventions 1077 Carpal tunnel syndrome 1134
Polyarteritis nodosa 1117
Pharmacological treatment 1078 Trigger finger 1134
Giant cell arteritis and polymyalgia
Non-pharmacological interventions 1080 rheumatica 1117 Periodic fever syndromes 1135
Osteoarthritis 1081 Antineutrophil cytoplasmic antibody-associated Anterior tibial compartment syndrome 1135
vasculitis 1118 Synovitis–acne–pustulosis–hyperostosis–
Crystal-induced arthritis 1086 osteitis syndrome 1135
Churg–Strauss syndrome 1118
Gout 1087
Henoch–Schönlein purpura 1119
Calcium pyrophosphate dihydrate crystal
Cryoglobulinaemic vasculitis 1119
deposition disease 1090
Behçet’s syndrome 1119
Basic calcium phosphate deposition
disease 1091 Relapsing polychondritis 1119

1057
 RHEUMATOLOGY AND BONE DISEASE

CLINICAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM

Extensor surfaces 2
Rheumatoid nodules 3 Face
Swollen bursa Rash
Psoriasis rash Alopecia
Mouth ulcers
Eyes

Butterfly rash in systemic

lupus erythematosus
Rheumatoid nodules

Hands 1
Swelling
Deformity
Nail changes
Tophi Scleritis in rheumatoid
Raynaud’s arthritis

4 Trunk
Kyphosis
Scoliosis
Tender spots

5 Legs
Deformity
Swelling
Restricted movement
Nail dystrophy in
psoriatic arthritis

Bone deformity in
Synovitis and deformity Paget’s disease
in rheumatoid arthritis
6 Feet
Deformity
Swelling
Redness

Observation
• General appearance
• Gait
Heberden and Bouchard • Deformity
nodes in osteoarthritis • Swelling
• Redness Acute gout
• Rash

1058
 Clinical examination of the musculoskeletal system

General Assessment of Locomotor System (GALS)

1 Gait 2 Arms

Inspect
hands for
swelling or
deformity
Press over supraspinatus
(tests for hyperalgesia)
Ask patient to put hands behind
Ask patient to head (tests shoulder movements)
make a fist and
open and close
fingers (tests
hand function)

Ask patient to walk for a
few steps, then come back.
Look for pain or limp
Squeeze
metacarpals Patient turns palms up and
down with elbows at side (tests
(tests for
inflammation) supination and pronation Patient flexes elbows to touch
of wrists and elbow) shoulder (tests elbow flexion)

3 Legs

Flex each hip

with hand on knee.
Rotate hips
internally and
externally (tests
hip movements
and detects Palpate each knee for warmth Inspect ankles and feet.
knee crepitus) and swelling Squeeze forefoot (tests for
(tests for synovitis and effusion) metatarsophalangeal synovitis)

4 Spine

Patient looks at ceiling Ask patient to try to put

and then puts chin on ear on shoulder (tests Patient slides hand down
chest (tests flexion and lateral flexion cervical leg to knee (tests lateral
extension cervical spine) spine) spine flexion)
Inspect spine from behind and side,
5 Record results looking for scoliosis, kyphosis or
localised deformity. Ask patient to
A normal screen Example of an abnormal screen touch toes
G A M G A M
A A
L L Stand behind
patient and hold
S S their pelvis.
G = gait A = appearance Ask them to turn
Antalgic gait from side to side
A = arms M = movement Right knee
L = legs without moving
Varus their feet (tests
S = spine ↓Flexion thoracolumbar
Crepitus++ rotation)
Effusion
Diagnosis: osteoarthritis right knee

1059
 RHEUMATOLOGY AND BONE DISEASE

25 Disorders of the musculoskeletal system affect all ages

and ethnic groups. In the UK, about 25% of new consul-
Diseases of the musculoskeletal system tend to be
more common in women and most increase in frequency
tations in general practice are for musculoskeletal symp- with increasing age. The two most common disorders
toms. Musculoskeletal diseases may arise from processes are osteoarthritis and osteoporosis (Box 25.1). Osteo-
affecting bones, joints, muscles, or connective tissues arthritis is the most common type of arthritis and affects
such as skin and tendon. The principal manifestations up to 80% of people over the age of 75. Osteoporosis is
are pain and impairment of locomotor function. the most common bone disease and affects 50% of
women and 20% of men by their eighth decade. Diseases
of the musculoskeletal system are the most common
25.1 Relative prevalence of musculoskeletal cause of physical disability in older people and account
disorders for one-third of physical disability at all ages.
Gender Age
Prevalence ratio association
‘Non-inflammatory’ conditions
Neck and back pain 20% F=M – FUNCTIONAL ANATOMY AND
Osteoarthritis PHYSIOLOGY
Knee 10% F>M ++
Hip 4% F=M + The musculoskeletal system is responsible for move-
Osteoporosis 15% F>M ++ ment of the body, provides a structural framework to
Regional ‘soft tissue’ pain 10% F>M ++ protect internal organs, and acts as a reservoir for storage
Fibromyalgia 3% F>M ++ of calcium and phosphate in the regulation of mineral
‘Inflammatory’ conditions homeostasis. The main components of the musculo-
Rheumatoid arthritis 1% F>M + skeletal system are depicted in Figure 25.1.
Gout 1.5% M>F –
Seronegative 0.8% F=M – Bone
spondyloarthritis Bones fall into two main types based on their embry-
Polymyalgia rheumatica 0.04% F>M ++
onic development. Flat bones, such as the skull, develop
Connective tissue 0.02% F>M –
by intramembranous ossification, in which embry-
diseases (mainly lupus)
onic fibroblasts differentiate directly into bone within

Muscle Articular cartilage

Myofilament Chondrocytes Calcified

cartilage
Myofibril

Fascicle

Tendon Subchondral
bone
Epiphyseal plate Enthesis

Bone Synovium
Calcified zone
Growth
plate Hypertrophic zone

Proliferative zone
Cortical bone
Synovial
lining cells Joint
Bone capsule

Trabecular bone

Osteoblasts Haversian system

Blood
vessels
Osteocytes
Collagen
lamellae
Osteoclasts
Osteocytes

1060 Fig. 25.1 Structure of the major musculoskeletal tissues.

 Functional anatomy and physiology

Bone-lining cells

RANK RANKL
Mineralisation Quiescence OPG
Osteoclasts
Osteocyte
Osteoblasts
Osteoid Microdamage Stromal cell
Osteocyte
Formation Apoptotic Resorption
osteoclast

T cell

Osteoclast
precursor
Reversal

Osteoblast Stromal
precursor cell LRP5 Wnt
SOST

25
Osteoclast
H+ Cl-
Osteoblast

Phosphate H+Cl- CatK

FGF23 excretion ↑

Osteocyte
Proton pump Chloride pump

Fig. 25.2 Regulation of bone remodelling. Bone is renewed and repaired during the bone remodelling cycle, in which old and damaged bone is
removed by osteoclasts and replaced by osteoblasts. Osteocytes play a central role in bone remodelling by secreting RANKL, which promotes osteoclast
differentiation and activity by binding to RANK. Osteocytes regulate bone formation by producing SOST, which binds to the LRP5 receptor and prevents
its activation by members of the Wnt family. Osteocytes also regulate phosphate homeostasis by producing fibroblast growth factor 23 (FGF23), which
is a circulating hormone that acts on the kidney to promote phosphate excretion. (CatK = cathepsin K; LRP5 = lipoprotein receptor protein 5; OPG =
osteoprotegerin; RANK = receptor activator of nuclear factor kappa B; RANKL = RANK ligand; SOST = sclerostin)

condensations of mesenchymal tissue during early fetal
life. Long bones, such as the femur and radius, develop
by endochondral ossification from a cartilage template.
During development, the cartilage is invaded by vascu-
lar tissue containing osteoprogenitor cells and is gradu-
ally replaced by bone from centres of ossification
situated in the middle and at the ends of the bone.
A thin remnant of cartilage called the growth plate or
epiphysis remains at each end of long bones, and
chondrocyte proliferation here is responsible for skeletal
growth during childhood and adolescence. During
puberty, the rise in levels of sex hormones halts cell divi-
sion in the growth plate. The cartilage remnant then dis-
appears as the epiphysis fuses and longitudinal bone
growth ceases.
The normal skeleton has two forms of bone tissue (see
Fig. 25.1). Cortical bone is formed from Haversian
systems, comprising concentric lamellae of bone tissue
surrounding a central canal that contains blood vessels.
Cortical bone is dense and forms a hard envelope around
the long bones. Trabecular or cancellous bone fills the
centre of the bone and consists of an interconnecting
meshwork of trabeculae, separated by spaces filled with
bone marrow.
There are three main cell types in bone:
• Osteoclasts: multinucleated cells of haematopoietic
origin, responsible for bone resorption.
• Osteoblasts: mononuclear cells of mesenchymal
origin, responsible for bone formation.
• Osteocytes: these differentiate from osteoblasts
during bone formation and become embedded in
bone matrix. Osteocytes are responsible for sensing
and responding to mechanical loading of the
skeleton and play a critical role in regulating bone
formation and bone resorption, by producing
receptor activator of nuclear factor kappa B ligand
(RANKL) and sclerostin (SOST). They also play a
central role in regulating phosphate metabolism by
producing the hormone fibroblast growth factor 23
(FGF23), which acts on the kidney to promote
phosphate excretion (Fig. 25.2). 1061
 RHEUMATOLOGY AND BONE DISEASE

25 Bone matrix and mineral

The most abundant protein of bone is type I collagen,
25.2 Regulators of bone remodelling
which is formed from two α1 peptide chains and one α2 Bone Bone
chain wound together in a triple helix. Type I collagen Factor resorption formation
is proteolytically processed inside the cell before being Parathyroid hormone (PTH) ↑ ↑
laid down in the extracellular space, releasing propep-
tide fragments that can be used as biochemical markers Receptor activator of nuclear ↑ ↔
of bone formation (p. 1066). Subsequently, the collagen factor kappa B ligand (RANKL)
fibrils become ‘cross-linked’ to one another by pyridin- Osteoprotegerin (OPG) ↓ ↔
ium molecules, a process that enhances bone strength. Sclerostin (SOST) ↔ ↓
When bone is broken down by osteoclasts, the cross-
Interleukin-1 (IL-1) ↑ ↓
links are released, providing biochemical markers of
bone resorption. Bone is normally laid down in an Tumour necrosis factor-α (TNF-α) ↑ ↓
orderly fashion, but when bone turnover is high, as in Thyroid hormone ↑ ↑
Paget’s disease or severe hyperparathyroidism, it is laid
Glucocorticoids ↑ ↓↓
down in a chaotic pattern, giving rise to ‘woven bone’,
which is mechanically weak. Bone matrix also contains Oestrogen/testosterone ↓ ↑
growth factors, other structural proteins and proteo- Mechanical loading ↓ ↑
glycans, thought to be involved in helping bone cells
attach to bone matrix and in regulating bone cell activity.
hormone (PTH) and oestrogen, and locally produced
The other major component of bone is mineral, com-
factors such as cytokines (Box 25.2). Many systemic hor-
prised of calcium and phosphate crystals deposited
mones exert effects on bone turnover by affecting local
between the collagen fibrils in the form of hydroxyapa-
expression of RANK, RANKL, OPG, SOST and mole-
tite [Ca10 (PO4)6 (OH)2]. Mineralisation is essential for
cules in the Wnt/LRP5 pathway (Fig. 25.2, Box 25.2).
bone’s rigidity and strength, but over-mineralisation can
increase brittleness, which contributes to bone fragility Joints
in diseases like osteogenesis imperfecta (p. 1131).
Bones are linked by joints. There are three main subtypes:
Bone remodelling fibrous, fibrocartilaginous and synovial (Box 25.3).
Bone remodelling is required for renewal and repair of Fibrous and fibrocartilaginous joints
the skeleton throughout life (see Fig. 25.2). It starts with
These comprise a simple bridge of fibrous or fibrocarti-
the attraction of osteoclast precursors in peripheral
laginous tissue joining two bones together where there
blood to the target site, probably by local release of
is little requirement for movement. The intervertebral
chemotactic factors from areas of microdamage. The
disc is a special type of fibrocartilaginous joint in which
osteoclast precursors differentiate into mature osteo-
an amorphous area, called the nucleus pulposus, lies in
clasts in response to RANKL, which is produced by
the centre of the fibrocartilaginous bridge. The nucleus
osteocytes, activated T cells and bone marrow stromal
has a high water content and acts as a cushion to improve
cells. RANKL activates the RANK receptor, which is
the disc’s shock-absorbing properties.
expressed on osteoclasts and precursors. This is blocked
by osteoprotegerin (OPG), a decoy receptor for RANKL Synovial joints
that inhibits osteoclast formation. Mature osteoclasts
Complex structures containing several cell types, these
attach to the bone surface by a tight sealing zone, and
are found where a wide range of movement is needed
secrete hydrochloric acid and proteolytic enzymes such
(Fig. 25.3).
as cathepsin K into the space underneath. The acid dis-
solves the mineral and cathepsin K degrades collagen. Articular cartilage
When resorption is complete, osteoclasts undergo pro- This avascular tissue covers the bone ends in synovial
grammed cell death, and bone formation begins with joints. Cartilage cells (chondrocytes) are responsible for
the attraction of osteoblast precursors to the resorption synthesis and turnover of cartilage, which consists of a
site. These differentiate into mature osteoblasts, which mesh of type II collagen fibrils that extend through a
deposit new bone matrix in the resorption lacuna, until hydrated ‘gel’ of proteoglycan molecules. The most
the hole is filled. Some osteoblasts become trapped in
bone matrix and differentiate into osteocytes. These act
as biomechanical sensors and produce several molecules 25.3 Types of joint
that influence bone remodelling and phosphate metabol-
ism. Bone formation is stimulated by Wnt proteins, Range of
which bind to and activate lipoprotein-related receptor Type movement Examples
protein 5 (LRP5), expressed on osteoblasts. This process Fibrous Minimal Skull sutures
is inhibited by SOST, which is produced by osteocytes
Fibrocartilaginous Limited Symphysis pubis
(see Fig. 25.2). Initially, the newly formed bone matrix Costochondral junctions
(osteoid) is uncalcified but subsequently becomes min- Intervertebral discs
eralised to form mature bone. Alkaline phosphatase Sacroiliac joints
(ALP), produced by osteoblasts, plays an important role
Synovial Large Most limb joints
in bone mineralisation by degrading pyrophosphate, an
Temporomandibular
inhibitor of mineralisation. Bone remodelling is regu-
Costovertebral
1062 lated by circulating hormones such as parathyroid
 Functional anatomy and physiology

Skin and glycosidases, responsible for the breakdown of GAGs.

subcutaneous
tissue
Bursa
Bone
Capsule Tendon
Synovium
Fibrocartilage Tendon
pad sheath
Joint space
Ligamentous
thickening
Hyaline articular of capsule
cartilage Muscle
Bursa
Fig. 25.3 Structure of a synovial joint.
Type II collagen Link protein
fibrils
Aggrecan
Keratan
sulphate
Chondroitin
sulphate
Core protein
Hyaluronan
Fig. 25.4 Ultrastructure of articular cartilage.
important proteoglycan is aggrecan, which consists of a
core protein to which several glycosaminoglycan (GAG)
side-chains are attached (Fig. 25.4). The GAGs are
polysaccharides that consist of long chains of disaccha-
ride repeats comprising one normal sugar and an amino
sugar. The most abundant GAGs in aggrecan are chon-
droitin sulphate and keratan sulphate. Hyaluronan
is another important GAG that binds to aggrecan
molecules to form very large complexes with a total
molecular weight of more than 100 million. Aggrecan
has a strong negative charge and avidly binds water
molecules to assume a shape that occupies the maximum
possible volume available. The expansive force of
the hydrated aggrecan, combined with the restrictive
strength of the collagen mesh, gives articular cartilage
excellent shock-absorbing properties.
With ageing, the concentration of chondroitin sul-
phate decreases, whereas that of keratan sulphate
increases, resulting in reduced water content and shock-
absorbing properties. These changes differ from those
found in osteoarthritis (p. 1081), where there is abnormal
chondrocyte division, loss of proteoglycan from matrix
and an increase in water content. Cartilage matrix is
constantly turning over and in health there is a perfect
balance between synthesis and degradation. Degrada-
tion of cartilage matrix is carried out by aggrecanases
and matrix metalloproteinases, responsible for the
breakdown of proteins and proteoglycans, and by
Pro-inflammatory cytokines, such as interleukin-1 (IL-1)
and tumour necrosis factor (TNF), stimulate production
of aggrecanase and metalloproteinases, which contrib-
ute to cartilage degradation in inflammatory arthritis.
Synovial fluid
The surfaces of articular cartilage are separated by
a space filled with synovial fluid, a viscous liquid
that lubricates the joint. It is an ultrafiltrate of plasma,
into which synovial cells secrete hyaluronan and
proteoglycans.
Intra-articular discs
Some joints contain fibrocartilaginous discs within the
joint space that act as shock absorbers. The most clini-
cally important are the menisci of the knee. These are
avascular structures that remain viable by diffusion of
oxygen and nutrients from the synovial fluid.
The synovial membrane, joint capsule and bursae
The bones of synovial joints are connected by the
joint capsule, a fibrous structure richly supplied with
blood vessels, nerves and lymphatics, which encases the
joint. Ligaments are discrete, regional thickenings of
the capsule that act to stabilise joints (see Fig. 25.3). The
inner surface of the joint capsule is the synovial mem-
brane, comprising an outer layer of blood vessels and
loose connective tissue that is rich in type I collagen, and
25
an inner layer 1–4 cells thick consisting of two main
cell types. Type A synoviocytes are phagocytic cells
derived from the monocyte/macrophage lineage and
are responsible for removing particulate matter from the
joint cavity; type B synoviocytes are fibroblast-like cells
that secrete synovial fluid. Most inflammatory and
degenerative joint diseases associate with thickening of
the synovial membrane and infiltration by lymphocytes,
polymorphs and macrophages.
Bursae are hollow sacs lined with synovium and
contain a small amount of synovial fluid. They help
tendons and muscles move smoothly in relation to bones
and other articular structures.
Skeletal muscle
Skeletal muscles are responsible for body movements
and respiration. Muscle consists of bundles of cells
(myocytes) embedded in fine connective tissue con-
taining nerves and blood vessels. Myocytes are large,
elongated, multinucleated cells formed by fusion of
mononuclear precursors (myoblasts) in early embryonic
life. The nuclei lie peripherally and the centre of the cell
contains actin and myosin molecules, which interdigi-
tate with one another to form the myofibrils that are
responsible for muscle contraction. The molecular mech-
anisms of skeletal muscle contraction are the same as for
cardiac muscle (p. 531). Myocytes contain many mito-
chondria that provide the large amounts of adenosine
triphosphate (ATP) necessary for muscle contraction,
and are rich in the protein myoglobin, which acts as a
reservoir for oxygen during contraction.
Individual myofibrils are organised into bundles
(fasciculi) that are bound together by a thin layer of
connective tissue (the perimysium). The surface of the
muscle is surrounded by a thicker layer of connective
tissue, the epimysium, which merges with the peri-
mysium to form the muscle tendon. Tendons are tough, 1063
 RHEUMATOLOGY AND BONE DISEASE
25 fibrous structures that attach muscles to a point of inser-
tion on the bone surface called the enthesis.
INVESTIGATION OF MUSCULOSKELETAL
DISEASE
Clinical history and examination usually provide suffi-
cient information for the diagnosis and management
of most musculoskeletal diseases. Investigations are
helpful in confirming the diagnosis, assessing disease
activity and indicating prognosis.
Joint aspiration
Joint aspiration with examination of synovial fluid (SF)
is pivotal in patients suspected of having septic arthritis,
crystal arthritis or intra-articular bleeding. It should be
done in all patients with acute monoarthritis, and
samples sent for microbiology and clinical chemistry.
It is possible to obtain SF by aspiration from most
peripheral joints, and only a small volume is required
for diagnostic purposes. Normal SF is present in small
volume, and is clear and either colourless or pale yellow
with a high viscosity. It contains few cells. With joint
inflammation, the volume increases, the cell count and
the proportion of neutrophils rise (causing turbidity),
and the viscosity reduces (due to enzymatic degradation
of hyaluronan and aggrecan). Turbid fluid with a high
neutrophil count occurs in sepsis, crystal arthritis and
reactive arthritis. High concentrations of urate crystals
or cholesterol can make SF appear white. Non-uniform
blood-staining usually reflects needle trauma to the syn-
ovium. Uniform blood-staining is most commonly due
to a bleeding diathesis, trauma or pigmented villonodu-
lar synovitis (p. 1134), but can occur in severe inflamma-
tory synovitis. A lipid layer floating above blood-stained
fluid is diagnostic of intra-articular fracture and is
caused by release of bone marrow fat into the joint.
Crystals can be identified by compensated polarised
light microscopy of fresh SF (to avoid crystal dissolution
and post-aspiration crystallisation). Urate crystals are
long and needle-shaped, and show a strong light inten-
sity and negative birefringence (Fig. 25.5A). Calcium
A B
Fig. 25.5 Compensated polarised light microscopy of synovial
fluids (× 400). A Monosodium urate crystals showing bright negative
birefringence under polarised light and needle-shaped morphology.
B Calcium pyrophosphate crystals showing weak positive birefringence
under polarised light and are few in number. They are more difficult to
1064 detect than urate crystals.
pyrophosphate crystals are smaller, rhomboid in shape
and usually less numerous than urate, and have weak
intensity and positive birefringence (Fig. 25.5B).
Imaging
Plain radiography
Radiographs show anatomical changes that are of value
in the differential diagnosis of many bone and joint dis-
eases (Box 25.4). The bones and joints to be X-rayed are
usually selected on the basis of symptoms or patterns of
involvement identified at clinical assessment.
Radiographs are of diagnostic value in osteoarthritis
(OA), where they demonstrate joint space narrowing
that tends to be focal rather than widespread, as in
inflammatory arthritis. Other features of OA detected on
X-ray include osteophytes, subchondral sclerosis, bone
cysts and calcified loose bodies within the synovium (see
Fig. 25.20, p. 1084). Radiographs may show erosions and
sclerosis of the sacroiliac joints and syndesmophytes in
the spine in patients with seronegative spondyloarthritis
(see Fig. 25.36, p. 1106). In peripheral joints, so-called
proliferative erosions, associated with new bone forma-
tion and a periosteal reaction, may be observed. In
tophaceous gout, well-defined punched-out erosions
may occur (see Fig. 25.26, p. 1089). Calcification of carti-
lage, tendons and soft tissues or muscle may occur in
chondrocalcinosis (see Fig. 25.27, p. 1090), calcific peri-
arthritis and connective tissue diseases.
Radiographs are of limited value in the diagnosis of
rheumatoid arthritis (RA) since features such as ero-
sions, joint space narrowing and periarticular osteoporo-
sis may only be detectable after several months or even
years. The main indication for radiographs in RA is in
the assessment of advanced disease, when structural
damage of the joints is suspected and arthroplasty is
being considered. Early evidence of articular damage in
RA is more usually obtained using magnetic resonance
imaging or ultrasonography.
25.4 X-ray abnormalities in selected
rheumatic diseases
Rheumatoid arthritis
• Periarticular osteoporosis • Joint space narrowing
• Bone erosions
Osteoporosis
• Osteopenia • Non-vertebral fractures
• Vertebral fractures
Paget’s disease
• Bone expansion • Osteosclerosis
• Abnormal trabecular pattern • Pseudofractures
• Osteolysis
Spondyloarthritis
• Sacroiliitis • Ligament calcification
• Syndesmophytes • Squaring of vertebral bodies
Osteoarthritis
• Joint space narrowing • Peaking of tibial spines
• Osteophytes • Subchondral cysts
• Subchondral sclerosis

Radionuclide bone scan
This is useful in patients suspected of having metastatic
bone disease and Paget’s disease. It involves gamma-
camera imaging following an intravenous injection of
99m
Tc-bisphosphonate. Early post-injection images reflect
vascularity and can show increased perfusion of
inflamed synovium, Pagetic bone, or primary or second-
ary bone tumours. Delayed images taken a few hours
later reflect bone remodelling as the bisphosphonate
localises to sites of active bone turnover. Scintigraphy
has a high sensitivity for detecting important bone and
joint pathology that is not apparent on plain X-rays (Box
25.5). Single photon emission computed tomography
(SPECT) combines radionuclide imaging with computed
tomography. It can provide accurate anatomical locali-
sation of abnormal tracer uptake within the bone and is
of particular value in the assessment of patients with
chronic low back pain of unknown cause.
25.5 Conditions detected by isotope
bone scanning
• Paget’s disease of bone
• Bone metastases
• Stress fractures
•
•
Reflex sympathetic dystrophy (algodystrophy, p. 1130)
Hypertrophic pulmonary osteoarthropathy (p. 1132)
Magnetic resonance imaging
Magnetic resonance imaging (MRI) gives detailed infor-
mation on anatomy, allowing three-dimensional visuali-
sation of bone and soft tissues that cannot be adequately
assessed by plain X-rays. The technique is valuable in
the assessment and diagnosis of many musculoskeletal
diseases (Box 25.6). T1-weighted sequences are useful
for defining anatomy, whereas T2-weighted sequences
are useful for assessing tissue water content, which is
often increased in synovitis and other inflammatory dis-
orders (Fig. 25.6). Contrast agents, such as gadolinium,
can be administered to increase sensitivity in detecting
erosions and synovitis.
Fig. 25.6 Magnetic resonance image showing synovitis. Coronal
fat-saturated post-contrast T1-weighted image shows extensive
enhancement consistent with synovitis (white areas, arrowed) in both wrists
and at the second metacarpophalangeal joint and proximal interphalangeal
joints of the right hand.
Investigation of musculoskeletal disease
25.6 Conditions detected by magnetic
resonance imaging
• Osteonecrosis • Malignancy
• Intervertebral disc • Fractures
disease • Meniscal disease
• Nerve root entrapment • Synovitis
• Spinal cord compression • Sacroiliitis and enthesitis
• Spinal stenosis • Inflammatory myositis
• Sepsis • Rotator cuff tears, bursitis
• Reflex sympathetic and tenosynovitis
dystrophy syndrome
Ultrasonography
Ultrasonography is a useful investigation for confirma-
tion of small joint synovitis and erosion, for anatomical
confirmation of periarticular lesions, and for guided
aspiration and injection of joints and bursae. Ultrasound
is more sensitive than clinical examination for the
detection of early synovitis and is used increasingly
in the diagnosis and assessment of patients with sus-
pected inflammatory arthritis. In addition to locating
synovial thickening and effusions, ultrasound can detect
increased blood flow within synovium using power
Doppler imaging, an option that is available on most
modern ultrasound machines (Fig. 25.7). 25
Fig. 25.7 Ultrasound image showing synovitis. Lateral image of a
metacarpophalangeal joint in inflammatory arthritis. The periosteum (P) of
the phalanx shows as a white line. The dark, hypo-echoic area indicates
an effusion. The coloured areas demonstrated by power Doppler indicate
increased vascularity. The inset shows a transverse image of the same joint.
Computed tomography
Computed tomography (CT) can be used in the as-
sessment of patients with bone and joint disease but
has largely been superseded by MRI, which gives
better visualisation of soft tissue structures. CT may be
used when MRI is contraindicated, or for evaluation
of articular regions in which an adjacent joint replace-
ment creates image artefacts on MRI.
Bone mineral density
Bone mineral density (BMD) measurements play a key
role in the diagnosis and management of osteoporosis.
The technique of choice is dual energy X-ray absorptio-
metry (DEXA), which is usually performed at the lumbar
spine and hip, and provides images of the region studied.
This technique works on the principle that calcium in 1065
 RHEUMATOLOGY AND BONE DISEASE

25 bone attenuates passage of X-ray beams through the

tissue in proportion to the amount of mineral present.
The greater the amount of bone mineral present, the
higher the BMD value. Most DEXA scanners give a BMD
readout expressed as grams of hydroxyapatite/cm2, and
as a T-score and Z-score value. The T-score is a measure
of the number of standard deviations by which the
patient’s BMD value differs from that in a young healthy
control, whereas the BMD Z-score is a measure of the
A normal or osteopenic range in patients who have osteo-
number of standard deviations by which the BMD devi-
ates from that of age-matched controls (Fig. 25.8). Osteo-
porosis is defined by a T-score value of 2.5 or below
(shaded red in the figure), whereas osteopenia is diag-
nosed when the T-score lies between −1.0 and −2.5
(shaded pink). Many healthy people, especially above
the age of 50, have BMD values in the osteopenic range.
Values of BMD above −1.0 and below +2.5 are considered
normal, whereas values above +2.5 can be found in osteo-
sclerotic diseases and OA. Results need to be interpreted
carefully. It is possible for BMD values to lie in the
porosis, due to coexisting conditions such as aortic calci-
fication, vertebral compression fractures, degenerative
disc disease and OA. These can sometimes be suspected
on the basis of antero-posterior or lateral DEXA images,
but abnormal appearances should be confirmed by X-ray
or other imaging as appropriate.

Blood tests
Haematology
Abnormalities in the full blood count (FBC) often occur
in inflammatory rheumatic diseases but changes are
usually non-specific. Examples include neutrophilia in
vasculitis, acute gout and sepsis; neutropenia in lupus;
and a raised erythrocyte sedimentation rate (ESR) in
many inflammatory diseases. Reduced levels of haemo-
B globin are a common and important finding in a range
1.3 +2.0
of rheumatological disorders. Many disease-modifying
+1.0 antirheumatic drugs (DMARDs) cause marrow toxicity
and require regular monitoring of the FBC.
BMD (g/cm2)

1.0 0.0
T-score

−1.0
Biochemistry
T
Routine biochemistry is useful for assessing metabolic
0.7 −2.0 bone disease, muscle diseases and gout. Several bone
Osteoporosis Z diseases, including Paget’s disease, renal bone disease
T-score −3.0 −3.0
Z-score −1.0
and osteomalacia, give a characteristic pattern that can
0.4 −4.0 be helpful diagnostically (Box 25.7). Serum levels of uric
20 40 60 80 acid are usually raised in gout but a normal level does
Age (years) not exclude it, especially during an acute attack, when
urate levels temporarily fall. Equally, an elevated serum
Fig. 25.8 Typical output from a dual energy X-ray absorptiometry
uric acid does not confirm the diagnosis, since most
(DEXA) scanner. A DEXA scan of the hip. B Bone mineral density
(BMD) values plotted in g/cm2 (left axis) and as the T-score values (right hyperuricaemic people never develop gout. Levels of
axis). The solid line represents the population average plotted against age, C-reactive protein (CRP) are a useful marker of infection
and the interrupted lines are ± 2 standard deviations from the average. and inflammation, and are more specific than the ESR.
The patient shown, aged 72, has an osteoporotic T-score of −3.0 but a An exception is in connective tissue diseases such as
Z-score of −1.0, which is within the ‘normal range’ for that age, reflecting systemic lupus erythematosus (SLE) and systemic scle-
the fact that bone is lost with age. rosis, where CRP may be normal but ESR raised in active

25.7 Biochemical abnormalities in bone disease

Serum calcium Serum phosphate Serum ALP Serum PTH Serum 25(OH)D
Osteoporosis N N N N N or ↓
Paget’s disease N N ↑↑ N or ↑ N
Renal osteodystrophy ↓ ↑↑ ↑ ↑↑ N
Vitamin D-deficient osteomalacia N or ↓ N or ↓ ↑↑ ↑↑ ↓
Hypophosphataemic rickets N ↓↓ ↑ N or ↑ N

(ALP = alkaline phosphatase; N = normal; PTH = parathyroid hormone; single arrow = increased or decreased; double arrow = greatly increased or decreased)
1066
 Investigation of musculoskeletal disease

25.8 Causes of an elevated serum Anti-citrullinated peptide antibodies

creatine kinase
• Inflammatory myositis • Trauma, strenuous exercise,
± vasculitis long lie after a fall
• Muscular dystrophy • Myocardial infarction*
• Motor neuron disease • Hypothyroidism, metabolic
• Alcohol, drugs (N.B. myopathy
statins) • Viral myositis
*The CK-MB cardiac-specific isoform is disproportionately elevated
compared with total CK.
inflammatory disease. Accordingly, an elevated CRP in
a patient with lupus or scleroderma suggests an inter-
current illness such as sepsis rather than active disease.
More detail on the interpretation of CRP and ESR
changes is given on page 84. Serum creatine kinase (CK)
levels are useful in the diagnosis of myopathy or myosi-
tis, but specificity and sensitivity are poor and raised
levels may occur in some conditions (Box 25.8). Bio-
chemical monitoring of renal and hepatic function is
important in ongoing care of patients on DMARD
therapy.
Autoantibodies
Autoantibody tests are widely used in the diagnosis of
rheumatic diseases. False-positive results are common
but high antibody titres or concentrations are generally
of greater clinical significance. Whatever test is used, the
results must be interpreted in light of the clinical picture
and the different detection and assay systems used in
different hospitals.
Rheumatoid factor
Rheumatoid factor (RF) is an antibody directed against
the Fc fragment of human immunoglobulin. In routine
clinical practice, IgM rheumatoid factor is usually meas-
ured, although different methodologies allow measure-
ment of IgG and IgA RFs too. Positive RF occurs in
a wide variety of diseases and some normal adults
(Box 25.9), particularly with increasing age. Although
the specificity is poor, about 70% of patients with RA
test positive. High RF titres are associated with more
severe disease and extra-articular disease.
Anti-citrullinated peptide antibodies (ACPA) recognise
peptides in which the amino acid arginine has been con-
verted to citrulline by peptidylarginine deiminase, an
enzyme abundant in inflamed synovium and in a variety
of mucosal structures. ACPA have similar sensitivity to
RF for RA (70%) but much higher specificity (> 95%),
and are increasingly being used in preference to RF in
the diagnosis of RA. ACPA are associated with more
severe disease progression, and can be detected in
asymptomatic patients several years before the develop-
ment of RA. Their pathological role is still debated but
it is likely that they amplify the synovial response at an
inflammatory stimulus.
Antinuclear antibodies
Antinuclear antibodies (ANA) are directed against one
or more components of the cell nucleus, including
nucleic acids themselves, and the proteins concerned
with processing of DNA or RNA. They occur in many
inflammatory rheumatic diseases but are also found at
low titre in normal individuals and in other diseases
(Box 25.10). High titres of ANA are of greater diagnostic
significance but circulating levels are not associated with
disease severity or activity. The most common indica-
tion for ANA testing is in patients suspected of having
SLE or connective tissue diseases. ANA has high sensi-
tivity for SLE (virtually 100%) but low specificity (10–
25
40%). A negative ANA virtually excludes SLE but a
positive result does not confirm it.
Anti-DNA antibodies bind to double-stranded DNA
and are highly specific for SLE (95%) but sensitivity is
poor (30%). They can be useful in disease monitoring
since very high titres are associated with more severe
disease, including renal or central nervous system (CNS)
involvement, and an increase in antibody titre may
precede relapse.
Antibodies to extractable nuclear antigens (ENA) act
as markers for certain connective tissue diseases and
some complications of SLE, but sensitivity and specifi-
city are poor (Box 25.11). For example, antibodies to Sm
are found in a minority of patients with SLE but are
associated with renal involvement. Antibodies to Ro
occur in SLE and in Sjögren’s syndrome (in association
with anti-La antibodies), and are associated with a

25.9 Conditions associated with a 25.10 Conditions associated with a positive

positive rheumatoid factor antinuclear antibody
Disease Frequency (%) Condition Approximate frequency
Rheumatoid arthritis with nodules and 100 Diseases where ANA is useful in diagnosis
extra-articular manifestations Systemic lupus erythematosus 100%
Rheumatoid arthritis (overall) 70 Systemic sclerosis 60–80%
Sjögren’s syndrome 40–70%
Sjögren’s syndrome 90
Dermatomyositis or polymyositis 30–80%
Mixed essential cryoglobulinaemia 90 Mixed connective tissue disease 100%
Primary biliary cirrhosis 50 Autoimmune hepatitis 100%
Infective endocarditis 40 Diseases where ANA is not useful in diagnosis
Systemic lupus erythematosus 30 Rheumatoid arthritis 30–50%
Autoimmune thyroid disease 30–50%
Tuberculosis 15 Malignancy Varies widely
Age > 65 yrs 20 Infectious diseases Varies widely

Normal healthy people can be positive for rheumatoid factor. N.B. 5% of healthy individuals have an ANA titre > 1:80.
1067
 RHEUMATOLOGY AND BONE DISEASE

25 25.11 Conditions associated with antibodies to

extractable nuclear antigens
fluorescence (c-ANCA), which is caused by antibodies
to proteinase-3 (PR3); and perinuclear fluorescence
(p-ANCA), which is caused by antibodies to myeloper-
Antibody (target/other
oxidase (MPO) and other proteins such as lactoferrin
name) Disease association
and elastase. These antibodies are not specific for vascu-
Anti-centromere CREST variant of systemic sclerosis litis and positive results may be found in autoimmune
antibody (sensitivity 60%, specificity 98%) liver disease, malignancy, infection (bacterial and human
Occasionally found in primary immunodeficiency virus, HIV), inflammatory bowel
Raynaud’s syndrome disease, rheumatoid arthritis, SLE and pulmonary
Anti-histone antibody Drug-induced lupus (80%) fibrosis.
Anti-Jo-1 Polymyositis, dermatomyositis or
(anti-histidyl-tRNA polymyositis–systemic sclerosis
synthetase) overlap (20–30%). Particularly Tissue biopsy
associated with interstitial lung
disease Tissue biopsy is useful in confirming the diagnosis in
Anti-La antibody Sjögren’s syndrome (60%) certain musculoskeletal diseases.
(anti-SS-B) SLE (20–60%) Synovial biopsy can be useful in selected patients
Anti- Mixed connective tissue disease
with chronic inflammatory monoarthritis or tenosynov-
ribonucleoprotein (100%) itis to rule out chronic infectious causes, especially
antibody SLE (25–50%), usually in conjunction mycobacterial infections. Characteristic changes on MRI
(anti-RNP) with anti-Sm antibodies can obviate the need for biopsy in many cases of sus-
pected tumour. Whatever the indication, synovial biopsy
Anti-Ro antibody SLE (35–60%): associated with
can be obtained arthroscopically (by conventional means
(anti-SS-A) photosensitivity, thrombocytopenia
or via use of needle arthroscope) or using ultrasound
and subacute cutaneous lupus
guidance under local anaesthetic.
Maternal anti-Ro antibodies
associated with neonatal lupus Temporal artery biopsy can be of value in patients
and congenital heart block suspected of having temporal arteritis, especially when
Sjögren’s syndrome (40–80%) the presentation is atypical, but a negative result does
not exclude the diagnosis. Biopsies of affected tissues,
Anti-RNA polymerase Diffuse systemic sclerosis (15%) such as skin, lung, nasopharynx, gut, kidney and muscle,
Anti Sm SLE (15–30%); associated with renal can be of value in the diagnosis of systemic vasculitis
(anti-Smith antibody) disease and granulomatosis with polyangiitis (also known as
Anti-Scl-70 Diffuse systemic sclerosis (15%); Wegener’s granulomatosis).
(anti-topoisomerase I associated with more severe organ Muscle biopsy plays an important role in the investi-
antibody) involvement, including pulmonary gation of myopathy and inflammatory myositis. It is
fibrosis usually taken from the quadriceps or deltoid through a
small skin incision under local anaesthetic. Since myosi-
(CREST = calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, tis can be patchy in nature, MRI is sometimes used to
telangiectasia)
localise the best site for biopsy. Immunohistochemical
staining, together with plain histology, gives informa-
tion on primary and secondary muscle and neuromus-
cular disease. Repeat biopsies are sometimes used to
monitor the response to treatment.
photosensitive rash and congenital heart block. Anti-
Bone biopsy is occasionally required where non-
bodies to ribonuclear protein (RNP) occur in SLE
invasive tests give inconclusive results and in the diag-
and also in mixed connective tissue disease, where
nosis of infiltrative disorders, chronic infections and
features of lupus, myositis and systemic sclerosis
malignancy. If a systemic disorder of mineralisation,
coexist. Anti-topoisomerase 1 (also termed Scl-70) anti-
such as osteomalacia, is suspected, the biopsy can be
bodies occur in diffuse systemic sclerosis, whereas
taken from the iliac crest using a large-diameter (8-mm)
anti-centromere antibodies are more specific for limited
trephine needle under local anaesthetic, and processed
systemic sclerosis.
without demineralisation. For focal lesions, the biopsy
Antiphospholipid antibodies should be taken under X-ray guidance or at open
Antiphospholipid antibodies bind to a number of phos- surgery, from an affected site.
pholipid binding proteins, but the most clinically rele-
vant are those that target beta2-glycoprotein 1 (β2GP1).
They may be detected in SLE and other connective Electromyography
tissue diseases or can be present in isolation or in the
antiphospholipid antibody syndrome (p. 1055). Electromyography (p. 1152) is of value in the investiga-
tion of suspected myopathy and inflammatory myositis,
Antineutrophil cytoplasmic antibodies when it shows the diagnostic triad of:
Antineutrophil cytoplasmic antibodies (ANCA) are IgG • spontaneous fibrillation
antibodies directed against the cytoplasmic constituents • short-duration action potentials in a polyphasic
of granulocytes and are useful in the diagnosis and disorganised outline
monitoring of systemic vasculitis. Two common pat- • repetitive bouts of high-voltage oscillations on
1068 terns are described by immunofluorescence: cytoplasmic needle contact with diseased muscle.
 Presenting problems in musculoskeletal disease

microscopy for crystals. Blood cultures should also be

PRESENTING PROBLEMS IN taken in patients suspected of having septic arthritis.
MUSCULOSKELETAL DISEASE CRP levels and ESR are raised in sepsis, crystal arthritis
and reactive arthritis, and this can be useful in assessing
the response to treatment. Serum uric acid measure-
Acute monoarthritis ments may be raised in gout but a normal level does not
exclude the diagnosis.
This term is used to describe sudden pain and swelling
in a single joint. The most important causes are crystal Management
arthritis, sepsis and reactive arthritis. Other potential If there is any suspicion of sepsis, intravenous antibiotics
causes are shown in Box 25.12. (Box 25.52, p. 1095) should be given promptly, pending
Clinical assessment the results of cultures. Otherwise, management should
be directed towards the underlying cause.
The clinical history, pattern of joint involvement, speed
of onset, and age and gender of the patient all give clues
to the most likely diagnosis. Reactive arthritis (p. 1107) Polyarthritis
is the most common cause in young men, gout in middle-
aged men and pseudogout in older women. Gout clas- This term is used to describe pain and swelling affecting
sically affects the first metatarsophalangeal (MTP) joint, five or more joints or joint groups. The possible causes
whereas the wrist and shoulder are typical sites for are listed in Box 25.13.
pseudogout. A very rapid onset (6–12 hours) is sugges-
tive of gout or pseudogout; joint sepsis develops more
slowly and continues to progress until treated. Haemar-
throsis typically causes a large effusion, in the absence
of periarticular swelling or skin change, in a patient who 25.13 Causes of polyarthritis
has suffered an injury. Pigmented villonodular synovitis
Cause Characteristics
(p. 1134) also presents with synovial swelling and a large
effusion, although the onset is gradual. A previous diar- Common
Rheumatoid arthritis Symmetrical, small and large joints,
25
rhoeal illness or recent sexual contact suggests reactive
arthritis, whereas intercurrent illness, dehydration or upper and lower limbs
surgery may act as a trigger for crystal-induced arthritis. Viral arthritis Symmetrical, small joints; may be
Rheumatoid arthritis seldom presents with monoarthri- associated with rash and prodromal
illness; self-limiting
tis and a sudden increase in pain and swelling involving
Osteoarthritis Symmetrical, targets PIP, DIP and first
a single joint in a patient with pre-existing RA is strongly
CMC joints in hands, knees, hips, back
suggestive of sepsis. Osteoarthritis can present with and neck; associated with Heberden’s
pain and stiffness affecting a single joint, but the onset and Bouchard’s nodes
is gradual and there is seldom evidence of significant Psoriatic arthritis Asymmetrical, targets PIP and DIP joints
joint swelling. of hands and feet (sausage appearance
Investigations on examination), nail pitting, large joints
also affected
Aspiration of the affected joint is mandatory. The fluid Ankylosing Tends to affect large joints, lower more
should be sent for culture and Gram stain to seek the spondylitis and than upper limbs, possible history of
presence of organisms, and should be checked by enteropathic arthritis inflammatory back pain
SLE Symmetrical, typically affecting small
joints, clinical evidence of synovitis
unusual
Less common
25.12 Causes of acute monoarthritis
Juvenile idiopathic Symmetrical, small and large joints,
Common arthritis upper and lower limbs
Chronic gout Affects distal more than proximal joints,
• Septic arthritis • Haemarthrosis history of acute attacks
• Gout • Seronegative spondyloarthritis Chronic sarcoidosis Symmetrical, small and large joints
• Pseudogout Psoriatic arthritis (p. 709)
• Reactive arthritis Ankylosing spondylitis Polymyalgia Symmetrical, small and large joints
• Trauma Enteropathic arthritis rheumatica
Less common Rare
• Erythema nodosum • Other infection Systemic sclerosis Small and large joints
• Rheumatoid arthritis Gonococcal and polymyositis
• Juvenile idiopathic Tuberculosis Hypertrophic Small joints, clubbing
arthritis • Leukaemia* osteoarthropathy
• Pigmented villonodular • Osteomyelitis* Haemochromatosis Small and large joints
synovitis (p. 972)
• Foreign body reaction Acromegaly (p. 792) Mainly large joints and spine

*In children, both leukaemia and osteomyelitis may present with (CMC = carpometacarpal; DIP = distal interphalangeal; PIP = proximal
monoarthritis. interphalangeal)
1069
 RHEUMATOLOGY AND BONE DISEASE

25 Clinical assessment
The hallmarks of inflammatory arthritis are early morn-
25.14 Extra-articular features of
inflammatory arthritis
ing stiffness and worsening of symptoms with inactiv- Clinical feature Disease association
ity, along with synovial swelling and tenderness on
Skin, nails and mucous membranes
examination. Clinical features in other systems can Psoriasis, nail pitting and Psoriatic arthritis
be helpful in determining the underlying cause (Box dystrophy
25.14). The most important diagnosis to consider is Raynaud’s phenomenon SLE, systemic
rheumatoid arthritis, which is characterised by sym- sclerosis
metrical involvement of the small joints of the hands Photosensitivity SLE
and feet, often in association with other joints. Viral Livedo reticularis SLE
arthritis should also be considered. This presents with Splinter haemorrhages, Vasculitis
an acute symmetrical inflammatory polyarthritis affect- nail-fold infarcts
ing small and large joints of upper and lower limbs, Oral ulcers SLE, reactive arthritis,
often with a rash. Behçet’s syndrome
The pattern of involvement can be helpful in reaching Large nodules (mainly extensor RA, gout
a diagnosis (Fig. 25.9). Asymmetry, lower limb pre- surfaces)
dominance and greater involvement of large joints are Clubbing Enteropathic arthritis,
characteristic of seronegative spondyloarthritis. Other metastatic lung cancer,
extra-articular features may also be present, giving a endocarditis
clue to the diagnosis. In psoriatic arthritis, the small Eyes
joints of the hand and feet are often affected, but Uveitis Seronegative
with involvement of the proximal and distal inter- spondyloarthritis
phalangeal (PIP and DIP) joints, as opposed to the meta- Conjunctivitis Reactive arthritis
carpophalangeal (MCP) and PIP joints in RA. The Episcleritis, scleritis RA, vasculitis
pattern of involvement also tends to be asymmetrical in Heart, lungs
psoriatic arthritis, and other clues such as nail pitting Pleuro-pericarditis SLE, RA
and a rash may be present. SLE can be associated with Fibrosing alveolitis RA, SLE, other connective
polyarthritis but more usually causes polyarthralgia and tissue disease
tenosynovitis (p. 1110). Abdominal organs
Hepatosplenomegaly RA, SLE
Investigations
Haematuria, proteinuria SLE, vasculitis, systemic
Blood samples should be taken for routine haematol- sclerosis
ogy, biochemistry, ESR, CRP, viral serology and an Urethritis Reactive arthritis
immunological screen, including ANA, RF and ACPA. Fever, lymphadenopathy Infection, systemic
Ultrasound examination or MRI may be required to juvenile idiopathic
confirm the presence of synovitis if this is not obvious arthritis
clinically.

A B C D

Fig. 25.9 Patterns of joint involvement in different forms of polyarthritis. A Rheumatoid arthritis typically targets the metacarpophalangeal and
proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet, as well as other joints, in a symmetrical pattern. B Psoriatic
arthritis targets proximal and distal interphalangeal joints of the hands and larger joints in an asymmetrical pattern. Sacroiliitis (often asymmetrical) may
occur. C Ankylosing spondylitis targets the spine, sacroiliac joints and large peripheral joints in an asymmetrical pattern. D Osteoarthritis targets the
1070 proximal and distal interphalangeal joints of the hands, first carpometacarpal joint at the base of the thumb, knees, hips, lumbar and cervical spine.
 Presenting problems in musculoskeletal disease

Management the fracture, X-rays may also show evidence of an under-

Management should be directed at the underlying lying disorder, such as osteoporosis, Paget’s disease or
condition, but treatment with non-steroidal anti- osteomalacia. If the X-ray fails to show evidence of a
inflammatory drugs (NSAIDs) and analgesics may be fracture but clinical suspicion remains high, MRI should
required for symptom control until a diagnosis has be performed, since this can demonstrate fractures that
been made. are radiographically occult. Patients who are over the
age of 50 and present with fragility fractures should be
screened for the presence of osteoporosis by DEXA.
Fracture Management
Fractures are a common presenting symptom of osteo- Management of fracture in the acute stage requires
porosis, but they also occur in other bone diseases, in adequate pain relief, with opiates if necessary, reduction
osteopenia and in some patients with normal bone. of the fracture to restore normal anatomy, and immobi-
lisation of the affected limb to promote healing. This can
Clinical assessment be achieved either by the use of an external cast or splint
The presentation is with localised bone pain, which is or by internal fixation. Femoral neck fractures present a
worsened by movement of the affected limb or region. special management problem since non-union and avas-
There is usually a history of trauma but spontaneous cular necrosis are common. This is especially true with
fractures can occur in the absence of trauma in those intracapsular hip fractures, which should be treated by
with severe osteoporosis. Fractures can be divided into joint replacement surgery. Following the fracture, reha-
several subtypes, based on the precipitating event and bilitation is required with physiotherapy and a super-
presence or absence of an underlying disease (Box 25.15). vised exercise programme (this is especially important
The main differential diagnosis is soft tissue injury, but in older patients to prevent muscle-wasting and loss of
fracture should be suspected when there is marked pain mobility). Elderly patients with hip fracture also benefit
and swelling, abnormal movement of the affected limb, from nutritional supplementation. Patients with high-
crepitus or deformity. Femoral neck fractures typically energy and fatigue fractures generally require no further
produce a shortened, externally rotated leg that is
painful to move.
investigation or treatment once the fracture has healed.
If the DEXA examination or other investigation shows
25
evidence of osteoporosis or other metabolic bone disease,
Investigations this should be treated appropriately (p. 172).
Radiographs of the affected site should be taken in at
least two planes and examined for discontinuity of the
cortical outline (Box 25.16). In addition to demonstrating Generalised musculoskeletal pain
Clinical assessment
Clinical history and examination can often indicate the
25.15 Characteristics of different fracture types underlying cause (Box 25.17). Relentlessly progressive
pain occurring in association with weight loss suggests
Precipitation
malignant disease with bone metastases. Generalised
Fracture type factor Disease
bone pain may also occur in Paget’s disease if the disease
Fragility fracture Fall from standing Osteoporosis is widespread, but Pagetic pain is usually more focal and
height or less Osteopenia localised to the site of involvement (p. 1128). Wide-
Vertebral fracture Bending, lifting, Osteoporosis spread pain can occur in OA but this also tends to be
falling localised to sites of involvement, such as the lumbar
Stress fracture Running, Normal spine, hips, knees and hands. Signs of OA may be appar-
excessive training ent on clinical examination. Osteomalacia (p. 1125) can
cause generalised bone pain that is associated with bone
High-energy fracture Major trauma Normal
tenderness and limb girdle weakness. Fibromyalgia can
Pathological fracture Spontaneous, Malignancy present with generalised pain particularly affecting the
minimal trauma Paget’s disease trunk, back and neck. Accompanying features include
Osteomalacia fatigue, poor concentration and focal areas of hyper-
algesia. Another potential cause is joint hypermobility,
the features of which should be apparent on clinical
examination (p. 1134).
25.16 How to investigate a suspected fracture
• Order X-rays in two projections at right angles to one another
• Include the whole bone and the joints at either end (this may
reveal an additional unsuspected fracture) 25.17 Causes of generalised pain
• Check for evidence of displacement
• Check for a break in the cortex • Metastatic bone disease • Paget’s disease
• In suspected vertebral fracture, check for depression of the • Fibromyalgia (p. 1092) • Polymyalgia rheumatica
end plate • Joint hypermobility (p. 1117)
• If clinical suspicion is high but no fracture is seen, request • Osteomalacia (p. 1125) • Myositis (p. 1114)
MRI • Osteoarthritis
1071
 RHEUMATOLOGY AND BONE DISEASE

25 Investigations
Radionuclide bone scanning is of value in patients sus-
pected of having bone metastases and Paget’s disease,
along with further imaging as appropriate. Myeloma
(p. 1046) should be excluded by plasma and urinary
protein electrophoresis. If these results are positive, a
radiological skeletal survey should be performed, since
the isotope bone scan may be normal in myeloma.
Routine biochemistry, vitamin D levels and PTH meas-
urement should be performed if osteomalacia is sus-
pected. In Paget’s disease, ALP may be elevated but can
be normal in localised disease. Laboratory investigations
are normal in patients with fibromyalgia and benign
hypermobility.
Management
Management should be directed towards the underlying
cause. Chronic pain of unknown cause and that associ-
ated with fibromyalgia responds poorly to analgesics
and NSAID, but may respond partially to antineuro-
pathic agents such as amitriptyline, duloxetine, gaba-
pentin and pregabalin.
Back pain
Back pain is a common symptom that affects 60–80% of
people at some time in their lives. Although the preva-
lence has not increased, reported disability from back
pain has risen significantly in the last 30 years. In
Western countries, back pain is the most common cause
of sickness-related work absence. In the UK, 7% of adults
25.18 Causes of low back pain
• Mechanical back pain • Spondylolysis (p. 1133)
• Prolapsed intervertebral • Bone metastases
disc • Spondylolisthesis (p. 1133)
• Osteoarthritis • Arachnoiditis
• Vertebral fracture (p. 1071) • Scheuermann’s disease
• Spinal stenosis (p. 1130)
• Paget’s disease
consult their GP each year with back pain. The most
important causes are summarised in Box 25.18.
Clinical assessment
The main purpose of clinical assessment is to differenti-
ate the self-limiting disorder of acute mechanical back
pain from serious spinal pathology, as summarised in
Figure 25.10. Mechanical back pain is the most common
cause of acute back pain in people aged 20–55. This
accounts for more than 90% of episodes, and is usually
acute and associated with lifting or bending. It is exac-
erbated by activity and is generally relieved by rest (Box
25.19). It is usually confined to the lumbar–sacral region,
buttock or thigh, is asymmetrical, and does not radiate
beyond the knee (which would imply nerve root irrita-
tion). On examination, there may be asymmetric local
paraspinal muscle spasm and tenderness, and painful
restriction of some but not all movements. Low back
pain is more common in manual workers, particularly
those in occupations that involve heavy lifting and
twisting. The prognosis is generally good. After 2 days,

Back pain

Mechanical Destructive Inflammatory Other

Common, Malignancy Ankylosing spondylitis Prolapsed disc
Acute onset Infection Psoriasis Spinal stenosis
Self-limiting Spondyloarthritis Paget’s disease
Fracture

Clinical assessment
(Box 25.21)

Persistent pain
Fever/weight loss Nerve root pain Cauda equina
Inflammatory features persisting > 4 wks syndrome

Further investigation Urgent investigation

and imaging ± neurosurgical referral

1072 Fig. 25.10 Initial triage assessment of back pain.


25.19 Features of mechanical low back pain
• Pain varies with physical activity (improved with rest)
• Sudden onset, precipitated by lifting or bending
• Recurrent episodes
• Pain limited to back or upper leg
• No clear-cut nerve root distribution
• No systemic features
• Prognosis good (90% recovery at 6 wks)
25.20 Red flags for possible spinal pathology
History
• Age: presentation < 20 yrs or > 55 yrs
• Character: constant, progressive pain unrelieved by rest
• Location: thoracic pain
• Past medical history: carcinoma, tuberculosis, HIV, systemic
corticosteroid use, osteoporosis
• Constitutional: systemic upset, sweats, weight loss
• Major trauma
Examination
• Painful spinal deformity
• Severe/symmetrical spinal deformity
• Saddle anaesthesia
•
•
Progressive neurological signs/muscle-wasting
Multiple levels of root signs
25.21 Clinical features of radicular pain
Nerve root pain
• Unilateral leg pain worse than low back pain
• Pain radiates beyond knee
• Paraesthesia in same distribution
• Nerve irritation signs (reduced straight leg raising that
reproduces leg pain)
• Motor, sensory or reflex signs (limited to one nerve root)
• Prognosis reasonable (50% recovery at 6 wks)
Cauda equina syndrome
• Difficulty with micturition
• Loss of anal sphincter tone or faecal incontinence
• Saddle anaesthesia
• Gait disturbance
• Pain, numbness or weakness affecting one or both legs
30% are better and 90% have recovered by 6 weeks.
Recurrences of pain may occur and about 10–15% of
patients go on to develop chronic back pain that may be
difficult to treat. Psychological elements, such as job dis-
satisfaction, depression and anxiety, are important risk
factors for the transition to chronic pain and disability.
Back pain secondary to serious spinal pathology has
different characteristics (Box 25.20). If there is clinical
evidence of spinal cord or nerve root compression, or a
cauda equina lesion (Box 25.21), urgent investigation is
needed. Spinal stenosis presents with leg discomfort on
walking that is relieved by rest (pseudoclaudication).
Bending forwards or walking uphill may also relieve the
pain. Common causes include Paget’s disease, in which
enlargement of the vertebrae may encroach on the
spinal canal, and osteoarthritis of the spine, in which
Presenting problems in musculoskeletal disease
osteophytes can have the same effect. Patients may
adopt a characteristic simian posture, with a forward
stoop and slight flexion at hips and knees.
Degenerative disc disease is a common cause of
chronic low back pain. Prolapse of an intervertebral
disc presents with nerve root pain, which can be accom-
panied by a sensory deficit, motor weakness, and asym-
metrical reflexes. Examination may reveal a positive
sciatic or femoral stretch test. About 70% of patients
improve by 4 weeks. Inflammatory back pain due to
seronegative spondyloarthritis has a gradual onset and
almost always occurs before the age of 40. It is associated
with morning stiffness and improves with movement.
Spondylolisthesis (p. 1133) may cause back pain that is
typically aggravated by standing and walking. Occa-
sionally, diffuse idiopathic skeletal hyperostosis (DISH;
p. 1133) can cause back pain but it is usually asympto-
matic. Arachnoiditis is a rare cause of chronic severe low
back pain. It is due to chronic inflammation of the nerve
root sheaths in the spinal canal and can complicate men-
ingitis, spinal surgery, or myelography with oil-based
contrast agents.
Investigations
Investigations are not required in patients with acute
mechanical back pain. Those with persistent pain
(> 6 weeks) or red flags (see Box 25.20) should undergo
further investigation. MRI is the investigation of choice
25
since it can demonstrate spinal stenosis, cord compres-
sion or nerve root compression, as well as inflammatory
changes in spondyloarthropathy, and infectious causes
such as spinal abscess. Plain radiographs can be of value
in patients suspected of having vertebral compression
fractures, OA and degenerative disc disease. If meta-
static disease is suspected, radionuclide bone scan or
SPECT should be considered. Additional investigations
that may be required include routine biochemistry and
haematology with measurement of ESR and CRP (to
screen for sepsis and inflammatory disease), protein and
urinary electrophoresis (for myeloma) and prostate spe-
cific antigen (for prostate carcinoma).
Management
Education is important in patients with mechanical back
pain. It should emphasise the self-limiting nature of the
condition and the fact that exercise is helpful rather than
damaging. Regular analgesia and/or NSAIDs may be
required to improve mobility and facilitate exercise.
Return to work and normal activity should take place as
soon as possible. Bed rest is not helpful and may increase
the risk of chronic disability. Referral for physiotherapy
or manipulation should be considered if a return to
normal activities has not been achieved by 6 weeks.
Low-dose tricyclic antidepressant drugs may help pain,
sleep and mood.
Other treatment modalities that are occasionally used
include epidural and facet joint injection, traction and
lumbar supports, though there is little evidence to
support their use (Box 25.22). Malignant disease, osteo-
porosis, Paget’s disease and spondyloarthropathies
require specific treatment of the underlying condition.
Surgery is required in less than 1% of patients with
low back pain but may be needed in spinal stenosis, in
spinal cord compression and in some patients with
nerve root compression. 1073
 RHEUMATOLOGY AND BONE DISEASE

25 25.22 Management of low back pain

Shoulder pain
Shoulder pain is a common complaint in both genders
• Reassure patients (favourable prognosis) over the age of 40, and is most often due to degenerative
• Advise patients to stay active disease of tendons in the rotator cuff (Box 25.24). Varying
• Prescribe medication if necessary (preferably at fixed time pain patterns associated with common lesions are
intervals) shown in Figure 25.11. Management is symptomatic,
• Paracetamol with analgesics, NSAID, local corticosteroid injections
• NSAID and physiotherapy aimed at restoring normal move-
• Consider opioids, muscle relaxants ment and function. Surgery may be required in patients
• Discourage bed rest who have debilitating symptoms in association with
• Consider spinal manipulation for pain relief rotator cuff tears. Adhesive capsulitis (frozen shoulder)
• Do not advise lumbar supports, back-specific exercises, presents with upper arm pain that can progress over
traction, acupuncture, epidural or facet injections. 4–10 weeks before subsiding over a similar time course.
• Koes BW. BMJ 2006; 332:1430–1434. Restriction of glenohumeral movement is characteristic.
In the early phase, there is marked anterior joint/
capsular tenderness and stress pain in a capsular pattern;
later there is painless restriction, often of all movements.
Frozen shoulder is more common in diabetes mellitus,
Regional musculoskeletal pain but may also be triggered by a rotator cuff tear, local
trauma, myocardial infarction or hemiplegia. Treatment
Regional musculoskeletal pain is a common presenting in the early stage is with analgesia, intra- and extracap-
complaint, usually occurring as the result of age-related sular steroid injection, and regular ‘pendulum’ exercises
degenerative disease of tendons and ligaments, OA and of the arm to prevent the capsule from over-tightening.
repetitive strain injuries due to overuse. Mobilising and strengthening exercises are the sole
treatment in the painless ‘frozen’ stage. The natural
Neck pain
Neck pain is a common symptom that can occur follow-
ing injury (for example, whiplash), after falling asleep in 25.24 Clinical findings in shoulder pain
an awkward position, as a result of stress, or in associa-
tion with OA of the spine. The causes are shown in Box Rotator cuff lesion
25.23. Most cases resolve spontaneously or with a short • Pain reproduced by resisted active movement:
course of NSAID or analgesics, and a soft collar. Patients Abduction: supraspinatus
with persistent pain that follows a nerve root distribu- External rotation: infraspinatus, teres minor
tion and those with neurological signs and symptoms Internal rotation: subscapularis
should be investigated by MRI scan, and if necessary
Subacromial bursitis
referred for a neurosurgical opinion.
• Pain on full abduction but no pain on resisted active
abduction
Bicipital (long head) tendinitis
25.23 Causes of neck pain • Tender over bicipital groove
• Pain reproduced by resisted active wrist supination or elbow
Mechanical flexion
• Postural • Disc prolapse
• Whiplash injury • Cervical spondylosis
Acromioclavicular Rotator cuff and
Inflammatory joint disease glenohumeral
• Infections • RA arthritis
• Spondylitis • Polymyalgia rheumatica Bicipital
• Juvenile idiopathic arthritis tendinitis
Metabolic
• Osteoporosis • Paget’s disease
• Osteomalacia
Neoplasia
• Metastases • Lymphoma
• Myeloma • Intrathecal tumours
Other
• Fibromyalgia • Torticollis
Referred pain
• Pharynx • Aortic aneurysm
• Cervical lymph nodes • Pancoast tumour
• Teeth • Diaphragm
• Angina pectoris Fig. 25.11 Pain patterns around the shoulder. The dark shading
1074 indicates sites of maximum pain.
 Presenting problems in musculoskeletal disease

history is for slow but complete recovery, sometimes Trochanteric Hip

taking up to 2 years. bursitis disease

Elbow pain
The most common causes are repetitive strain injury
affecting the lateral epicondyle (tennis elbow) and
medial epicondyle (golfer’s elbow) (Box 25.25). Manage-
ment is by rest, analgesics and topical or systemic
NSAID. Symptoms may also respond to local applica-
tion of glyceryl trinitrate patches. Local corticosteroid
injections may be required in resistant cases. Olecranon
bursitis can also follow local repetitive trauma but other
causes include infections, gout and RA.

25.25 Local causes of elbow pain

Lesion Pain Examination findings
Tennis Lateral epicondyle Tender over epicondyle
elbow Radiation to Pain reproduced by resisted
extensor forearm active wrist extension
Golfer’s Medial epicondyle Tender over epicondyle
elbow Radiation to flexor Pain reproduced by resisted
forearm active wrist flexion
Olecranon Olecranon Fluctuant tender swelling Fig. 25.12 Pain patterns of hip disease and trochanteric bursitis.
bursitis over olecranon The dark shading indicates sites of maximum pain.
25
Hand and wrist pain 25.26 Local causes of hip pain
Pain from hand or wrist joints is well localised to the
affected joint, except for pain from the first metacarpal Lesion Pain Examination findings
joint, commonly targeted by OA; although maximal at Trochanteric Upper lateral thigh, Tender over greater
the thumb base, the pain often radiates down the thumb bursitis worse on lying on trochanter
and to the radial aspect of the wrist. Non-articular causes that side at night
of hand pain include: Gluteal Upper lateral thigh, Tender over greater
• Tenosynovitis: flexor or extensor (pain and swelling, enthesopathy worse on lying on trochanter
with or without fine crepitus on volar or extensor that side at night Pain reproduced by
aspect). De Quervain’s tenosynovitis involves the resisted active hip
tendon sheaths of abductor pollicis longus and abduction
extensor pollicis brevis, and produces pain maximal Adductor Upper inner thigh Tender over adductor
over the radial aspect of the distal forearm and tendinitis Usually clearly origin/tendon/muscle
wrist. It usually occurs as the result of a repetitive sports-related Pain reproduced by
strain injury. There is tenderness (with or without resisted active hip
warmth, linear swelling and fine crepitus) over the adduction
distal radius and marked pain on forced ulnar Ischiogluteal Buttock, worse on Tender over ischial
deviation of the wrist with the thumb held across bursitis sitting prominence
the patient’s palm (Finkelstein’s sign).
• Raynaud’s phenomenon (p. 602). lliopectineal Anterior groin Tender (± fluctuant
• C8/T1 radiculopathy. bursitis swelling) lateral to
femoral pulse, not
• Reflex sympathetic dystrophy (p. 1130).
worsened by internal
rotation of hip (cf.
Hip pain hip pain)
Pain from the hip joint is usually maximal deep in the
anterior groin, with variable radiation to the buttock,
anterolateral thigh, knee or shin (Fig. 25.12). Trochanteric abscess, retroperitoneal haemorrhage or pelvic inflam-
bursitis is a common cause (Box 25.26), typically affect- mation, which can cause inguinal and lateral thigh pain
ing obese women, and occurring in isolation or second- that is aggravated by resisted hip flexion.
ary to an abnormal gait, such as in hip or knee OA. Pain
in the hip region may also be referred from the back. Knee pain
Root entrapment can cause pain in the lateral thigh The most common cause of knee pain is OA, the features
(T12–L1) or the inguinal region and lateral thigh (L2–4), of which are described on page 1082. Pain that is associ-
but is worsened by coughing and straining more than ated with locking of the knee (sudden painful inability
by movement and is often accompanied by sensory to extend fully) is usually due to a meniscal tear or
disturbance. Other less common causes include psoas osteochondritis dissecans. Referred pain from the hip 1075
 RHEUMATOLOGY AND BONE DISEASE

25 25.27 Local causes of knee pain

pain and is characterised by a high arch and clawing of
the toes. It may be an isolated phenomenon or secondary
to neurological disorders such as Friedreich’s ataxia
Lesion Pain Examination findings
(p. 1199) or spina bifida (p. 1222). Management should
Pre-patellar Anterior Tender fluctuant follow the general principles outlined on page 1077. Bur-
bursitis patella swelling in front of sitis and enthesitis resistant to standard measures may
patella respond to local steroid injections. Morton’s neuroma is
Superficial and Anterior Tender fluctuant the name given to an entrapment neuropathy of the
deep infrapatellar knee, inferior swelling in front of interdigital nerves of the feet, which presents with shoot-
bursitis to patella (superficial) or behind ing pain that is usually located between the third and
(deep) patella tendon fourth metatarsal heads. Women are most commonly
Anserine bursitis Upper medial Tenderness (± warmth, affected. Local sensory loss and a palpable tender swell-
tibia swelling) over upper ing between the metatarsal heads may be detected. Foot-
medial tibia wear adjustment, with or without a local corticosteroid
Inferior medial
injection, often helps but surgical decompression may be
Upper medial Localised tenderness of
collateral tibia upper medial tibia required if symptoms persist.
ligament Pain reproduced by
enthesopathy valgus stress on partly
flexed knee
Muscle pain and weakness
Popliteal cyst Popliteal Tender swelling of Muscle pain and weakness can arise from a variety of
(Baker’s cyst) fossa popliteal fossa, usually causes. It is important to distinguish between a subjec-
reducible by massage tive feeling of generalised weakness or fatigue, and an
with knee in mid-flexion objective weakness with loss of muscle power and func-
Patella tendon Anterior Tenderness and firm tion. The former is a non-specific manifestation of many
enthesopathy upper tibia swelling of tibial tubercle diseases, including depression, whereas the latter is
Osteochondritis Anterior Affects adolescents often a sign of primary muscle disease.
(Osgood– upper tibia Pain on resisted active Clinical assessment
Schlatter disease) knee extension
Proximal muscle weakness suggests the presence of a
myopathy or myositis, which typically causes difficulty
with standing from a seated position, squatting and
may present at the knee and is reproduced by hip not lifting overhead. The causes are shown in Box 25.28.
knee movement. Pain from periarticular lesions is well Worsening of symptoms on exercise and post-exertional
localised to the involved structure (Box 25.27). Anterior cramps suggest a metabolic myopathy, such as glycogen
knee pain may be due to bursitis occurring as the result storage disease (p. 450). A strong family history and
of repetitive occupational kneeling, as well as infection onset in childhood or early adulthood suggests muscular
and gout. Anterior knee pain, aggravated by sports, may dystrophy (p. 1228). Alcohol excess can cause an inflam-
occur in adolescent girls but is usually self-limiting. matory myositis and atrophy of type 2 muscle fibres.
Rarely, anterior knee pain may be the result of chondro- Proximal myopathy may be a complication of cortico-
malacia patellae, in which degenerative changes of the steroid therapy and of osteomalacia. Myopathy and
articular cartilage occur. myositis can also occur in association with statin use and
viral infections, including HIV infection, when it may be
Ankle and foot pain due to HIV itself or treatment with zidovudine. Clinical
Pain from the mortice joint of the ankle (the tibiofibular– examination should document the presence, pattern and
talar joint) is felt between the malleoli and is worse on severity of muscle weakness, and the latter should be
weight-bearing. Pain from the subtalar joint is also worse assessed using the Medical Research Council (MRC)
on weight-bearing on uneven surfaces. The mortice joint scale, in which muscle strength is graded on a six-point
is commonly affected by OA, whereas RA tends to affect scale ranging from no power (0) to full power (5).
the subtalar joint. Pain under the heel can arise from
plantar fasciitis or subcalcaneal bursitis. Pain affecting Investigations
the back of the heel may be due to Achilles tendinitis or Investigations should include routine biochemistry and
bursitis. Patients with seronegative spondyloarthritis haematology, ESR, and measurement of CRP and CK.
may develop enthesopathy affecting this region, result- Serum 25(OH) vitamin D levels and PTH should be
ing in plantar fasciitis, which presents with pain and checked in suspected osteomalacia. Raised CK levels
tenderness under the heel, or as Achilles enthesitis, suggest muscle pathology but do not establish the cause.
which presents with pain at the tendon insertion into the The ESR and CRP may be raised in inflammatory myo-
calcaneus. The MTP joints of the feet are commonly sitis. Muscle biopsy and electromyography (EMG) are
involved in RA. The presentation is with pain on walking usually required to make the diagnosis, but MRI can be
below the metatarsal heads, often described as ‘walking used to identify focal areas of muscle abnormality and
on marbles’. Patients with active inflammation of the increase the diagnostic yield from muscle biopsies.
MTP joints have pain when the forefoot is squeezed
(p. 1059). Involvement of the first MTP joint is common Management
in OA and is associated with a valgus deformity (hallux Management is determined by the cause but all patients
valgus). This joint is also a classical target in acute gout. with muscle disease may benefit from physiotherapy
1076 Claw foot (pes cavus) can be associated with anterior foot and graded exercises to maximise muscle function.
 Principles of management of musculoskeletal disorders

25.28 Causes of proximal muscle pain 25.29 Core interventions for patients with
or weakness rheumatic diseases
Inflammatory Core
• Polymyositis • Inclusion body myositis • Education • Reduction of adverse
• Dermatomyositis • Polymyalgia rheumatica • Exercise mechanical factors
Endocrine (Ch. 20) Aerobic conditioning Pacing of activities
Strengthening Appropriate footwear
• Hypothyroidism • Cushing’s syndrome • Simple analgesia • Weight reduction if obese
• Hyperthyroidism • Addison’s disease
Other options
Metabolic (Ch. 16)
• Other analgesic drugs • Local corticosteroid injections
• Myophosphorylase • Carnitine deficiency Oral NSAIDs • Physical treatments
deficiency • Myoadenylate deaminase Topical agents Heat, cold, aids, appliances
• Phosphofructokinase deficiency Opioid analgesics • Surgery
deficiency • Osteomalacia (p. 1125) Amitriptyline • Coping strategies
• Hypokalaemia Gabapentin/pregabalin
Drugs/toxins • Disease-modifying
therapy
• Alcohol • Statins
• Cocaine • Penicillamine
• Fibrates • Zidovudine
Infections (Ch. 13) Simple and safe interventions should be tried first.
• Viral (HIV, cytomegalovirus, • Bacterial (Clostridium Symptoms and signs will change with time, so the plan
rubella, Epstein–Barr, echo) perfringens, staphylococci, requires regular review and re-adjustment. Effective
• Parasitic (schistosomiasis, tuberculosis, Mycoplasma) management may require the expertise of a variety of
cysticercosis, toxoplasmosis) health professionals, with a coordinated multidiscipli-
nary team approach.
Core interventions that should be considered for 25
everyone with a painful musculoskeletal condition
are listed in Box 25.29. There are also other non-
pharmacological and drug options, the choice depend-
PRINCIPLES OF MANAGEMENT OF ing largely on the nature and severity of the diagnosis.
MUSCULOSKELETAL DISORDERS
Although management of musculoskeletal disease Education and lifestyle interventions
depends on the underlying diagnosis, certain aspects of
management are common to many disorders. The Education
general aims of management are to: Patients must always be informed about the nature of
• educate the patient their condition and its investigation, treatment and
• control pain prognosis, as education can improve outcome. Informa-
• optimise function tion and therapist contact can reduce pain and disability,
• modify the disease process where this is improve self-efficacy and reduce the health-care costs
possible of many musculoskeletal conditions, including OA and
• identify and treat related comorbidity. RA. The mechanisms are unclear but in part may
These aims are interrelated and success in one area often result from improved adherence. Benefits are modest
benefits others. Successful management requires careful but potentially long-lasting, safe and cost-effective (Box
assessment of the person as a whole, as well as his 25.30). Education can be provided through one-to-one
or her musculoskeletal system. The management plan discussion, written literature, patient-led group educa-
should be individualised and patient-centred, should tion classes and interactive computer programs. Inclu-
involve all necessary members of the multidisciplinary sion of the patient’s partner or carer is often appropriate;
team, and should be agreed and understood by both the this is essential for childhood conditions but also helps
patient and involved practitioners. It must also take into in many chronic adult conditions, such as RA or
account: fibromyalgia.
• the person’s daily activity requirements, and work
and recreational aspirations Exercise
• risk factors and associations of the musculoskeletal Two types of exercise should be prescribed (Box 25.30):
condition (obesity, muscle weakness, non- • Aerobic fitness training can produce long-term
restorative sleep) reduction in pain and disability. It improves
• the person’s perceptions and knowledge of the well-being, encourages restorative sleep and
condition benefits common comorbidity such as obesity,
• medications and coping strategies already tried by diabetes, chronic heart failure and hypertension.
the patient • Local strengthening exercise for muscles that act
• comorbid disease and its therapy over compromised joints also reduces pain and
• the availability, costs and logistics of appropriate disability, with improvements in the reduced
evidence-based interventions. muscle strength, proprioception, coordination and 1077
 RHEUMATOLOGY AND BONE DISEASE
25 25.30 Education and exercise in the management
of arthritis
‘Both patient education and exercise regimens have a modest,
yet clinically important influence on patients’ well-being.’
‘Both aerobic walking and home-based quadriceps-
strengthening exercises reduce pain and disability from knee
osteoarthritis.’
• Devos-Combey L, et al. J Rheumatol 2006; 33:744–756.
• Roddy E, et al. Ann Rheum Dis 2005; 64:544–548.
balance that associate with chronic arthritis. ‘Small
amounts often’ of strengthening exercise are better
than protracted sessions performed infrequently.
Joint protection
Excessive impact-loading and adverse repetitive use of
a compromised joint or periarticular tissue can often be
reduced: for example, cessation of contact sports, or
altered use of machinery or tools at the workplace.
Simple ‘pacing’ of activities – dividing physically
onerous tasks into shorter segments with brief breaks in
between – is helpful. Use of shock-absorbing footwear
with thick soft soles can reduce impact-loading through
feet, knees, hips and back, and improve symptoms at
these sites. A walking stick held on the contralateral side
takes the weight off a painful hip, knee or foot.
Weight loss
Obesity aggravates pain at most sites of the body
through increased mechanical strain and is a risk factor
for more rapid progression of joint damage in patients
with arthritis. This should be explained to obese patients
and strategies offered on how to lose and then maintain
an appropriate weight (p. 117).
Pharmacological treatment
Analgesics
Paracetamol (1 g up to 4 times daily) is the oral analgesic
of first choice and, if successful, the preferred long-term
oral analgesic. It inhibits prostaglandin synthesis in the
brain but has less effect on peripheral prostaglandin
production. It is generally well tolerated and has few
adverse effects and drug interactions. There is a possible
increased risk of both gastrointestinal events and car-
diovascular disease with chronic usage, but it is uncer-
tain whether this is due to the underlying disease or
the drug itself. If paracetamol fails to achieve an ade-
quate response, it can be used in combination with
opioids such as codeine and dihydrocodeine in com-
pound analgesic preparations like co-codamol (codeine
and paracetamol) or co-dydramol (dihydrocodeine and
paracetamol). Although these are more effective than
paracetamol, side-effects include constipation, headache
and confusion, especially in the elderly. The centrally
acting analgesics tramadol and meptazinol may be
useful for temporary control of severe pain unrespon-
sive to other measures. Both may cause nausea, bowel
upset, dizziness and somnolence, and withdrawal
symptoms after chronic use. The non-opioid analgesic
1078 nefopam (30–90 mg 3 times daily) can help moderate
pain, though side-effects (nausea, anxiety, dry mouth)
often limit its use. Patients with severe or intractable
pain may require stronger opioid analgesics such as oxy-
codon and morphine.
Non-steroidal anti-inflammatory drugs
These are among the most widely prescribed drugs, but
their use has declined over recent years because of con-
cerns about an increased risk of cardiovascular disease.
Oral NSAIDs are particularly useful in the management
of pain that has an inflammatory component, and a
long-acting NSAID taken in the evening may help
reduce early morning stiffness. There is marked vari-
ability in individual tolerance and response; patients
who do not respond to one NSAID may still gain
relief from another. The mechanism of NSAID action
is through inhibition of prostaglandin H synthase
and cyclo-oxygenase (COX) enzymes. Arachidonic acid,
derived from membrane phospholipids, is metabolised
to produce prostaglandins and leukotrienes by the COX
and 5-lipoxygenase pathways respectively (Fig. 25.13).
There are two isoforms of COX, encoded by different
genes. COX-1 is constitutively expressed and fulfils a
‘housekeeping’ function in the gastric mucosa, platelets
and kidneys. The COX-2 enzyme is largely induced at
sites of inflammation, producing prostaglandins that
cause local pain and inflammation, but COX-2 is also
up-regulated in the CNS, where it plays a role in
the central mediation of pain and fever. Traditional
NSAIDs, such as ibuprofen, diclofenac and naproxen,
inhibit both COX enzymes, whereas newer NSAIDs,
such as celecoxib and etoricoxib, selectively inhibit
COX-2. Whilst NSAIDs have anti-inflammatory activity,
they are not thought to have a disease-modifying effect
in either OA or inflammatory rheumatic diseases.
Membrane
phospholipid
Phospholipase A2
Arachidonic
acid Lipoxygenase
Traditional
NSAID
COX-1 COX-2
‘house-keeping’ ‘inflammatory’
(constitutive) (inducible)
COX-2 selective
NSAID
Gut mucosal integrity Mitogenesis and growth
Platelet aggregation Regulation of female
Renal function reproduction
Bone formation
Renal function
Fig. 25.13 COX-1 and COX-2 pathways.
 Principles of management of musculoskeletal disorders

25.31 Commonly used NSAIDs and their relative

25.32 Risk factors for NSAID-induced ulcers
risk of gastrointestinal bleeding and perforation
Idiosyncratic • Age > 60 yrs*
Daily adult Doses/ side-effects, • Past history of peptic ulcer*
Drug dose day comments • Past history of adverse event with NSAID
Very low risk • Concomitant corticosteroid use
Celecoxib 100–200 mg 1–2 Selective COX-2 • High-dose or multiple NSAID
inhibitor • High-risk NSAID (see Box 25.31)
Etoricoxib 60–120 mg 1 Selective COX-2 *The most important risk factors.
inhibitor
Low risk
Ibuprofen 600–1600 mg 3–4 Weak anti-
inflammatory 25.33 Recommendations for the use of NSAID
effect at this
• Use with caution in patients with cardiovascular disease
dose
• Use the lowest dose for the shortest time possible to control
Etodolac 600 mg 1 Partially
symptoms
selective COX-2
• Avoid NSAID in patients on warfarin
inhibitor
• Allow 2–3 weeks to assess efficacy. If response is
Meloxicam 7.5–15 mg 1 Partially
inadequate, consider trial of another NSAID
selective COX-2
• Never prescribe more than one NSAID at a time
inhibitor
• Co-prescribe proton pump inhibitor for patients with risk
Nabumetone 1–2 g 1–2 Partially
factors for gastrointestinal adverse effects (see Box 25.32)
selective COX-2
inhibitor
Medium risk
Ibuprofen 1600–2400 mg 3–4 25.34 Use of oral NSAID in old age
Naproxen
Diclofenac
500–1000 mg
75–150 mg
1–2
2–3 Abnormal liver • Gastrointestinal complications: age is a strong risk factor
25
function tests for bleeding and perforation and peptic ulceration. Elderly
High risk
patients are more likely to die if they suffer NSAID-associated
bleeding or perforation.
Indometacin 50–200 mg 3–4 High incidence
• Cardiovascular disease: use NSAID with caution in patients
of dyspepsia and
with cardiovascular disease. Therapy with NSAID may
CNS side-effects
exacerbate hypertension and heart failure.
(headache,
• Renal disease: use of NSAID may cause renal impairment.
dizziness,
confusion)
Ketoprofen 100–200 mg 2–4
Highest risk with all NSAIDs, including COX-2 selective NSAIDs,
Piroxicam 20–30 mg 1–2 Restricted use in even though the risk of gastrointestinal events with
those > 60 yrs these is low. Since chronic PPI therapy is associated
Azapropazone 600–200 mg 2–4 Uricosuric with an increased risk of hip fracture, the merits of
action. giving PPI therapy with a COX-2 selective drug need
Restricted use in to be weighed up carefully.
those > 60 yrs Other side-effects of NSAID include fluid retention
and renal impairment due to inhibition of renal prosta-
glandin production, non-ulcer-associated dyspepsia,
Non-selective NSAIDs can damage the gastric and abdominal pain and altered bowel habit, and rashes.
duodenal mucosal barrier and are associated with Interstitial nephritis, asthma and anaphylaxis can also
an increased risk of upper gastrointestinal ulceration, occur but are rare. Recommendations for NSAID pre-
bleeding and perforation. The adjusted increased risk scribing are summarised in Box 25.33. Because of the risk
(odds ratio) of bleeding or perforation from all NSAIDs of adverse effects, NSAIDs should be used with great
is 4–5, though differences exist between NSAIDs care in the elderly (Box 25.34).
(Box 25.31). Dyspepsia is a poor guide to the presence
of NSAID-associated ulceration and bleeding, and Topical agents
the principal risk factors are shown in Box 25.32. Topical NSAID creams and gels and capsaicin (chilli
Co-prescription of omeprazole (20 mg daily) or miso- extract; 0.025%) cream can help in the treatment of OA
prostol (200 μg twice or 3 times daily) reduces but and superficial periarticular lesions affecting hands,
does not eliminate NSAID-induced ulceration and elbows and knees. They may be used as monotherapy
bleeding, but H2-antagonists in standard doses are inef- or as an adjunct to oral analgesics. Topical NSAIDs can
fective. The COX-2 selective NSAIDs celecoxib and penetrate superficial tissues and even reach the joint
etoricoxib are much less likely to cause gastrointestinal capsule, though intrasynovial levels mainly reflect
toxicity but benefit is attenuated in patients on low- blood-borne drug delivery. Capsaicin selectively binds
dose aspirin. In the UK, National Institute for Health to the protein transient receptor potential vanilloid
and Clinical Excellence (NICE) guidelines advise that a type 1 (TRPV1), which is a heat-activated calcium
proton pump inhibitor (PPI) should be co-prescribed channel on the surface of peripheral type C nociceptor 1079
 RHEUMATOLOGY AND BONE DISEASE

25 fibres. Initial application causes a burning sensation

but continued use depletes presynaptic substance P,
25.35 Surgical procedures in rheumatology and
bone disease
with subsequent pain reduction that is optimal after
Procedure Indication
1–2 weeks.
Soft tissue release
Carpal tunnel Median nerve compression
Non-pharmacological interventions Tarsal tunnel Posterior tibial nerve entrapment
Flexor tenosynovectomy Relief of ‘trigger’ fingers
Ulnar nerve transposition Ulnar nerve entrapment at elbow
Physical and occupational therapy Fasciotomy Severe Dupuytren’s contracture
Local heat, ice packs, wax baths and other local external
Tendon repairs and transfers
applications can induce muscle relaxation and tem-
Hand extensor tendons Extensor tendon rupture
porary relief of symptoms in a range of rheumatic
Thumb and finger flexor Flexor tendon rupture
diseases. tendons
Hydrotherapy induces muscle relaxation and facili-
tates enhanced movement in a warm, pain-relieving Synovectomy
environment without the restraints of gravity and Wrist and extensor tendon Pain relief and prevention of
normal load-bearing. Various manipulative techniques sheath (+ excision of radial extensor tendon rupture in RA,
head) resistant inflammatory synovitis
may also help improve restricted movement. The com-
Knee synovectomy Resistant inflammatory synovitis
bination of these with education and therapist contact
enhances their benefits. Osteotomy
Splints can give temporary rest and support for Femoral osteotomy Early OA of hip
painful joints and periarticular tissues, and prevent Tibial osteotomy Unicompartmental knee OA
Deformed tibia in OA or Paget’s
harmful involuntary postures during sleep. Prolonged
disease
rest, however, must be avoided.
Orthoses are more permanent appliances used to Excision arthroplasty
reduce instability and excessive abnormal movement. First metatarsophalangeal Painful hallux valgus
They include working wrist splints, knee orthoses, and joint (Keller’s procedure)
iron and T-straps to control ankle instability. Orthoses Radial head Painful distal radio-ulnar joint
Lateral end of clavicle Painful acromioclavicular joint
are particularly suited to severely disabled patients in
Metatarsal head Painful subluxed
whom a surgical option is inappropriate, and often need
metatarsophalangeal joints
to be custom-made for the individual.
Aids and appliances can provide dignity and inde- Joint replacement arthroplasty
pendence to patients with respect to activities of daily Knee, hip, shoulder, elbow Painful damaged joints in OA
living. Common examples are a raised toilet seat, raised and RA
chair height, extended handles on taps, a shower instead Arthrodesis
of a bath, thick-handled cutlery, and extended ‘hands’ Wrist Damaged joint: pain relief,
to pull on tights and socks. Full assessment and advice improvement of grip
from an occupational therapist maximise the benefits Ankle/subtalar joints Damaged joint: pain relief,
of these. stabilisation of hindfoot
Fracture repair
Surgery Hip arthroplasty Fractured neck of femur
A variety of surgical interventions can relieve pain and External fixation Multiple fractures, open fractures
conserve or restore function in patients with bone, joint Intramedullary nailing Tibial and femur fractures
and periarticular disease (Box 25.35). Soft tissue release Screw, plating and wiring Wrist and other fractures
and tenosynovectomy may reduce inflammatory symp- Other procedures
toms, improve function and prevent or retard tendon Nerve root decompression Spinal stenosis, nerve
damage for variable periods, sometimes indefinitely. entrapment
Synovectomy of joints does not prevent disease progres- Kyphoplasty Painful vertebral fracture
sion but may be indicated for pain relief when drugs, Vertebroplasty Painful vertebral fracture
physical therapy and intra-articular injections have
provided insufficient relief. The main approaches for
damaged joints are osteotomy (cutting bone to alter joint patient. Assessment of motivation, social support and
mechanics and load transmission), excision arthroplasty environment is no less important than careful considera-
(removing part or all of the joint), joint replacement tion of patients’ general health, their risks for major
(insertion of prosthesis in place of the excised joint) and surgery, the extent of disease in other joints, and their
arthrodesis (joint fusion). Surgical fixation of fractures is ability to mobilise following surgery. For some severely
frequently required in patients with osteoporosis and compromised people, pain relief and functional inde-
other bone diseases. pendence are better served by provision of a suitable
The main aims of surgery are to provide pain relief wheelchair, home adjustments and social services than
and improve function and quality of life. If surgery is by surgery that is technically successful but following
to be successful, the aims and consequences of each which the patient cannot mobilise.
operation should be considered as part of an integrated
programme of management and rehabilitation, by Self-help and coping strategies
multidisciplinary teams of surgeons, allied health pro- These help patients to cope better with, and adjust to,
1080 fessionals and physicians, and carefully explained to the chronic pain and disability. They may be useful at any

25.36 Self-help and coping strategies
• Yoga and relaxation techniques to reduce stress
• Avoiding negative situations or activities that produce stress,
and increasing pleasant activities that give satisfaction
• Information and discussion to alter beliefs about and
perspectives on disease
• Reducing or avoiding catastrophising and maladaptive pain
behaviour
• Imagery and distraction techniques for pain
• Expanding social contact and better use of social services
stage but are particularly so for patients with incurable
problems, who have tried all available treatment options.
The aim is to increase self-management through self-
assessment and problem-solving, so that patients can
recognise negative but potentially remediable aspects of
their mood (stress, frustration, anger or low self-esteem)
and their situation (physical, social, financial). These
may then be addressed by changes in attitude and
behaviour, as shown in Box 25.36.
Involvement of the spouse or partner in mutual goal-
setting can improve partnership adjustment. Such
approaches are often an element of group education
classes and pain clinics, but may require more formal
clinical psychological input.
OSTEOARTHRITIS
Osteoarthritis (OA) is by far the most common form of
arthritis. It is strongly associated with ageing and is a
major cause of pain and disability in older people. Osteo-
arthritis is characterised by focal loss of articular carti-
lage, subchondral osteosclerosis, osteophyte formation
at the joint margin, and remodelling of joint contour
with enlargement of affected joints. Inflammation can
occur but is not a prominent feature. Joint involvement
in OA follows a characteristic distribution, mainly tar-
geting the hips, knees, PIP and DIP joints of the hands,
neck and lumbar spine (see Fig. 25.9). The prevalence of
OA rises progressively with age and it has been esti-
mated that 45% of all people develop knee OA and 25%
hip OA at some point during life. Although some of
these patients are asymptomatic, the lifetime risk of
having a total hip or knee replacement for OA in someone
aged 50 is about 11% in women and 8% in men. Symp-
toms attributable to OA are more prevalent in women,
except at the hip, where men are equally affected.
Pathophysiology
OA is a complex disorder with both genetic and envi-
ronmental components (Fig. 25.14). Repetitive adverse
loading of joints during occupation or competitive
sports is also an important predisposing factor in farmers
(hip OA), miners (knee OA) and elite or professional
athletes (knee OA). For most people, however, participa-
tion in recreational sport does not appear to increase the
risk of OA, unless there has been significant joint trauma.
Congenital abnormalities of the joint, such as slipped
femoral epiphysis, are also associated with a high risk
of OA, presumably due to abnormal load distribution
Osteoarthritis
tiona
l susc
ep
itu tib
st
n
Heredity
ili
Co
ty
Gender/hormonal status
Obesity
High bone mineral density
Ageing
Trauma
Joint shape
Alignment
Usage
– occupational
– recreational
M rs
ec
hanical facto
Fig. 25.14 Risk factors for the development of osteoarthritis.
within the joint, and this is also thought to be the expla-
nation for the increased risk of OA in Paget’s disease of
bone. Obesity is another strong risk factor. Although this
25
is likely to be due in part to increased mechanical loading
of the joints, it has been speculated that cytokines
released from adipose tissue may also play a role. The
increased incidence of OA in women has led to specula-
tion that sex hormones may play a causal role. While
there is no evidence to suggest that circulating sex
hormone levels or reproductive history predispose to
OA, some studies have shown a lower prevalence of
OA in women who use hormone replacement therapy
(HRT), as compared with non-users. Genetic factors play
a key role in the pathogenesis of OA, and family-based
studies have estimated that the heritability of OA ranges
between about 43% at the knee to between 60% and
65% at the hip and hand, respectively. Recent genome-
wide association studies have identified several loci
that predispose to OA, but many others remain to be
discovered.
Major alterations in cartilage structure are character-
istic of OA. Chondrocytes divide to produce nests of
metabolically active cells (Fig. 25.15A). Initially, matrix
components are produced at an increased rate, but at the
same time there is increased degradation of the major
structural components of cartilage, including aggrecan
and type II collagen (see Fig. 25.4, p. 1063). Eventually,
the concentration of aggrecan in matrix falls and makes
the cartilage vulnerable to load-bearing injury. Fissuring
of the cartilage surface (‘fibrillation’) then occurs, leading
to the development of deep vertical clefts (Fig. 25.15B),
localised chondrocyte death and decreased cartilage
thickness; this is focal rather than generalised in nature
and mainly affects the maximum load-bearing part of
the joint, although, eventually, large parts of the carti-
lage surface can be damaged. Calcium pyrophosphate
and basic calcium phosphate crystals often become
deposited in the abnormal cartilage.
The subchondral bone is also abnormal, with osteo-
sclerosis and subchondral cyst formation (Fig. 25.15C). 1081
 RHEUMATOLOGY AND BONE DISEASE
25 A B
C
Fig. 25.15 Pathological changes in osteoarthritis. A Abnormal
nests of proliferating chondrocytes (arrows) interspersed with matrix devoid
of normal chondrocytes. B Fibrillation of cartilage in OA. C Radiograph
of knee joint affected by OA, showing osteophytes at joint margin (white
arrows), subchondral sclerosis (black arrows) and subchondral cyst (open
arrow).
Fibrocartilage is produced at the joint margin, which
undergoes endochondral ossification to form osteo-
phytes. Bone remodelling and cartilage thinning slowly
alter the shape of the OA joint, increasing its surface
area. Patients with OA also have higher BMD values at
sites distant from the joint, and this is particularly related
to osteophyte formation. The reason for this is not com-
pletely understood but it may reflect the fact that
common signalling pathways are involved in the regula-
tion of bone and cartilage metabolism.
The synovium undergoes variable degrees of hyper-
plasia, and inflammatory changes may sometimes be
observed, although to a much lesser extent than in RA
and other inflammatory arthropathies. Osteochondral
bodies commonly occur within the synovium, reflecting
chondroid metaplasia or secondary uptake and growth
of damaged cartilage fragments. The outer capsule also
thickens and contracts, usually retaining the stability of
the remodelling joint. The muscles surrounding affected
joints commonly show evidence of wasting and non-
specific type II fibre atrophy.
Clinical features
The main presenting symptoms are pain and functional
restriction in a patient over the age of 45, but more
often over 60 years. The causes of pain in OA are not
completely understood but may relate to increased
pressure in subchondral bone (mainly causing night
pain), trabecular microfractures, capsular distension and
low-grade synovitis, or may result from bursitis and
enthesopathy secondary to altered joint mechanics.
Typical OA pain has the characteristics listed in Box
25.37. For many people, functional restriction of the
hands, knees or hips is an equal, if not greater, problem
than pain. The clinical findings vary according to sever-
1082 ity but are principally those of joint damage.
25.37 Symptoms and signs of osteoarthritis
Pain
• Insidious onset over months or years
• Variable or intermittent over time (‘good days, bad days’)
• Mainly related to movement and weight-bearing, relieved
by rest
• Only brief (< 15 mins) morning stiffness and brief (< 5 mins)
‘gelling’ after rest
• Usually only one or a few joints painful
Clinical signs
• Restricted movement due to capsular thickening, or blocking
by osteophyte
• Palpable, sometimes audible, coarse crepitus due to rough
articular surfaces
• Bony swelling around joint margins
• Deformity, usually without instability
• Joint-line or periarticular tenderness
• Muscle weakness and wasting
• Synovitis mild or absent
The correlation between the presence of structural
change, pain and disability varies markedly according
to site. It is stronger at the hip than the knee, and poor
at most small joints. Risk factors for pain and disability
may differ from those for structural change. At the knee,
for example, reduced quadriceps muscle strength and
adverse psychosocial factors (anxiety, depression) cor-
relate more strongly with pain and disability than the
degree of radiographic change.
Radiological evidence of OA is very common in
middle-aged and older people, and the disease may
coexist with other conditions, so it is important to remem-
ber that pain in a patient with OA may be due to another
cause. Generalised OA, knee OA, hip OA and spine OA
(spondylosis) will be considered individually.
Generalised nodal OA
Characteristics of this common form of OA are shown
in Box 25.38. Some patients are asymptomatic whereas
others develop pain, stiffness and swelling of one or
more PIP joints of the hands from the age of about
40 years onward. Gradually, these develop postero-
lateral swellings on each side of the extensor tendon
that slowly enlarge and harden to become Heberden’s
(DIP) and Bouchard’s (PIP) nodes (Fig. 25.16). Typically,
each joint goes through a phase of episodic symptoms
(1–5 years) while the node evolves and OA develops.
Once OA is fully established, symptoms may subside
and hand function often remains good. Affected joints
are enlarged as the result of osteophyte formation and
25.38 Characteristics of generalised nodal
osteoarthritis
• Polyarticular finger interphalangeal joint OA
• Heberden’s (± Bouchard’s) nodes
• Marked female preponderance
• Peak onset in middle age
• Good functional outcome for hands
• Predisposition to OA at other joints, especially knees
• Strong genetic predisposition

Fig. 25.16 Nodal osteoarthritis. Heberden’s nodes and lateral (radial/
ulnar) deviation of distal interphalangeal joints, with mild Bouchard’s nodes
at the proximal interphalangeal joints.
Fig. 25.17 X-ray appearances in hand osteoarthritis. There is
marked loss of joint space at all of the distal interphalangeal joints, with
osteophyte formation most marked at the first and second DIP joints. The
fifth proximal interphalangeal joint also shows loss of joint space with
osteophyte formation.
often show characteristic lateral deviation, reflecting the
asymmetric focal cartilage loss of OA (Fig. 25.17).
Involvement of the first carpometacarpal joint (CMC) is
also common, leading to pain on trying to open bottles
and jars and functional impairment. Clinically, it may be
detected by the presence of crepitus on joint movement,
and squaring of the thumb base.
Generalised nodal OA has a very strong genetic com-
ponent: the daughter of an affected mother has a 1 in 3
chance of developing nodal OA herself. People with
nodal OA are at increased risk of OA at other sites,
especially the knee.
Knee OA
OA principally targets the patello-femoral and medial
tibio-femoral compartments at this site but eventually
spreads to affect the whole of the joint (Fig. 25.18). It may
be isolated or occur as part of generalised nodal OA.
Most patients, particularly women, have bilateral and
symmetrical involvement. With men, trauma is a more
important risk factor and may result in unilateral OA.
The pain is usually localised to the anterior or medial
aspect of the knee and upper tibia. Patello-femoral pain
is usually worse going up and down stairs or inclines.
Osteoarthritis
Fig. 25.18 X-ray appearances in knee osteoarthritis. There is
almost complete loss of joint space affecting both compartments, and
sclerosis of subchondral bone.
25
Fig. 25.19 Typical varus deformity resulting from marked medial
tibio-femoral osteoarthritis.
Posterior knee pain suggests the presence of a complicat-
ing popliteal cyst (Baker’s cyst). Prolonged walking,
rising from a chair, getting in or out of a car, or bending
to put on shoes and socks may be difficult. Local exami-
nation findings may include:
• a jerky, asymmetric (antalgic) gait with less time
weight-bearing on the painful side
• a varus (Fig. 25.19), less commonly valgus, and/or
fixed flexion deformity
• joint-line and/or periarticular tenderness
(secondary anserine bursitis and medial ligament
enthesopathy (see Box 25.27, p. 1076), causing
tenderness of the upper medial tibia)
• weakness and wasting of the quadriceps muscle
• restricted flexion/extension with coarse crepitus
• bony swelling around the joint line.
Calcium pyrophosphate dihydrate (CPPD) crystal
deposition in association with OA is most common
at the knee. This may result in a more overt inflamma-
tory component (stiffness, effusions) and super-added
acute attacks of synovitis (‘pseudogout’, p. 1090), which 1083
 RHEUMATOLOGY AND BONE DISEASE

25 may predict more rapid radiographic and clinical

progression.

Hip OA
Hip OA most commonly targets the superior aspect of
the joint (Fig. 25.20). This is often unilateral at presenta-
tion, frequently progresses with superolateral migration
of the femoral head, and has a poor prognosis. The less
common central (medial) OA shows more central carti-
lage loss and is largely confined to women. It is often
bilateral at presentation and may associate with gener-
alised nodal OA. It has a better prognosis than superior
hip OA and progression to axial migration of the femoral
head is uncommon.
The hip shows the best correlation between symp-
toms and radiographic change. Hip pain is usually
maximal deep in the anterior groin, with variable radia-
tion to the buttock, anterolateral thigh, knee or shin. Fig. 25.21 X-ray of spine showing typical changes of
osteoarthritis. Cervical spondylosis showing disc space narrowing
Lateral hip pain, worse on lying on that side with ten-
between C6 and C7, osteophytes at the anterior vertebral body margins
derness over the greater trochanter, suggests secondary (arrows) and osteosclerosis at the apophyseal joints.
trochanteric bursitis. Common functional difficulties are
the same as for knee OA; in addition, restricted hip
abduction in women may cause pain on intercourse. Spine OA
Examination may reveal: The cervical and lumbar spine are predominantly tar-
• an antalgic gait geted by OA, then referred to as cervical spondylosis
• weakness and wasting of quadriceps and gluteal and lumbar spondylosis, respectively (Fig. 25.21). Spine
muscles OA may occur in isolation or as part of generalised OA.
• pain and restriction of internal rotation with the hip The typical presentation is with pain localised to the low
flexed – the earliest and most sensitive sign of hip back region or the neck, although radiation of pain to
OA; other movements may subsequently be the arms, buttocks and legs may also occur due to nerve
restricted and painful root compression. The pain is typically relieved by rest
• anterior groin tenderness just lateral to the femoral and worse on movement. On physical examination, the
pulse range of movement may be limited and loss of lumbar
• fixed flexion, external rotation deformity of the hip lordosis is typical. The straight leg-raising test or femoral
• ipsilateral leg shortening with severe joint attrition stretch test may be positive and neurological signs may
and superior femoral migration. be seen in the legs where there is complicating spinal
Although obesity is not a major risk factor for devel- stenosis or nerve root compression.
opment of hip OA, it is associated with more rapid
progression.
Early-onset OA
Unusually, typical symptoms and signs of OA may
present before the age of 45. In most cases, a single joint
is affected and there is a clear history of previous trauma.
C However, specific causes of OA need to be considered
N S in people with early-onset disease affecting several
O joints, especially those not normally targeted by OA,
rare causes need to be considered (Box 25.39). Kashin–
Beck disease is a rare form of OA that occurs in children,
O typically between the ages of 7 and 13, in some regions

25.39 Causes of early-onset osteoarthritis

Monoarticular
• Previous trauma, localised instability
Pauciarticular or polyarticular
• Juvenile idiopathic arthritis (p. 1103)
• Metabolic or endocrine disease
Haemochromatosis (p. 972)
Ochronosis
Acromegaly (p. 792)
• Spondylo-epiphyseal dysplasia
• Late avascular necrosis
Fig. 25.20 X-ray of hip showing changes of osteoarthritis. Note • Neuropathic joint
the superior joint space narrowing (N), subchondral sclerosis (S), marginal • Kashin–Beck disease
1084 osteophytes (white arrows) and cysts (C).

of China. The cause is unknown but suggested predis-
posing factors are selenium deficiency and contamina-
tion of cereals with mycotoxin-producing fungi.
Erosive OA
This term is used to describe rare patients with hand OA
who have a more prolonged symptom phase, more overt
inflammation, more disability and worse outcome than
those with nodal OA. Distinguishing features include
preferential targeting of PIP joints, subchondral erosions
on X-rays, occasional ankylosis of affected joints and
lack of association with OA elsewhere. It is unclear
whether erosive OA is part of the spectrum of hand OA
or a discrete subset.
Investigations
A plain X-ray of the affected joint should be performed
and often this will show one or more of the typical fea-
tures of OA (see Figs 25.17–25.21). In addition to provid-
ing diagnostic information, X-rays are used to assess the
severity of structural change, which is useful if joint
replacement surgery is being considered. Non-weight-
bearing postero-anterior views of the pelvis are ade-
quate for assessing hip OA. Patients with suspected
knee OA should have standing antero-posterior radio-
graphs taken to assess tibio-femoral cartilage loss, and a
flexed skyline view to assess patello-femoral involve-
ment. Spine OA can often be diagnosed on plain X-ray,
which typically shows evidence of disc space narrowing
and osteophytes. If nerve root compression or spinal
stenosis is suspected, MRI should be performed.
Routine biochemistry, haematology and autoanti-
body tests are usually normal. Synovial fluid aspirated
from an affected joint is viscous with a low cell count.
Radioisotope bone scans performed for other reasons
often show, as an incidental finding, discrete increased
uptake in OA joints due to increased bone remodelling.
Unexplained early-onset OA requires additional
investigation, guided by the suspected underlying con-
dition. X-rays may show typical features of dysplasia or
avascular necrosis, widening of joint spaces in acro-
megaly, multiple cysts and chondrocalcinosis in haemo-
chromatosis (p. 972), or disorganised architecture in
neuropathic joints.
Management
Treatment follows the principles outlined on pages
1077–1081 and in Box 25.40. Measures that are pertinent
in older people are summarised in Box 25.41.
Education and other
general measures
It is important to explain the nature of the condition
fully, outlining the role of relevant risk factors (obesity,
heredity, trauma) and the fact that established structural
changes are permanent but that pain and function
can improve. The prognosis should also be discussed
(good for nodal hand OA, more optimistic for knee
than hip OA), as should how appropriate action can
improve the prognosis of large-joint OA. Exercise has
beneficial effects in OA, including both strengthening
and aerobic exercise, preferably with reinforcement by
Osteoarthritis
25.40 Management of osteoarthritis
‘The following measures have been shown to be effective:
• weight loss (if overweight)
• quadriceps strengthening exercises (knee OA)
• paracetamol and/or topical NSAID
• oral NSAID
• joint replacement surgery for disabling symptoms.’
For further information www.nice.org.uk/CG59
25.41 Osteoarthritis in old age
• Pain and disability: OA is the principal cause in old age.
• Calcium phosphate deposition disease: may cause acute
attacks of synovitis (pseudogout) on a background of
chronic OA.
• Falls: reduced muscle strength and pain associated with
lower limb OA increase the risk.
• Muscle strengthening exercises: safely reduce the pain
and disability of knee OA with accompanying improvements
in balance and reduced tendency to fall.
• Oral paracetamol and topical NSAID: safe in older people,
with no important drug interactions or contraindications.
• Intra-articular injection of corticosteroid: a very safe and
often effective treatment, particularly useful for tiding a
patient over a special event.
25
• Total joint replacement: an excellent cost-effective
treatment for severe disabling knee or hip OA in older
people. There is no age limit for joint replacement surgery.
a physiotherapist (see Box 25.30, p. 1078). Quadriceps
strengthening exercises are particularly beneficial in
knee OA. Weight loss can have a substantial beneficial
effect on symptoms if the patient is obese and is probably
one of the most effective treatments for reducing pain,
particularly in OA of the lower limbs. Shock-absorbing
footwear, pacing of activities, use of a walking stick for
painful knee or hip OA, or provision of built-up shoes
to equalise leg lengths can all improve symptoms.
Analgesics and anti-inflammatory
drugs
If symptoms do not respond to non-pharmacological
measures, paracetamol should be given. Addition of a
topical NSAID, and then capsaicin, for knee and hand
OA can also be helpful. Oral NSAID should be consid-
ered in patients who remain symptomatic. These drugs
are significantly more effective than paracetamol and
can be successfully combined with paracetamol or com-
pound analgesics such as co-codamol if the pain is
severe. Opiates may occasionally be required. For tem-
porary benefit of moderate to severe pain, intra-articular
injection of corticosteroids can be helpful (see below).
Local physical therapies such as heat or cold can some-
times give temporary relief. Acupuncture and transcu-
taneous electrical nerve stimulation (TENS) have also
been shown to be effective in knee OA. Antineuropathic
drugs, such as amitriptyline, gabapentin and pregabalin,
are sometimes used in patients with symptoms that
are difficult to control, but the evidence base for their
use is poor. 1085
 RHEUMATOLOGY AND BONE DISEASE

25 Corticosteroid injections
Intra-articular corticosteroid injections are effective in
most provide life-long, pain-free function. However,
some 20% of patients are not satisfied with the outcome,
and a few experience little or no improvement in pain.
the treatment of knee OA and are also used for sympto-
matic relief in the treatment of OA at the first CMC joint.
The duration of effect is usually short but trials of serial CRYSTAL-INDUCED ARTHRITIS
corticosteroid injections every 3 months in knee OA
have shown efficacy for up to 1 year. A variety of crystals can deposit in and around joints
and cause an acute inflammatory arthritis, as well as a
Chondroitin and glucosamine
Chondroitin sulphate and glucosamine sulphate have
been used alone and in combination for the treatment of 25.42 Crystal-associated arthritis and deposition
knee OA. There is evidence from randomised controlled in connective tissue
trials that these agents can improve knee pain to a small Crystal Associations
extent (3–5%), as compared with placebo. Although Common
NICE did not consider these differences to be clinically Monosodium urate Acute gout
significant, the beneficial effects of paracetamol in knee monohydrate Chronic tophaceous gout
OA are equally small. Calcium pyrophosphate Acute ‘pseudogout’
dihydrate Chronic (pyrophosphate) arthropathy
Hyaluronan injections Chondrocalcinosis
In knee OA, intra-articular injection of one of several Basic calcium Calcific periarthritis
forms of hyaluronan (polymers of hyaluronate), usually phosphates Calcinosis
given as a course of weekly injections for 3–5 weeks, Uncommon
may give modest pain relief for several months. Cholesterol Chronic effusions in RA
However, evidence for efficacy is heterogeneous and the Calcium oxalate Acute arthritis in dialysis patients
expense of this treatment and the common requirement Extrinsic crystals/semi-
for serial injection mean that hyaluronan injections are crystalline particles
not recommended for OA by NICE. Synthetic crystals Acute synovitis
Plant thorns/sea Chronic monoarthritis, tenosynovitis
Disease-modifying therapies urchin spines
There are no licensed drugs that can halt the progression
of OA. Glucosamine sulphate was shown in one study
Solute excess
to slow the rate of radiological progression in knee OA
and to reduce the number of subjects who progressed to
[X] x [Y]
joint replacement but the study has been criticised on
methodological grounds. A recent randomised control-
led trial suggested that strontium ranelate might also be (pH) (Temperature)
(Pressure)
effective in reducing the rate of progression of knee OA
but it is not licensed for this indication. Nucleating
Tissue inhibitory
factors
Surgery factors

Surgery should be considered for patients with OA Growth-promoting

whose pain, stiffness and reduced function impact sig- factors
nificantly on their quality of life and are refractory to
other treatments. Osteotomy can prolong the life of
malaligned joints and relieve pain by reducing intra-
osseous pressure, but is performed infrequently. Total Bone
joint replacement surgery is by far the most common
surgical procedure for patients with OA. It can trans-
form the quality of life for people with severe knee or
Crystals
hip OA and is indicated when there is significant
structural damage on X-ray, and pain and functional Inflammation
impairment are limiting quality of life despite the use of Reduced solute levels Trauma
medical therapy. Although surgery should not be under- Reduced solute levels
taken at an early stage during the development of OA,
it is important to consider it before functional limitation
has become advanced since this may compromise the
surgical outcome. Patient-specific factors, such as age,
gender, smoking and presence of obesity, should not be
barriers to referral for joint replacement.
Only a small proportion of patients with OA progress
to the extent that total joint replacement is required, but Dissolution
OA is by far the most frequent indication for a total joint Shedding
replacement. Over 95% of joint replacements continue to Fig. 25.22 Factors affecting the balance of crystal formation and
1086 function well into the second decade after surgery and tissue concentration.
 Crystal-induced arthritis

more chronic arthritis associated with progressive joint

De novo
damage (Box 25.42). Crystals can be the primary patho- purine (≅ 600–700 mg/day)
genic agent, as in gout, or an accessory factor, as in synthesis
calcium pyrophosphate deposition disease, in which
crystals are deposited in joints that are already abnor-
mal. Several factors influence crystal formation (Fig. (≅ 300–600
25.22). There must be sufficient concentration of the mg/day)
chemical components (ionic product), but whether a
crystal then forms depends on the balance of tissue Dietary Purine Tissue
factors that promote and inhibit crystal nucleation and purines nucleotides nucleotides
growth. Many tissues are supersaturated for the various
products but depend on natural inhibitors to prevent
crystallisation. The inflammatory potential of crystals
resides in their physical irregularity and high negative
surface charge, which can induce inflammation and Purine
damage cell membranes. Crystals may also cause bases
mechanical damage to tissues and act as wear particles
at the joint surface. Crystals can paradoxically reside in
cartilage or tendon for years without causing inflamma-
tion or symptoms, and it is only when they are released
that they trigger inflammation. This may occur sponta-
neously but can also result from local trauma, changes
in the concentration of the components that form crys- Uric acid
tals, or be part of an acute phase response due to inter- pool
current illness or surgery. ≅ 1200 mg
2/3rd 1/3rd

Gout
25
Gout is an inflammatory disease caused by deposition Renal excretion Intestinal excretion
(≅ 600 mg/day) (≅ 300 mg/day)
of monosodium urate monohydrate crystals in and
around synovial joints. Fig. 25.23 The uric acid pool. Origins and disposal of uric acid.

Epidemiology
The prevalence of gout varies between populations but 25.43 Causes of hyperuricaemia and gout
is approximately 1–2%, with a greater than 5 : 1 male
preponderance. It is the most common inflammatory Diminished renal excretion
arthritis in men and in older women. The risk of devel- • Increased renal tubular • Drugs
oping gout increases with age and with serum uric acid reabsorption* Thiazide and loop diuretics
(SUA) levels, which are normally distributed in the • Renal failure Low-dose aspirin
general population. Levels are higher in men, increase • Lead toxicity Ciclosporin
with age and are associated with body weight. Levels • Lactic acidosis Pyrazinamide
are higher in some ethnic groups (such as Maoris and • Alcohol
Pacific islanders). Hyperuricaemia is defined as an SUA Increased intake
level greater than 2 standard deviations above the mean
• Red meat • Offal
for the population. Gout has become more common over
• Seafood
recent years in parallel with increased longevity and the
higher prevalence of metabolic syndrome, of which Over-production of uric acid
hyperuricaemia is an integral component. Although • Myeloproliferative and • Inherited disorders
hyperuricaemia is an independent risk factor for hyper- lymphoproliferative disease Lesch–Nyhan syndrome
tension, vascular disease, renal disease and cardiovascu- • Psoriasis (HPRT mutations)
lar events, only a minority of hyperuricaemic people • High fructose intake Phosphoribosyl
develop gout. There is currently no evidence to support • Glycogen storage disease pyrophosphate synthetase
the use of urate-lowering therapy in patients with (p. 450) 1 mutations
asymptomatic hyperuricaemia.
*Usually genetically determined (see text).
(HPRT = hypoxanthine guanine phosphoribosyl transferase)
Pathophysiology
About one-third of the body uric acid pool is derived
from dietary sources and two-thirds from endogenous conversion of hypoxanthine to xanthine and then xan-
purine metabolism (Fig. 25.23). The concentration of uric thine to uric acid.
acid in body fluids depends on the balance between The causes of hyperuricaemia are shown in Box 25.43.
endogenous synthesis, and elimination by the kidneys In over 90% of patients, the main abnormality is reduced
(two-thirds) and gut (one-third). Purine nucleotide syn- uric acid excretion by the renal tubules, which impairs
thesis and degradation are regulated by a network of the body’s ability to respond to a purine load. In many
enzyme pathways. Xanthine oxidase catalyses the end cases, this is genetically determined and recent studies 1087
 RHEUMATOLOGY AND BONE DISEASE
25 have identified polymorphisms in several genes that are
associated with gout, the most important of which is
SLC2A9, which regulates urate excretion by the kidney.
Impaired renal excretion of urate also accounts for the
occurrence of hyperuricaemia in chronic renal failure,
and for the association between hyperuricaemia and
treatment with thiazide diuretics.
Other risk factors for gout include metabolic syn-
drome (p. 805), high alcohol intake (predominantly beer,
which contains guanosine), generalised osteoarthritis, a
diet relatively high in red meat or fructose or relatively
low in vitamin C or coffee, and lead poisoning (satur-
nine gout). The association between OA and gout is
thought to be due to reduction in levels of proteoglycan
and other inhibitors of crystal formation in osteoarthritic
cartilage, predisposing to crystal formation.
Some patients develop gout because they over-
produce uric acid. The mechanisms are poorly under-
stood, except in the case of a few rare disorders, in which
gout is inherited in a Mendelian manner as the result of
mutations in genes responsible for purine synthesis (see
Box 25.43). Lesch–Nyhan syndrome for example, is an
X-linked recessive form of gout that is also associated
with mental retardation, self-mutilation and choreo-
athetosis. Such conditions should be suspected if other
clinical features are present or there is an early age at
onset with a positive family history. Severe hyperuricae-
mia can also occur in patients with leukaemia undergo-
ing chemotherapy due to increased purine turnover.
Clinical features
The classical presentation is with an acute monoarthritis,
which in over 50% of cases affects the first MTP joint
(Fig. 25.24). Other common sites are the ankle, midfoot,
knee, small joints of hands, wrist and elbow. The axial
skeleton and large proximal joints are rarely involved.
Typical features include:
• rapid onset, reaching maximum severity in
2–6 hours, and often waking the patient in the
early morning
Fig. 25.24 Podagra. Acute gout causing swelling, erythema and extreme
1088 pain and tenderness of the first metatarsophalangeal joint.
• severe pain, often described as the ‘worst pain ever’
• extreme tenderness, such that the patient is unable
to wear a sock or to let bedding rest on the joint
• marked swelling with overlying red, shiny skin
• self-limiting over 5–14 days, with complete
resolution.
During the attack, the joint shows signs of marked
synovitis, swelling and erythema. There may be accom-
panying fever, malaise and even confusion, especially if
a large joint such as the knee is involved. As the attack
subsides, pruritus and desquamation of overlying skin
are common. The main differential diagnosis is septic
arthritis, infective cellulitis or reactive arthritis. Acute
attacks may also manifest as bursitis, tenosynovitis or
cellulitis, which have the same clinical characteristics.
Many patients describe milder episodes lasting just a
few days. Some have attacks in more than one joint.
Others have further attacks in other joints a few days
later (cluster attacks), the first possibly acting as a trigger.
Simultaneous polyarticular attacks are unusual.
Some people never have a second episode after an
acute attack. In others, several years may elapse before
the next attack. In many, however, a second attack
occurs within 1 year and may progress to chronic gout,
with chronic pain and joint damage, and occasionally
severe deformity and functional impairment. Patients
with uncontrolled hyperuricaemia who suffer multiple
attacks of acute gout may also progress to chronic gout.
Crystals may be deposited in the joints and soft
tissues to produce irregular firm nodules called tophi.
These have a predilection for the extensor surfaces of
fingers, hands, forearm, elbows, Achilles tendons and
sometimes the helix of the ear. Tophi have a white
colour, differentiating them from rheumatoid nodules
(Fig. 25.25). Tophi can ulcerate, discharging white gritty
material, become infected or induce a local inflamma-
tory response, with erythema and pus in the absence
of secondary infection. They are usually a feature of
long-standing gout but can sometimes develop within
Fig. 25.25 Tophus with white monosodium urate monohydrate
crystals visible beneath the skin. Diuretic-induced gout in a patient
with pre-existing nodal OA.
 Crystal-induced arthritis

12 months in patients with chronic renal failure. Occa-
sionally, tophi may develop in the absence of previous
acute attacks, especially in patients on thiazide therapy
who have coexisting OA.
In addition to causing musculoskeletal disease,
chronic hyperuricaemia may be complicated by renal
stone formation (p. 507) and, if severe, renal impairment
due to the development of interstitial nephritis as the
result of urate deposition in the kidney. This is particu-
larly common in patients with chronic tophaceous gout
who are on diuretic therapy.
Investigations
The diagnosis of gout can be confirmed by the identifica-
tion of urate crystals in the aspirate from a joint, bursa
or tophus (see Fig. 25.5A, p. 1064). In acute gout, syno-
vial fluid shows increased turbidity due to the greatly
elevated cell count (> 90% neutrophils). In chronic gout,
the appearance is more variable but occasionally the
fluid appears white due to the high crystal load. Between
attacks, aspiration of an asymptomatic first MTP joint or
knee may still reveal crystals.
A biochemical screen, including renal function, uric
acid, glucose and lipid profile, should be performed
because of the association with metabolic syndrome.
Although hyperuricaemia is usually present, this does
not confirm the diagnosis. Conversely, normal uric acid
levels during an attack do not exclude gout, as serum
urate falls during the acute phase response. Elevated
ESR and CRP and a neutrophilia are typical of acute
gout, and they return to normal as the attack subsides.
Tophaceous gout may be accompanied by a modest but
chronic elevation in ESR and CRP.
Radiographs are usually normal in acute gout but
well-demarcated erosions may be seen in patients with
chronic or tophaceous gout (Fig. 25.26). Tophi may also
be visible on X-rays as soft tissue swellings. In late
disease, destructive changes may occur similar to those
in other forms of advanced inflammatory arthritis.
Management
Oral NSAIDs are effective for pain relief in the acute
attack and are the standard treatment, but have to be
prescribed with caution in old age. Local ice packs can
also be used for symptomatic relief. Patients with recur-
rent episodes can keep a supply of an NSAID and take
it as soon as the first symptoms occur, continuing until
the attack resolves. Oral colchicine, which works by
inhibiting microtubule assembly in neutrophils, is also
very effective. It is usually given in doses of 0.5 mg twice
or 3 times daily. The most common adverse effects are
nausea, vomiting and diarrhoea. Joint aspiration can
give pain relief, and may be combined with an intra-
articular steroid injection if the diagnosis is clear and
infection can be excluded. A short course of oral or intra-
muscular corticosteroids can also be highly effective in
treating acute attacks.
Patients who have more than one acute attack within
12 months and those with complications should be
offered urate-lowering therapy (Box 25.44). The long-
term therapeutic aim is to prevent attacks occurring by
bringing uric acid levels below the level at which mono-
sodium urate monohydrate crystals form. A therapeutic
target of 360 μmol/L (6 mg/dL) is recommended in the
British Society of Rheumatology guidelines, whereas the
European League Against Rheumatism guidelines rec-
ommend a threshold of 300 μmol/L (5 mg/dL).
Allopurinol is the drug of first choice. It is a xanthine
oxidase inhibitor, which reduces the conversion of
hypoxanthine and xanthine to uric acid. The recom-
mended starting dose is 100 mg daily, or 50 mg in older
25
patients and in renal impairment. The dose of allopuri-
nol should be increased by 100 mg every 4 weeks (50 mg
in the elderly and those with renal impairment) until the
target uric acid level is achieved, side-effects occur or the
maximum recommended dose is reached (900 mg/day).
Acute flares of gout often occur following initiation of
urate-lowering therapy. The patient should be warned
about this and told to continue therapy, even if an attack
occurs. The risk of flares can be reduced by administra-
tion of oral colchicine (0.5 mg twice daily) or NSAID
therapy for the first few months. In the longer term,
annual monitoring of uric acid levels is recommended.
In most patients, urate-lowering therapy needs to be
continued indefinitely.
Febuxostat is a xanthine oxidase inhibitor that is
useful in patients who fail to respond adequately to
allopurinol, and those in whom it is contraindicated or
has been poorly tolerated. It undergoes hepatic metabo-
lism and so no dose adjustment is required for renal
impairment. It is more effective than allopurinol at
reducing uric acid levels and, as a result, commonly
provokes attacks at the recommended starting dose
(80 mg daily). In view of this, treatment with colchicine
or NSAID should be considered for the initial 6 months.
Uricosuric drugs, such as probenecid or sulfinpyra-
zone, can be effective but require several doses each
day and maintenance of a high urine flow to avoid uric

25.44 Indications for urate-lowering drugs

• Recurrent attacks of
acute gout
• Tophi
Fig. 25.26 Erosive arthritis in chronic gout. Punched-out erosions • Evidence of bone or joint
are visible (arrows), in association with a destructive arthritis affecting the damage
first metatarsophalangeal joint.
• Renal impairment
• Nephrolithiasis
• Very high levels of serum
uric acid
1089
 RHEUMATOLOGY AND BONE DISEASE
25 25.45 Gout in old age
• Aetiology: a higher proportion of older patients have gout
secondary to diuretic use and chronic kidney disease. Gout
is often associated with OA.
• Presentation: may be atypical, with painful tophi and chronic
symptoms, rather than acute attacks. Joints of the upper
limbs are more frequently affected.
• Management: acute attacks are best treated by aspiration
and intra-articular injection of corticosteroids, followed by
early mobilisation. NSAID and colchicine should be used with
caution because of increased risk of toxicity. Low doses of
allopurinol (50 mg/day) should be given, and increased
gradually to avoid toxicity.
acid crystallisation in renal tubules. Salicylates antago-
nise the uricosuric action of these drugs and should
be avoided. Uricosurics are contraindicated in over-
producers, those with renal impairment and in urolithi-
asis (they increase stone formation). The uricosuric
benzbromarone can be very effective and safe in mild to
moderate renal impairment, but can cause hepatotoxic-
ity. It is not licensed in the UK for the treatment of
hyperuricaemia.
Pegloticase is a biological treatment in which the
enzyme uricase has been conjugated to monomethoxy-
polyethylene glycol. It is indicated for the treatment of
tophaceous gout resistant to standard therapy and is
administered as an intravenous infusion every 2 weeks
for up to 6 months. It is highly effective at controlling
hyperuricaemia and causes regression of tophi. The
main adverse effects are infusion reactions (which can
be treated with antihistamines or steroids) and flares of
gout during the first 3 months of therapy. A limiting
factor for longer-term treatment is the development of
antibodies to pegloticase, which occur in a high propor-
tion of cases and are associated with an impaired thera-
peutic response.
In addition to drug treatment, predisposing factors
should be corrected if possible. Patients should be
advised to lose weight where appropriate and to reduce
excessive alcohol intake, especially beer. Thiazide diu-
retics should be stopped if possible and substituted with
angiotensin-converting enzyme (ACE) inhibitors, as
these have a uricosuric effect. Patients should be advised
to avoid large amounts of seafood and offal, which have
a high purine content, but a highly restrictive diet is not
necessary.
Calcium pyrophosphate dihydrate
crystal deposition disease
This condition is associated with deposition of calcium
pyrophosphate dihydrate (CPPD) crystals within articu-
lar and hyaline cartilage and is sometimes known as
‘pseudogout’. It is rare under the age of 55, but occurs
in 10–15% of people between the ages of 65 and 75 years
and in 30–60% of those over 85. The knee (hyaline carti-
lage and menisci) is by far the most common site, fol-
lowed by the wrist (triangular fibrocartilage) and pelvis
(symphysis pubis). Risk factors are shown in Box 25.46.
1090 In many patients, chondrocalcinosis is asymptomatic
25.46 Risk factors for chondrocalcinosis
Common
• Age
• Osteoarthritis*
• Primary hyperparathyroidism
Rare
• Familial*
• Haemochromatosis*
• Hypophosphatasia
• Hypomagnesaemia
• Wilson’s disease
*May be associated with structural damage to affected joints.
O
H
M N
Fig. 25.27 Chondrocalcinosis of the knee. The X-ray shows
calcification of the fibrocartilaginous menisci (M) and articular hyaline
cartilage (H). There is also narrowing (N) and osteophyte (O) of the medial
tibio-femoral compartment.
and an incidental finding on X-ray examination, but
others present with an acute inflammatory arthritis
(pseudogout) or a chronic inflammatory arthropathy
superimposed on a background of OA, especially at the
knee (Fig. 25.27), associated with joint damage and func-
tional limitation.
Pathophysiology
The underlying mechanisms of crystal deposition are
poorly understood. Clinical studies have shown that
pyrophosphate levels are raised in patients with
CPPD crystal deposition disease, possibly due to
over-production, but why this occurs is unclear. In
hypophosphatasia, the predisposing factor is thought to
be impaired degradation of pyrophosphate due to muta-
tions in the genes that encode ALP. OA is thought to
predispose to CPPD crystal deposition disease because
of a reduction in the amounts of proteoglycan and other
natural inhibitors of crystal formation in the abnormal
cartilage.
Clinical features
A common presentation is with an acute inflammatory
arthritis that resembles acute gout, sometimes termed
‘pseudogout’. Examination reveals a warm, tender
 Crystal-induced arthritis

erythematous joint with signs of a large effusion. Fever 25.47 Rheumatic diseases associated with
is common and the patient may appear confused and ill. basic calcium phosphate deposition
The knee is most commonly affected, followed by the
Disease Site of calcification
wrist, shoulder, ankle and elbow. Trigger factors include
trauma, intercurrent illness and surgery. Sepsis and gout Calcific periarthritis Tendons and ligaments
are the main differential diagnoses. Dermatomyositis and Subcutaneous tissue
Chronic arthropathy may also occur in association polymyositis
with CPPD crystal deposition disease, affecting the same Systemic sclerosis and Subcutaneous tissue
joints that are involved in acute pseudogout. The pres- CREST syndrome
entation is with chronic pain, early morning stiffness,
inactivity gelling and functional impairment. Acute Mixed connective tissue Subcutaneous tissue
attacks of pseudogout may be superimposed. Affected disease
joints usually show features of OA, with varying degrees Paget’s disease of bone Blood vessels
of synovitis. Effusion and synovial thickening are Ankylosing spondylitis Ligaments
usually most apparent at knees and wrists; wrist involve-
Fibrodysplasia ossificans Subcutaneous tissues and muscle
ment may result in carpal tunnel syndrome. Inflamma-
progressiva
tory features may be sufficiently pronounced to suggest
RA, but tenosynovitis and extra-articular involvement Milwaukee shoulder Tendons and ligaments
are absent, and large and medium rather than small syndrome
joints are targeted. Severe damage and instability of Albright’s hereditary Muscle
knees or shoulders may occasionally lead to considera- osteodystrophy
tion of a neuropathic joint, but no neurological abnor-
malities will be found. (CREST = calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly,
telangiectasia)
Investigations
Examination of synovial fluid using compensated polar-
ised microscopy will demonstrate CPPD crystals (see
Fig. 25.5B, p. 1064) and permit distinction from gout. The
Pathophysiology 25
Under normal circumstances, inhibitors of mineralisa-
aspirated fluid is often turbid and may be uniformly tion, such as pyrophosphate and proteoglycans, inhibit
blood-stained, reflecting the severity of inflammation. calcification of soft tissues. When these protective mech-
Since sepsis and pseudogout can coexist, Gram stain anisms break down, abnormal calcification occurs. There
and culture of the fluid should be performed to are many causes (Box 25.47). In most situations, calcifica-
exclude sepsis, even if CPPD crystals are identified in tion is of no consequence, but when the crystals are
synovial fluid. released, an inflammatory reaction may be initiated,
X-rays of the affected joint may show evidence of causing local pain and inflammation.
calcification in hyaline cartilage and/or fibrocartilage,
although absence of calcification does not exclude the Calcific periarthritis
diagnosis. Signs of OA are frequently present. Screening
Deposition of BCP in tendons may result in an acute
for secondary causes (see Box 25.46) should be under-
inflammatory response. The most commonly affected
taken, especially in patients who present under the age
site is the supraspinatus tendon (Fig. 25.28) but other
of 25 and those with polyarticular disease.
sites may also be affected, including the tendons around
Management the hip, feet and hands. The presentation is with acute
pain, swelling and local tenderness that develops rapidly
Joint aspiration can often provide symptomatic relief in
pseudogout and sometimes no further treatment is
required. Patients with persistent symptoms can be
treated with intra-articular corticosteroids, colchicine
or NSAID. Since most patients with pseudogout are
elderly, NSAID must be used with caution. Early active
mobilisation is also important. Chronic pyrophosphate-
induced arthropathy should be managed as for OA
(p. 1085).

Basic calcium phosphate

deposition disease
Basic calcium phosphate (BCP) deposition disease is
caused by the deposition of hydroxyapatite or apatite
crystals and other basic calcium phosphate salts (octa-
calcium phosphate, tricalcium phosphate) in soft tissues.
The main affected sites are tendons, ligaments and
hyaline cartilage in patients with degenerative disease,
and skeletal muscle and subcutaneous tissues in connec- Fig. 25.28 Shoulder X-ray showing supraspinatus tendon
tive tissue diseases. calcification (arrow). 1091
 RHEUMATOLOGY AND BONE DISEASE
25 over 4–6 hours. The overlying skin may be hot and red,
raising the possibility of infection. Attacks sometimes
occur spontaneously but can also be triggered by trauma.
Modest systemic upset and fever are common. X-rays
show tendon calcification. If the affected joint or bursa
is aspirated, inflammatory fluid containing many
calcium-staining (alizarin red S) aggregates may be
obtained. During an acute attack, there may be a neu-
trophilia with an elevation in ESR and CRP. Routine
biochemistry is normal. Treatment is with analgesics
and NSAID. Attacks may also respond to a local injec-
tion of corticosteroid. The condition usually resolves
spontaneously over 1–3 weeks and this is often accom-
panied by dispersal and disappearance of small to
medium-sized BCP deposits on X-ray. Large deposits
sometimes accumulate, causing limitation of joint move-
ment, and may require surgical removal.
Acute inflammatory arthritis
Deposition of BCP occurs commonly in OA, both alone
and in combination with CPPD crystals, when it is
referred to as mixed crystal deposition disease. It may
present with pseudogout or be an incidental finding.
Milwaukee shoulder syndrome
This is a rare syndrome, in which extensive deposition
of BCP crystals in large joints is associated with progres-
sive joint destruction. It is more common in women than
in men. The onset is gradual with joint pain, sometimes
precipitated by injury or overuse. The disease progresses
over a few months to cause severe pain and disability,
associated with joint destruction. X-rays show joint
space narrowing, osteophytes and calcification. Aspira-
tion yields large volumes of relatively non-inflammatory
fluid containing abundant BCP aggregates and often
cartilage fragments. The differential diagnosis is end-
stage avascular necrosis, chronic sepsis or neuropathic
joint. There is no acute phase response and synovial
fluid cultures are negative.
Treatment is with analgesics, intra-articular injection
of corticosteroids, local physical treatments and physio-
therapy. The clinical outcome is poor, however, and
most patients require joint replacement. The cause is
incompletely understood but it has been speculated that
deposition of BCP crystals activates collagenase and
other proteases in articular cells, which are responsible
for the tissue damage.
Connective tissue disease
Deposition of BCP may occur in the subcutaneous
tissues and muscle of patients with scleroderma and
other connective tissue disease. Usually, the deposits are
asymptomatic but can be associated with pain and local
ulceration. There is no specific treatment.
FIBROMYALGIA
This is a common cause of generalised regional pain and
disability, and is frequently associated with medically
unexplained symptoms in other systems (p. 236). The
prevalence in the UK and US is about 2–3%. Although
fibromyalgia can occur at any age, including adoles-
cence, it increases in prevalence with age, to reach a peak
1092 of 7% in women aged over 70. There is a strong female
25.48 Predisposing factors for fibromyalgia
‘Epidemiological studies show that widespread body pain,
fatigue, psychological distress and multiple hyperalgesic tender
sites cluster together and associate with stressful life events.’
• Wolfe F, et al. Arthritis Rheum 1995; 38:19–28.
• Croft P, et al. BMJ 1994; 309:696–699.
Regional pain Disease Anxiety
syndrome Illness Life crisis
Sleep disturbance
Non-restorative sleep
Pain
Reduced activity
Fatigue
Poor aerobic
fitness Functional
disturbance
Fig. 25.29 Possible causative mechanisms in fibromyalgia.
predominance of around 10 : 1. Risk factors include life
events that cause psychosocial distress, such as marital
disharmony, alcoholism in the family, injury or assault,
low income and self-reported childhood abuse (Box
25.48). It occurs in a wide variety of races and cultures.
Pathophysiology
The cause of fibromyalgia is poorly understood but two
abnormalities that may be interrelated (Fig. 25.29) have
been consistently reported in affected patients.
Sleep abnormality
Delta waves are characteristic of deep stages of
non-rapid eye movement (non-REM) sleep, usually
occurring in the first few hours and thought to have an
important restorative function. People with fibromyal-
gia have reduced delta sleep in a pattern distinct from
that seen with depression. Furthermore, deprivation of
delta but not REM sleep in normal volunteers produces
the symptoms and signs of fibromyalgia, supporting it
as a non-restorative sleep disorder.
Abnormal peripheral and central pain processing
A reduced threshold of pain perception and tolerance at
characteristic sites throughout the body is characteristic
of fibromyalgia. Affected people have peripheral sensi-
tisation and spinal cord ‘wind-up’ (pain amplification),
with an exaggerated skin flare response to topically
applied capsaicin, and frequent occurrence of dermato-
graphism and allodynia (normally non-noxious stimuli
become painful). Abnormal central pain processing is
suggested by altered cerebrospinal fluid levels of sub-
stance P (increased) and serotonin (reduced); reduced
basal levels of regional cerebral blood flow in the
 Fibromyalgia

caudate and thalamus with an augmented processing they may be unable to perform tasks such as shopping
response on functional MRI; low basal free cortisol and or housework. They may have experienced major
reduction in evening trough; and altered descending difficulties at work or even retire because of pain
inhibition via the hypothalamic–pituitary–adrenal and and fatigue.
growth hormone somatomedin axes. Examination is unremarkable, apart from the pres-
ence of hyperalgesia on moderate digital pressure in
Clinical features multiple sites (Fig. 25.30). The tenderness can be quan-
The main presenting feature is widespread pain, which titated using metered dolorimeters but moderate digital
is often worst in the neck and back (Box 25.49). The pain pressure, enough just to whiten the nail, is sufficient for
is characteristically diffuse and unresponsive to analge- clinical diagnosis. Patients with other musculoskeletal
sics and NSAID. Physiotherapy often makes it worse. diseases can develop fibromyalgia and it is important to
Fatiguability, most prominent in the morning, is another determine to what extent symptoms are related to fibro-
major problem and disability is often marked. Although myalgia or a coexisting disease.
people can usually dress, feed and groom themselves,
Investigations and management
There are no abnormalities on routine blood tests or
25.49 Clinical features in fibromyalgia imaging, but it is important to screen for other condi-
tions that could contribute to some of the patient’s
Usual symptoms symptoms (Box 25.50).
• Multiple regional pain • Low affect, irritability, The aims of management are to educate the patient
• Marked fatigability weepiness about the condition, achieve pain control and improve
• Marked disability • Poor concentration, sleep. Wherever possible, education should include the
• Broken, non-restorative forgetfulness
sleep
Variable locomotor symptoms 25.50 Minimum investigation screen in
fibromyalgia
• Early morning stiffness
• Swelling of hands, fingers
• Numbness, tingling of all
fingers Test Condition screened 25
Additional, variable, non-locomotor symptoms Full blood count Anaemia, lymphopenia of SLE
• Non-throbbing bifrontal headache (tension headache) Erythrocyte sedimentation Inflammatory disease
• Colicky abdominal pain, bloating, variable bowel habit rate, C-reactive protein
(irritable bowel syndrome) Thyroid function Hypothyroidism
• Bladder fullness, nocturnal frequency (irritable bladder)
• Hyperacusis, dyspareunia, discomfort when touched Calcium, alkaline Hyperparathyroidism,
(allodynia) phosphatase osteomalacia
• Frequent side-effects with drugs (chemical sensitivity) Antinuclear antibodies SLE

Skin-fold rolling Interspinous

of mid-trapezius ligaments C5–7
Second/third
costochondral Mid-supraspinatus
junctions

Interspinous
ligaments L4/5

1 cm distal to
lateral epicondyle Mid-gluteal

Medial fat pad

(upper medial tibia)

Fig. 25.30 Typical tender spots in fibromyalgia. 1093

 RHEUMATOLOGY AND BONE DISEASE
25 spouse, family or carer. It should be acknowledged that
the cause of fibromyalgia is not fully understood but the
widespread pain does not reflect inflammation, tissue
damage or disease. The model of a self-perpetuating
cycle of poor sleep and pain (see Fig. 25.29) is a useful
framework for problem-based management. Under-
standing the diagnosis can often help the patient come
to terms with the symptoms. Repeat or drawn-out inves-
tigation may reinforce beliefs in occult serious pathology
and should be avoided.
Low-dose amitriptyline (10–75 mg at night), with or
without fluoxetine, may help by encouraging delta sleep
and reducing spinal cord wind-up. Many people with
fibromyalgia, however, are intolerant of even small
doses of amitriptyline. There is limited evidence for
the use of tramadol, serotonin–noradrenaline (norepi-
nephrine) re-uptake inhibitors (SNRIs) such as duloxet-
ine, and the anticonvulsants pregabalin and gabapentin.
A graded increase in aerobic exercise can improve well-
being and sleep quality. The use of self-help strategies
and a cognitive behavioural approach with relaxation
techniques should be encouraged. Sublimated anxiety
relating to distressing life events should be specifically
explored with appropriate counselling. There are patient
organisations that provide additional information and
support.
The prognosis for hospital-diagnosed fibromyalgia is
poor. Although treatment may improve quality of life
and ability to cope, most people do not lose their symp-
toms over 5 years. Subjects diagnosed in primary care,
or who have sublimated anxiety that can be successfully
addressed, may fare better.
BONE AND JOINT INFECTION
Septic arthritis
Septic arthritis is the most rapid and destructive joint
disease, and is associated with significant morbidity and
a mortality of 10%. This has not improved over the last
20 years, despite advances in antimicrobial therapy. The
incidence is 2–10 per 100 000 in the general population,
and 30–70 per 100 000 in those with pre-existing joint
disease or joint replacement.
Septic arthritis is usually due to haematogenous
spread from either skin or upper respiratory tract; infec-
tion from direct puncture wounds or secondary to joint
aspiration is uncommon. Risk factors include increasing
age, pre-existing joint disease (principally RA), diabetes
mellitus, immunosuppression (by drugs or disease) and
intravenous drug misuse. In RA, the skin is a frequent
portal of entry because of maceration of skin between
the toes due to joint deformity and difficulties with foot
hygiene due to hand deformity. Box 25.51 describes the
particular considerations in old age.
Clinical features
The usual presentation is with acute or subacute mono-
arthritis and fever. The joint is usually swollen, hot
and red, with pain at rest and on movement. Although
any joint can be affected, lower limb joints, such as
the knee and hip, are commonly targeted. Patients with
pre-existing arthritis may present with multiple joint
1094 involvement.
25.51 Joint and bone infection in old age
• Vertebral infection: more common. Recognition may be
delayed, as symptoms may be attributed to compression
fractures caused by osteoporosis.
• Peripheral vascular disease: leads to more frequent
involvement of the bones of the feet, and diabetic foot ulcers
are also commonly complicated by osteomyelitis.
• Prosthetic joint infections: now more common because of
the increased frequency of prosthetic joint insertion in older
people.
• Gram-negative bacilli: more frequent pathogens than in
younger people.
In adults, the most likely organism is Staphylococcus
aureus, particularly in patients with RA and diabetes. In
young, sexually active adults, disseminated gonococcal
infection occurs in up to 3% of untreated gonorrhoea,
usually presenting with migratory arthralgia, low-grade
fever and tenosynovitis, which may precede the devel-
opment of oligo- or monoarthritis. Painful pustular skin
lesions may also be present. Amongst the elderly and
intravenous drug users, Gram-negative bacilli or group
B, C and G streptococci are important causes. Group A
streptococci, pneumococci, meningococci and Haemo-
philus influenzae are occasionally isolated.
Investigations
The pivotal investigation is joint aspiration but blood
cultures should also be taken. The synovial fluid is
usually turbid or blood-stained but may appear normal.
If the joint is not readily accessible, aspiration should be
performed under imaging guidance or in theatre. Pros-
thetic joints should only be aspirated in theatre.
Synovial fluid should be sent for Gram stain and
culture; cultures are positive in around 90% of cases, but
the Gram stain is positive in only 50%. In contrast, syno-
vial fluid culture is positive in only 30% of gonococcal
infections, making it important to obtain concurrent cul-
tures from the genital tract (positive in 70–90% of cases).
There is a leucocytosis with raised ESR and CRP in most
patients, but these features may be absent in elderly or
immunocompromised patients, or early in the disease
course. Serial measurements of CRP and ESR are useful
in following the response to treatment.
Management
The principles of management are summarised in Box
25.52. The patient should be admitted to hospital for
pain relief and administration of parenteral antibiotics.
Flucloxacillin (2 g IV 4 times daily) is the antibiotic of
first choice pending the results of cultures, since it will
cover most staphylococcal and streptococcal infections.
If there is reason to suspect a Gram-negative infection,
then a cephalosporin or gentamicin should be added.
Microbiology advice should be sought in complicated
situations such as intravenous drug users, patients in
intensive care and those who might be colonised by
resistant organisms. It is traditional to continue intra-
venous antibiotics for 2 weeks and to follow this with
oral treatment for another 4 weeks, but there is no evi-
dence to support the optimal duration of treatment. Joint
aspiration should be performed using a large-bore
needle once or twice daily. If this is not possible,

25.52 Emergency management of suspected
septic arthritis
Admit patient to hospital
Perform urgent investigations
• Aspirate joint
Send synovial fluid for Gram stain and culture
Use imaging guidance if required (e.g. for hip)
• Send blood for culture, routine biochemistry and
haematology, including ESR and CRP
• Consider sending other samples (sputum, urine, wound
swab) for culture, depending on patient history, to determine
primary source of infection
Commence intravenous antibiotic
• Flucloxacillin 2 g 4 times daily
• If penicillin-allergic, give clindamycin 450–600 mg 4 times
daily
• If at high risk of Gram-negative sepsis (elderly, frail,
recurrent urinary tract infection), add a cephalosporin
(cefuroxime 1.5 g 3 times daily)
Relieve pain
• Oral and/or intravenous analgesics
• Consider local ice-packs
Aspirate joint
• Perform serial needle aspiration to dryness (1–3 times/day or
as required)
• Consider arthroscopic drainage if needle aspiration difficult
Arrange physiotherapy
• Early regular passive movement, progressing to active
movements once pain controlled and effusion not
re-accumulating
arthroscopic or open surgical drainage may need to be
undertaken. Regular passive movement should be
undertaken from the outset, and active movements
encouraged once the condition has stabilised. Infected
prosthetic joints require management by the orthopae-
dic team, but often prolonged antibiotic treatment on its
own is ineffective and removal of the prosthesis is
required for eradication of the infection.
Arthritis may be a feature of Lyme disease caused by
members of the Borrelia species of microorganisms. It
is generally a late manifestation, which usually affects
large joints. Brucellosis presents with an acute febrile
illness, followed in some cases by the development of
localised infection, which can result in arthritis, bursitis,
osteomyelitis, sacroiliitis and paravertebral or psoas
abscesses. These conditions are discussed on pages 332
and 333.
Viral arthritis
The usual presentation is with acute polyarthritis, fol-
lowing a febrile illness, which may be accompanied by
a rash. Most cases of viral arthritis are self-limiting and
settle down within 4–6 weeks. Human parvovirus
(mainly B19, p. 315) arthropathy is the most common in
Europe; adults may not have the characteristic ‘slapped
cheek’ facial rash seen in children. The diagnosis can be
confirmed by a rise in specific IgM. Polyarthritis may
also occur rarely with hepatitis B and C, rubella (includ-
ing rubella vaccination) and HIV infection. A variety of
Bone and joint infection
25.53 Musculoskeletal manifestations of HIV
mosquito-borne viruses may cause epidemics of acute
polyarthritis, including Ross River (Australia, Pacific),
Chikungunya and O’nyongnyong (Asia, Africa), and
Mayaro viruses (South America). A wide variety of
articular symptoms have been associated with HIV,
mainly in the later stages of infection (Box 25.53). Man-
agement is symptomatic, with NSAID and analgesics.
Osteomyelitis
In osteomyelitis, the primary site of infection is bone and
bone marrow. Any part of a bone may be involved but 25
there is preferential targeting of the juxta-epiphyseal
regions of long bones adjacent to joints. The usual source
is through haematogenous spread, although directly
introduced infection may complicate trauma or ortho-
paedic surgery. The organisms most frequently impli-
cated are staphylococci, Pseudomonas and Mycobacterium
tuberculosis. Osteomyelitis occurs most commonly in
childhood and adolescence. Risk factors include diabe-
tes mellitus (especially involving the foot), compromised
immunity (including AIDS) and sickle cell disease,
which particularly increases the risk of Salmonella infec-
tion. The infection often results in a florid inflammatory
response, with a greatly increased intraosseous pres-
sure. If untreated, the condition may cause localised
areas of osteonecrosis, leading to the development of a
fragment of necrotic bone that is called a sequestrum.
Eventual perforation of the cortex by pus stimulates
local new bone formation (involucrum) in the peri-
osteum, often leading to the development of sinuses that
discharge through the skin.
Clinical features and investigations
The presentation is with localised bone pain and tender-
ness, often accompanied by malaise, night sweats and
pyrexia. The adjacent joint may be painful to move and
may develop a sterile effusion or secondary septic arthri-
tis. X-rays may show evidence of osteopenia, localised
osteolysis and osteonecrosis, but the imaging modality
of choice is MRI, which is much more sensitive for
detecting early changes. Cultures should be performed,
where possible, by open or imaging-guided biopsy.
Blood cultures should be taken, which may also reveal
the causative organism.
Management
Early recognition and management is critical; once
osteomyelitis becomes established and chronic, it
may prove very hard to eradicate the infection with 1095
 RHEUMATOLOGY AND BONE DISEASE
25 antibiotics alone. The principles are those followed for
septic arthritis, with parenteral antibiotics for at least
2 weeks, followed by oral antibiotics for at least 4 weeks.
Resection of the infected bone and subsequent recon-
struction are often required. Complications of chronic
osteomyelitis include secondary amyloidosis (p. 86) and
skin malignancy at the margin of a discharging sinus
(Marjolin’s ulcer).
Tuberculosis
Tuberculosis can affect the musculoskeletal system,
usually targeting the spine (Pott’s disease) or large joints
such as the hip, knee or ankle. The presentation is with
pain, swelling and fever. The X-ray changes are non-
specific and mycobacteria are seldom identified in the
synovial fluid, so tissue biopsy is required for a definite
diagnosis. Medical management is described on page
693. In some cases, surgical débridement may be required
for extensive joint disease, and spinal involvement may
require surgical stabilisation and decompression.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is the most common persist-
ent inflammatory arthritis, occurring throughout the
world and in all ethnic groups. The prevalence is lowest
in black Africans and Chinese, and highest in Pima
Indians. In Caucasians, approximately 0.8–1.0% are
affected, with a female to male ratio of 3 : 1. The clinical
course is prolonged, with intermittent exacerbations and
remissions. Patients with RA have an increased mortal-
ity when compared with age-matched controls, prima-
rily due to an increased risk of cardiovascular disease.
This is most marked in those with severe disease, with
a reduction in expected lifespan by 8–15 years. Around
40% of RA patients are registered as disabled within
3 years of onset, and around 80% are moderately to
severely disabled within 20 years. Functional capacity
decreases most rapidly at the beginning of disease and
the functional status of patients within their first year of
RA is often predictive of long-term outcome. Factors that
associate with a poorer prognosis are disability at pres-
entation, female gender, involvement of MTP joints,
radiographic damage at presentation, smoking and a
positive RF or ACPA. It is likely that the prognosis of
RA will improve as more effective treatment regimens
are introduced in patients with early disease. In former
years, around 25% of patients required a large joint
replacement but rates are now falling, probably reflect-
ing more aggressive and effective medical therapy.
Pathophysiology
Genetic, epigenetic and environmental factors are impli-
cated in the pathogenesis of RA. The concordance
rate of RA is higher in monozygotic (12–15%) than in
dizygotic twins (3%), and there is an increased frequency
of disease in first-degree relatives of patients. Genome-
wide association studies have detected more than 30 loci
that are associated with the risk of developing RA or
1096 with severity of disease once it is established. Many of
the risk genes are involved in the function of the immune
system, and include major histocompatibility complex
(MHC) class II, PTPN22, CD40L and CTLA4. The MHC
class II gene, HLA-DR4, is the major susceptibility haplo-
type in most ethnic groups, occurring in 50–75% of Cau-
casian patients with RA, compared to 20–25% of the
normal population. However, DR1 is more important in
Indians and Israelis, and DW15 in Japanese. It has long
been thought that RA may be triggered by an infectious
agent in a genetically susceptible host, but a specific
pathogen has not been identified. Periodontal disease
and oral pathogens have been implicated, as have gas-
trointestinal organisms, and viruses such as Epstein–
Barr and cytomegalovirus. Cigarette smoking is a strong
risk factor for developing RA, especially in people with
HLA-DR4, and is also associated with greater disease
severity and reduced responsiveness to DMARD and
biological treatment. Susceptibility is increased post-
partum and by breastfeeding, indicating that hormone/
immune interactions may be important.
The clinical onset of RA is characterised by infiltration
of the synovial membrane with lymphocytes, plasma
cells, dendritic cells and macrophages. CD4+ T lym-
phocytes, including Th1 cells (interferon-gamma (IFN-γ)
producers) and Th17 cells (IL-17A, IL-17F and IL-22 pro-
ducers), play a central role by interacting with other cells
in the synovium. Lymphoid follicles form within the
synovial membrane in which T cell–B cell interactions
lead B cells to produce cytokines and autoantibodies,
including RF and ACPA. Synovial macrophages are acti-
vated by immune complexes and local damage-associated
molecules acting via Toll-like receptors, to produce pro-
inflammatory cytokines, including TNF, IL-1, IL-6 and
IL-15. These act on synovial fibroblasts, to promote
swelling of the synovial membrane and damage to soft
tissues and cartilage. Fibroblasts, in particular, form a
rich source of inflammatory cytokines, chemokines,
leukotrienes and matrix metalloproteinases that drive
local tissue damage and remodelling. Similarly, activa-
tion of osteoclasts by RANKL and chondrocytes by
cytokines such as IL-1 and TNF drives destruction of
bone and cartilage respectively (Fig. 25.31). The RA joint
is hypoxic and this promotes new blood vessel formation
(neoangiogenesis). Thus the inflamed synovium becomes
vascularised, with highly activated endothelial cells sup-
porting the recruitment of yet more leucocytes to per-
petuate the inflammatory process. Amongst the range of
inflammatory mediators present in the RA joint, TNF
plays an important role by regulating production of
other cytokines, whose actions are shown in Figure 25.31,
and by activating the endothelium. IL-6 similarly plays
a critical inflammatory role within the joint and also in
regulating the systemic effects of RA by inducing the
acute phase response, anaemia of chronic disease, fatigue
and reduced cognitive function.
The inflammatory granulation tissue (pannus) formed
by the above sequence of events spreads over and under
the articular cartilage, which is progressively eroded
and destroyed. Maturation of osteoclasts in the synovial
membrane and in adjacent bone combine to erode bony
structures. Later, fibrous or bony ankylosis may occur.
Muscles adjacent to inflamed joints atrophy and may be
infiltrated with lymphocytes. This leads to progressive
biomechanical dysfunction and may further amplify
destruction.
 Rheumatoid arthritis

Abatacept
T cell Blood
Co-stimulation vessel Vasculitis
Antigen Vasodilatation
presentation Immune
complexes
Dendritic cell Rituximab
IL-6 PGE
B cell
Macrophage IL-17 Co-stimulation Autoantibodies
T cell
IL-1
TH17 Synovial IL-6
TNF fibroblast
Acute phase
response Tocilizumab IL-6 Plasma
cell

Denosumab RANKL ADAMTS5 TNF Anti-TNF

MMP

Cartilage
erosion
Cartilage
Chondrocyte

Bone
Osteoclast
erosion Bone 25

Fig. 25.31 Pathophysiology of rheumatoid arthritis. Some of the cytokines and cellular interactions believed to be important in RA are shown, along
with the targets for currently available biological drugs. (ADAMTS5 = aggrecanase; IL = interleukin; MMP = matrix metalloproteinases; PGE = prostaglandin
E; TNF = tumour necrosis factor; RANKL = RANK ligand)

Rheumatoid nodules consist of a central area of fibri-

25.54 Criteria for diagnosis of
noid material surrounded by a palisade of proliferating
rheumatoid arthritis*
mononuclear cells. Similar granulomatous lesions may
occur in the pleura, lung, pericardium and sclera. Lymph Criterion Score
nodes in RA are often hyperplastic, showing many lym- Joints affected
phoid follicles with large germinal centres and numer- 1 large joint 0
ous plasma cells in the sinuses and medullary cords. 2–10 large joints 1
Immunofluorescence confirms RF and ACPA synthesis
1–3 small joints 2
by plasma cells in synovium and lymph nodes. The bone
marrow in RA is similarly hyperplastic, with evidence 4–10 small joints 5
of lymphocyte activation and proliferation and local Serology
cytokine production. The bone marrow forms a selective Negative RF and ACPA 0
survival niche for plasma cells that, in turn, produce Low positive RF or ACPA 2
autoantibodies. Importantly, these plasma cells are
CD20-negative and, as such, escape therapies that target High positive RF or ACPA 3
CD20, such as rituximab (see below). Duration of symptoms
< 6 wks 0

Clinical features > 6 wks 1

Acute phase reactants
The typical presentation is with pain, joint swelling and Normal CRP and ESR 0
stiffness affecting the small joints of the hands, feet and Abnormal CRP or ESR 1
wrists. Large joint involvement, systemic symptoms
Patients with a score ≥ 6 are considered
and extra-articular features may also occur. Clinical cri-
to have definite RA.
teria for the diagnosis of RA are shown in Box 25.54.
Sometimes RA has a very acute onset, with florid *European League Against Rheumatism/American College of Rheumatology
morning stiffness, polyarthritis and pitting oedema. This 2010 Criteria.
(ACPA = anti-citrullinated peptide antibodies; CRP = C-reactive protein;
occurs more commonly in old age. Other patients may ESR = erythrocyte sedimentation rate; RF = rheumatoid factor)
present with proximal muscle stiffness mimicking 1097
 RHEUMATOLOGY AND BONE DISEASE

25 polymyalgia rheumatica (p. 1117). Occasionally, the

onset is palindromic, with relapsing and remitting epi-
with the cyst but is prevented from returning to the joint
by a valve-like mechanism. Rupture, often induced by
sodes of pain, stiffness and swelling that last for only a knee flexion in the presence of a large effusion, leads to
few hours or days. calf pain and swelling that may mimic a deep venous
Examination reveals typical features of symmetrical thrombosis (DVT).
swelling of the MCP and PIP joints. These and other joints
are tender on pressure when actively inflamed and have Extra-articular features
stress pain on passive movement. Erythema is unusual Anorexia, weight loss and fatigue are common and
and its presence suggests coexistent sepsis. Characteristic may occur throughout the disease course. Generalised
deformities may develop with long-standing uncon- osteoporosis and muscle-wasting result from systemic
trolled disease, including ‘swan neck’ deformity, the bou- inflammation. Extra-articular features are most common
tonnière or ‘button hole’ deformity, and a Z deformity of in patients with long-standing seropositive erosive
the thumb (Fig. 25.32B). Dorsal subluxation of the ulna at disease but may occasionally occur at presentation,
the distal radio-ulnar joint is common and may contrib- especially in men. Most are due to serositis, granuloma
ute to rupture of the fourth and fifth extensor tendons. and nodule formation or vasculitis (Box 25.55).
Triggering of fingers may occur because of nodules in the
flexor tendon sheaths. Deformities of the hand are less Cutaneous and vascular features
common now, as a result of more aggressive treatment. Rheumatoid nodules occur almost exclusively in sero-
In the foot, dorsal subluxation of the MTP joints may positive patients, usually at sites of pressure or friction,
result in ‘cock-up’ toe deformities. This causes pain on such as the extensor surfaces of the forearm (Fig. 25.33),
weight-bearing on the exposed MTP heads and develop- sacrum, Achilles tendon and toes. They may be compli-
ment of secondary adventitious bursae and callosities. cated by ulceration and secondary infection. Rheuma-
In the hindfoot, calcaneovalgus (eversion) is the most toid vasculitis may occur in older seropositive patients
common deformity, reflecting damage to the ankle and and is indicated by systemic symptoms (fatigue, fever)
subtalar joint. This is often associated with loss of the and multiple extra-articular features. Vasculitis can vary
longitudinal arch (flat foot) due to rupture of the tibialis
posterior tendon.
Popliteal (‘Baker’s’) cysts may occur in combination
with knee synovitis, where synovial fluid communicates 25.55 Extra-articular manifestations of
rheumatoid disease
Systemic
A • Fever • Fatigue
• Weight loss • Susceptibility to infection
Musculoskeletal
• Muscle-wasting • Bursitis
• Tenosynovitis • Osteoporosis
Haematological
• Anaemia • Eosinophilia
• Thrombocytosis
Lymphatic
• Felty’s syndrome • Splenomegaly
(see Box 25.56)
Nodules
• Sinuses • Fistulae
Ocular
B • Episcleritis • Scleromalacia
• Scleritis • Keratoconjunctivitis sicca
Vasculitis
• Digital arteritis • Mononeuritis multiplex
• Ulcers • Visceral arteritis
• Pyoderma gangrenosum
Cardiac
• Pericarditis • Conduction defects
• Myocarditis • Coronary vasculitis
• Endocarditis • Granulomatous aortitis
Pulmonary
• Nodules • Bronchiolitis
• Pleural effusions • Caplan’s syndrome
• Fibrosing alveolitis
Fig. 25.32 The hand in rheumatoid arthritis. A Ulnar deviation Neurological
of the fingers with wasting of the small muscles of the hands and • Cervical cord compression • Peripheral neuropathy
synovial swelling at the wrists, the extensor tendon sheaths, the • Compression neuropathies • Mononeuritis multiplex
metacarpophalangeal and proximal interphalangeal joints. B ‘Swan neck’ Amyloidosis (p. 86)
1098 deformity of the fingers.

Fig. 25.33 Rheumatoid nodules and olecranon bursitis. Nodules
were palpable within as well as outside the bursa.
from relatively benign nail-fold infarcts to widespread
cutaneous ulceration and skin necrosis. Rarely, involve-
ment of medium-sized arteries can lead to mesenteric,
renal or coronary artery occlusion.
Ocular involvement
The most common symptom is dry eyes (keratoconjunc-
tivitis sicca) due to secondary Sjögren’s syndrome
(p. 1114). Painless episcleritis frequently accompanies
nodular seropositive disease; it may cause intense
redness of superficial vessels but sight is unimpaired.
Scleritis is more serious and potentially sight-threatening;
the eye is red and painful, vision is impaired, and
the sclera shows a deep red blush beneath the
individual red superficial vessels (p. 1058). Scleromala-
cia is painless bilateral thinning of the sclera, with the
affected area appearing blue or grey (the colour of the
underlying choroid). Corneal melting is a rare but dev-
astating manifestation. It occurs in long-standing disease
and is associated with systemic vasculitis. It causes pain,
redness and blurred vision with corneal thinning.
If it is untreated, progression to perforation is common,
so urgent high-dose steroid and immunosuppressive
therapy is indicated.
Cardiac and pulmonary involvement
Cardiac involvement occurs in up to 30% of patients
with seropositive RA but is usually asymptomatic.
Symptomatic pericardial effusions and constrictive peri-
carditis are rare. Occasionally, granulomatous lesions
can cause heart block, cardiomyopathy, coronary artery
occlusion or aortic regurgitation. Serositis is commonly
asymptomatic but may present as pleurisy or breathless-
ness. Pulmonary fibrosis can occur in advanced RA and
may cause dyspnoea (p. 712). In addition to the above
manifestations, which are due to the direct effects of the
inflammatory process, the risk of atheroma and cardio-
vascular disease is increased in RA. This is caused by a
combination of conventional risk factors, such as high
cholesterol, smoking, hypertension and reduced phy-
sical activity, and the effects of inflammatory factors,
such as immune complexes, cytokines and chemokines,
on the endothelium and adipose tissue. The risk of
cardiovascular disease may be increased by NSAID
and corticosteroids, whereas there is some evidence
that DMARD and biological medicines are protective.
Rheumatoid arthritis
A B
Fig. 25.34 Subluxation of cervical spine. A Flexion, showing
widening of the space (arrow) between the odontoid peg of the axis
(behind) and the anterior arch of the atlas (in front). B Extension, showing
reduction in this space.
Neurological complications
Peripheral entrapment neuropathies may result from
compression by hypertrophied synovium or by joint
subluxation. Median nerve compression in the carpal
tunnel is most common and bilateral compression can
25
occur as an early presenting feature of RA. Other syn-
dromes include ulnar nerve compression at the elbow or
wrist, compression of the lateral popliteal nerve at the
head of the fibula, and tarsal tunnel syndrome (entrap-
ment of the posterior tibial nerve in the flexor retinacu-
lum), which causes burning, tingling and numbness in
the distal sole and toes. Diffuse symmetrical peripheral
neuropathy and mononeuritis multiplex may occur in
patients with rheumatoid vasculitis.
Cervical cord compression can result from subluxa-
tion of the cervical spine at the atlanto-axial joint or at a
subaxial level (Fig. 25.34). Atlanto-axial subluxation is a
common finding in long-standing RA and is due to
erosion of the transverse ligament posterior to the
odontoid peg. If unrecognised, it can lead to cord
compression or sudden death following minor trauma
or manipulation. Atlanto-axial subluxation should be
suspected in any RA patient who describes new onset of
occipital headache, particularly if symptoms of paraes-
thesia or electric shock are present in the arms. The onset
is often insidious, with subtle loss of function that is
initially attributed to active disease. Reflexes and power
can be very difficult to assess in the presence of marked
joint damage and therefore sensory or upper motor
signs are most important. Patients with spinal cord com-
pression may require operative stabilisation and fixa-
tion, though the outcome is poor if the patient already
has tetraparesis.
Other complications
Amyloidosis is a rare complication of prolonged active
disease and usually presents with nephrotic syndrome.
Microcytic anaemia can occur due to iron deficiency
resulting from NSAID-induced gastrointestinal blood
loss, and normochromic, normocytic anaemia with
thrombocytosis is present in active disease. Felty’s
syndrome is the association of splenomegaly and 1099
 RHEUMATOLOGY AND BONE DISEASE

25 25.56 Felty’s syndrome

25.57 Investigations and monitoring of
rheumatoid arthritis
Risk factors To establish diagnosis
• Age of onset 50–70 yrs • Deforming but inactive • Clinical criteria • Rheumatoid factor and
• Female > male disease • ESR and CRP anti-citrullinated peptide
• Caucasians > blacks • Seropositive for RF • Ultrasound or MRI antibodies
• Long-standing RA To monitor disease activity and drug efficacy
Common clinical features • Pain (visual analogue scale) • Joint swelling
• Splenomegaly • Keratoconjunctivitis sicca • Early morning stiffness • DAS28 score
• Lymphadenopathy • Vasculitis, leg ulcers (minutes) • ESR and CRP
• Weight loss • Recurrent infections • Joint tenderness • Ultrasound
• Skin pigmentation • Nodules To monitor disease damage
Laboratory findings • X-rays • Functional assessment
• Normochromic, • Thrombocytopenia To monitor drug safety
normocytic anaemia • Impaired T- and B-cell
• Neutropenia immunity • Urinalysis • Urea, creatinine and liver
• Abnormal liver function • Full blood count function tests

neutropenia with RA (Box 25.56). Generalised and local 25.58 How to calculate the DAS28 score
lymphadenopathy affecting nodes draining actively
inflamed joints may both occur. Patients with persistent
lymphadenopathy should be biopsied since there is an
increased risk of lymphoma in patients with long-
standing RA.

Investigations
The diagnosis of RA is based on clinical grounds but
investigations are useful in confirming the diagnosis and
assessing disease activity (Box 25.57). The ESR and CRP
are usually raised but normal results do not exclude the
diagnosis. ACPA are positive in about 70% of cases and
are highly specific for RA, occurring in many patients
before clinical onset of the disease. Similarly RF is posi-
tive in about 70% of cases, many of whom also test posi-
tive for ACPA. Low titres of RF are found in about 10%
of the normal population and in other diseases (p. 1067).
Ultrasound examination and MRI are not routinely
required in patients with obvious clinical signs. Their
main value is in patients with symptoms suggestive of • Count the number of tender joints
an inflammatory arthritis, where there is uncertainty • Count the number of swollen joints
about the presence of synovitis. They are also a sensitive • Measure the ESR
means of detecting early erosions. Plain X-rays of the • Ask the patient to rate global activity of arthritis during the
hands, wrist and feet are of limited value in early RA past week from 0 (no symptoms) to 100 (very severe)
• Enter data into an online calculator1 or work out using a
but certain changes are characteristic, including peri-
formula2
articular osteoporosis and marginal joint erosions. The
main indication for X-ray is in the assessment of patients 1
www.4s-dawn.com/DAS28.
with problem joints to determine if significant structural 2
DAS28 = 0.56 × square root (tender joints) + 0.28 × square
damage has occurred. Patients who are suspected of root (swollen joints) + 0.70 × loge(ESR) + 0.014 (global activity
having atlanto-axial disease should have lateral X-rays score)
taken in flexion and extension, and the degree of
cord compression should be established with MRI. In
patients with Baker’s cyst, ultrasound may be required visual analogue scale, to generate a numerical score. The
to establish the diagnosis, since DVT and Baker’s cyst higher the value, the more active the disease (Box 25.58).
may coexist.
The DAS28 score is widely used to assess disease
activity, the response to treatment and the need for Management
biological therapy. It involves counting the number
of swollen and tender joints in the upper limbs The mainstay of treatment in RA comprises the early
and knees, and combining this with the ESR and the use of small-molecule disease-modifying antirheumatic
1100 patient’s assessment of his/her general health on a drugs (DMARDs), and corticosteroids for induction of
 Rheumatoid arthritis

remission. There is evidence that early use of DMARD
therapy improves clinical outcome in RA. Partial or non-
response to DMARD therapy should prompt escalation
of the dose or use of an additional DMARD, with pro-
gression to biological drugs if necessary (Fig. 25.35).
Regular monitoring of DMARD therapy is essential
because of the risk of liver and haematological toxicity.
Some DMARDs are contraindicated in pregnancy,
especially during the first trimester (Box 25.59). Patients
who wish to become pregnant should be counselled to
stop DMARD treatment while they try to conceive. Since
RA almost always undergoes remission during preg-
nancy, it is usually possible to manage the condition
without DMARD therapy over this period. Details of the
dose regimens, toxicity and monitoring requirements
are shown in Box 25.60.

25.59 Rheumatoid arthritis in pregnancy

ds
roi

• Immunological changes in pregnancy: most patients with

ste

Abatacept RA go into remission during pregnancy.

r

NS
ula

Rituximab • Conception: methotrexate and leflunomide should be

tic

AID
Tocilizumab
discontinued for at least 3 months before trying to conceive.
-ar

Anti-TNF #2
an
• Paracetamol: the oral analgesic of choice during pregnancy.
a
ntr

da
• Oral NSAIDs and selective COX-2 inhibitors: can be used
di

na
an

Anti-TNF #1 after implantation up until the last trimester.

lge
lar

• Corticosteroids: may be used to control disease flares; the

sic
cu

main maternal risks are hypertension, glucose intolerance

s
us

Combination DMARD and osteoporosis.

ram

• DMARDs that may be used: sulfasalazine,

Int

Methotrexate + corticosteroids hydroxychloroquine, azathioprine or ciclosporin if required to

control inflammation.
• DMARDs that must be avoided: methotrexate, leflunomide,

Diagnosis of RA
cyclophosphamide, gold and penicillamine.
• Biological therapies: safety during pregnancy is currently
25
unclear.
Fig. 25.35 Management of early rheumatoid arthritis. See text for • Breastfeeding: methotrexate, leflunomide,
details of each drug. (DMARD = disease-modifying antirheumatic drug; cyclophosphamide, ciclosporin, azathioprine, sulfasalazine
NSAID = non-steroidal anti-inflammatory drug; TNF = tumour necrosis and hydroxychloroquine are contraindicated.
factor)

25.60 Commonly used small-molecule disease-modifying antirheumatic drugs in rheumatoid arthritis

Mechanism Usual Monitoring Monitoring
Drug of action maintenance dose Principal side-effects requirement frequency
Methotrexate Inhibits DNA 5–25 mg/wk GI upset, stomatitis, rash, FBC, LFTs Initially monthly,
synthesis and alopecia, hepatotoxicity, acute then every 3 mths
cell division pneumonitis
Sulfasalazine Unknown 2–4 g/day Nausea, GI upset, rash, FBC, LFTs Monthly for 3 mths,
hepatitis, neutropenia, then 3-monthly
pancytopenia (rare)
Hydroxychloroquine Unknown 200–400 mg/day Rash, nausea, diarrhoea, Visual 12-monthly
headache, corneal acuity,
deposits, retinopathy fundoscopy
(rare)
Leflunomide Blocks T-cell 10–20 mg/day Nausea, GI upset, rash, FBC, LFTs, 2–4-weekly
division alopecia, hepatitis, BP
hypertension
D-Penicillamine Unknown 250–750 mg/day Rash, stomatitis, metallic FBC, urine Initially 1–2-weekly;
taste, proteinuria, (for protein) 4–6-weekly for
thrombocytopenia maintenance
Gold Unknown 50 mg/mth by IM Rash, stomatitis, alopecia, FBC, urine Each injection
injection proteinuria, thrombocytopenia, (protein)
myelosuppression
Ciclosporin Blocks T-cell 150–300 mg/day Nausea, GI upset, renal FBC, LFTs, 2–4-weekly
activation impairment, hypertension U&E, BP

(BP = blood pressure; FBC = full blood count; LFT = liver function tests; U&E = urea and electrolytes)
1101
 RHEUMATOLOGY AND BONE DISEASE
25 Disease-modifying antirheumatic
drugs
Methotrexate
Methotrexate is the anchor DMARD in RA. It is usually
given as a starting weekly oral dose of 7.5–10 mg and
this is increased in 2.5 mg increments every 2–4 weeks
until benefit occurs or toxicity is limiting. The maximum
recommended dose is 25 mg. The benefits of methotrex-
ate usually start to appear within 1–2 months but a
6-month course should be given before concluding that
it has been ineffective. The most common adverse effects
are nausea, vomiting and malaise within 24–48 hours of
administration. Patients who experience these can some-
times be successfully treated with subcutaneous metho-
trexate. Folic acid (5 mg/week) reduces the incidence
of adverse effects without reducing efficacy. Patients
should be warned of drug interaction with sulphona-
mides and to avoid excess alcohol, which enhances
methotrexate hepatotoxicity. Acute pulmonary toxicity
(pneumonitis) is rare but can occur at any time during
treatment. Patients should therefore be warned to seek
early advice if they develop any new respiratory symp-
toms. Methotrexate should be stopped immediately if
pneumonitis is suspected and high-dose steroids should
be given.
Sulfasalazine
Sulfasalazine (SSZ) is widely used, both alone and in
combination with methotrexate and other drugs. The
mechanism of action is incompletely understood.
Nausea and gastrointestinal intolerance are the main
adverse effects. The usual starting dose is 500 mg
daily, building up gradually to a maintenance dose of
2–4 g/day. The patient should be warned of possible
orange staining of urine and contact lenses. Monitoring
should be performed for liver and haematological
toxicity.
Hydroxychloroquine
Hydroxycholoroquine is given in a dose of 400 mg daily,
usually in combination with other DMARDs. Ocular
toxicity can occur with long-term use due to retinal
damage. It is usual to check visual acuity before starting
treatment and to repeat this periodically whilst treat-
ment is continued.
Leflunomide
Leflunomide can be used alone or in combination with
other drugs. It works by inhibiting lymphocyte prolif-
eration and activation. It is usually well tolerated and
has low marrow toxicity, but may cause liver dysfunc-
tion. The usual maintenance dose is 10–20 mg/day. It is
possible to give a loading dose of 100 mg on 3 consecu-
tive days at the start of treatment, but this is seldom used
in routine clinical practice. Monitoring should be per-
formed for liver and haematological toxicity.
Gold, penicillamine and ciclosporin A
These are only occasionally used due to the availability
of drugs with a better risk–benefit profile. Gold (sodium
aurothiomalate) is given by deep intramuscular injection
of 50 mg after an initial 10 mg test dose. Treatment is
continued weekly for up to 6 months until benefit occurs,
1102 when the frequency is reduced to fortnightly and then
monthly. Penicillamine is given in a starting dose of
125–250 mg daily on an empty stomach, and increased
in 125-mg increments every 6 weeks until benefit occurs
or adverse effects develop. Ciclosporin A inhibits lym-
phocyte division and activation. It is given in a dose of
150–300 mg/day with monitoring of blood pressure and
renal function.
Corticosteroids
Systemic corticosteroids have disease-modifying activ-
ity, but their primary role is in the induction of remis-
sion in patients with early RA who are starting synthetic
DMARD treatment. Various regimens have been used
but there is little evidence to suggest that one is supe-
rior to another. One strategy is to give a high dose of
oral prednisolone initially (60 mg daily) and to reduce
and stop this gradually over a period of 3 months as the
DMARD starts to take effect. Another is to employ low-
dose prednisolone (5–10 mg daily for 6–24 months) or
to give intramuscular injections of methylprednisolone
or triamcinolone every 6–8 weeks. Intramuscular ster-
oids are often used to treat flares of disease activity in
patients who are established on DMARD therapy. Intra-
articular corticosteroids are primarily indicated when
there are one or two ‘problem joints’ with persistent
synovitis despite good general control of the disease.
Although corticosteroids are very useful, they also
have significant adverse effects (p. 776). In the context
of RA, osteoporosis is probably the most important
since this is a known complication of RA, even in the
absence of corticosteroid therapy. Accordingly DEXA
scanning followed by bone protection should be consid-
ered in any patient with RA who is expected to be on
more than 7.5 mg prednisolone daily for more than
3 months.
Biological therapies
The use of biological agents (often abbreviated to ‘bio-
logics’) is reserved for the treatment of patients who
have high disease activity despite having had an ade-
quate trial of traditional DMARDs. These agents are
targeted towards specific cytokines and other cell-
surface molecules regulating the immune response.
Although generally well tolerated, biological therapies
increase the risk of serious infections due to suppression
of the immune response. Although biological treatment
is more effective than standard DMARD therapy, treat-
ment costs are significantly greater. Because of this,
many countries have set guidelines restricting their use.
Current UK recommendations are that biological therapy
should be initiated only in active RA (DAS28 > 5.1;
p. 1100) when an adequate trial of at least two other
DMARDs (including methotrexate) has failed. Details of
the individual agents, their mechanisms of action and
their toxicity are shown in Box 25.61.
Anti-TNF therapy
Anti-TNF therapy is the first-line biological drug in RA.
Several agents are available, as summarised in Box 25.61.
With the exception of infliximab, which must be pre-
scribed with methotrexate to reduce the risk of neutralis-
ing antibodies developing, these agents can be used as
monotherapy. In clinical practice, however, most are
co-prescribed with methotrexate, as this is more effica-
cious. The main adverse effects are serious infections

25.61 Commonly used biological drugs in rheumatoid arthritis
and reactivation of latent tuberculosis. There is evidence
that TNF blockade can increase the risk of some malig-
nancies, particularly basal cell carcinoma of the skin, and
that it can accelerate progression of cancer in patients
with prior malignant disease. In contrast, the risk of
vascular disease in RA patients seems to be reduced by
anti-TNF therapy.
Rituximab
Rituximab is an antibody directed against the CD20
receptor, which is expressed on B lymphocytes and
immature plasma cells. It is given by two intravenous
infusions, 2 weeks apart, usually in combination with
intravenous corticosteroid. It causes depletion of periph-
eral and synovial B cells, which is sustained for several
months after administration. The treatment is repeated
usually when signs of improvement are wearing off
(anything from 6 months to 1 year). It is mostly used in
the treatment of patients with resistant RA who have
failed to respond to TNF blockade.
Abatacept
Abatacept is an agent in which the Fc domain of IgG is
fused to the extracellular domain of CTLA4. It blocks the
interaction between CD28 and CD80/86 that is required
for full activation of T cells following antigen presenta-
tion by dendritic cells or macrophages. Abatacept has a
good safety profile and is as efficacious as anti-TNF
therapy in biological-naïve patients who fail to respond
to conventional DMARD therapy.
Tocilizumab
This agent is an antibody directed against the IL-6 recep-
tor, and is licensed for the treatment of rheumatoid
arthritis. It prevents IL-6 activating its receptor within
the synovial membrane and in other tissues such as liver
and muscle. It has similar efficacy to anti-TNF therapy
and is licensed for use as monotherapy or in combina-
tion with methotrexate. Adverse effects include leuco-
penia, hypercholesterolaemia and an increased risk of
Juvenile idiopathic arthritis
25
infections. It is generally used as second-line treatment
in patients who have failed to respond to anti-TNF
therapy, except in those who are intolerant of methotrex-
ate, in which case it is used as a first-line treatment.
Anakinra
Anakinra is a decoy receptor for IL-1. It has some activ-
ity in RA but is seldom used since it appears to be less
effective than other biological drugs.
Other treatments
Surgery
Synovectomy of the wrist or finger tendon sheaths of the
hands may be required for pain relief or to prevent
tendon rupture when medical interventions have failed.
In later stages when joint damage has occurred, osteo-
tomy, arthrodesis or arthroplasty may be required (see
Box 25.35, p. 1080).
General measures
The general principles outlined on page 1077 should be
followed. Physical rest, analgesics and NSAID may be
required to control symptoms. Passive exercises and
joint protection measures should be encouraged with
the aim of conserving function in affected joints. During
treatment, periodic assessment of disease activity, pro-
gression and disability is essential. In the vast majority,
management is outpatient- or day patient-based, but
hospital admission can be helpful in patients with very
active disease for a period of bed rest, multiple joint
injections, splinting, regular hydrotherapy, physio-
therapy and education.
JUVENILE IDIOPATHIC ARTHRITIS
Inflammatory arthritis occurs rarely in children. Several
distinct subtypes are recognised (Box 25.62). Systemic
juvenile idiopathic arthritis (JIA; formerly known as 1103
 RHEUMATOLOGY AND BONE DISEASE

25 25.62 Clinical features of juvenile idiopathic arthritis

Subtype Frequency Clinical features Immunology
Systemic JIA 5% Fever, rash, arthralgia, hepatosplenomegaly Autoantibody-negative
Oligoarthritis (≤ 4 joints) 60% Large-joint arthritis, uveitis ANA-positive
Polyarthritis (≥ 5 joints) 20% Polyarthritis. May be extended form of oligoarthritis ANA-positive
Enthesis-related 5% Sacroiliitis, enthesopathy HLA-B27-positive
Rheumatoid factor-positive 5% Polyarthritis, similar to RA RF-positive, ACPA-positive
Psoriatic arthritis 5% Same as adult disease (p. 1108) Autoantibody-negative
(ACPA = anti-citrullinated peptide antibodies; ANA = antinuclear antibody; HLA = human leucocyte antigen; RF = rheumatoid factor)

Adult-onset Still’s disease

25.63 Juvenile idiopathic arthritis in adolescence
• Uveitis: may be clinically silent and persist into adulthood,
necessitating routine screening for eye involvement.
• Persistence into adulthood: persists in 50% of cases,
especially in systemic disease, necessitating long-term
follow-up.
• Reduced peak bone mass: common in polyarthritis and
systemic JIA but little data on fracture risk, and evidence
base for treatment is poor
• Biological drugs: effective in JIA but long-term safety
remains unclear.
Still’s disease) is a systemic disorder characterised by
fever, rash, arthritis, hepatosplenomegaly and serositis
in association with a raised ESR and CRP. Autoantibody
tests are negative.
Oligoarthritis is the most common form, accounting
for about 60% of cases. Two subtypes are recognised,
depending on the extent of involvement, but they prob-
ably form part of a single disease spectrum. Oligoarticu-
lar JIA is more common in females and tends to affect
large joints in an asymmetrical pattern. There is an asso-
ciation with uveitis and many patients are ANA-positive.
Rheumatoid factor-negative polyarthritis is a hetero-
geneous form. Some patients are ANA-positive and
these probably represent a subtype of oligoarticular JIA
with more extensive joint involvement. Other patients
present with polyarticular disease that is similar to adult
seronegative RA. Juvenile forms of ankylosing spondyli-
tis and psoriatic arthritis also occur.
Patients with JIA should be referred to a paediatric
rheumatologist. The principles of management are
similar to those in adult inflammatory disease, and cor-
ticosteroids and methotrexate are required for systemic
JIA. Recent trials indicate that TNF blockers, IL-1 inhibi-
tors and tocilizumab may also be effective. Steroids and
methotrexate are also indicated for oligoarticular and
polyarticular JIA, with progression to anti-TNF therapy
in poor responders.
The prognosis of oligoarthritis is good and in many
patients the condition resolves at puberty. Polyarticular
and systemic JIA have a poorer prognosis, however, and
in about 50% of cases the disease remains active into
adulthood, requiring extended follow-up by adult rheu-
matology services. Common issues encountered during
transition of paediatric patients into adulthood are
1104 shown in Box 25.63.
This is a rare systemic inflammatory disorder of
unknown cause, similar to juvenile idiopathic arthritis,
which presents with intermittent fever, rash and
arthralgia. Splenomegaly, hepatomegaly and lymph-
adenopathy may be present. Investigations typically
show evidence of an acute phase response, with a
markedly elevated serum ferritin. Tests for RF and
ANA are negative. Most patients respond to cortico-
steroids but DMARDs may also be required as steroid-
sparing agents. Anecdotal reports indicate that anakinra
(p. 1103), anti-TNF therapy and tocilizumab may be
helpful in patients with resistant disease, but none
of these has been tested in a randomised trial.
SERONEGATIVE
SPONDYLOARTHROPATHIES
These comprise a group of related inflammatory joint
diseases, which show considerable overlap in their clini-
cal features and a shared immunogenetic association
with the HLA-B27 antigen (Box 25.64). They include:
• ankylosing spondylitis
• axial spondyloarthritis
• reactive arthritis, including Reiter’s syndrome
• psoriatic arthritis
• arthropathy associated with inflammatory bowel
disease.
The synovitis is non-specific and is often indistin-
guishable from RA. However, the distinctive feature of
this group of diseases is the marked degree of extrasyno-
vial inflammation, especially of the enthesis but also of
the joint capsule, periosteum, cartilage and subchondral
bone. There is a striking association with carriage of the
HLA-B27 allele, particularly for ankylosing spondylitis
(> 95%) and reactive arthritis (90%), and especially asso-
ciated with sacroiliitis, uveitis or balanitis. Understand-
ing of the cause is incomplete but an aberrant response
to infection is thought to be involved in genetically pre-
disposed individuals. In some situations, a triggering
organism can be identified, as in reactive arthritis fol-
lowing bacterial dysentery or chlamydial urethritis, but
in others the environmental trigger remains obscure.
Familial clustering not only is common to the specific
condition occurring in the proband, but also may extend
to other diseases in the seronegative spondyloartho-
pathy group.

25.64 Clinical features common to seronegative
spondyloarthritis
• Asymmetrical inflammatory oligoarthritis (lower > upper limb)
• Sacroiliitis and inflammatory spondylitis
• Inflammatory enthesitis
• Tendency for familial aggregation
• RF and ACPA negative
• Absence of nodules and other extra-articular features of RA
• Typical overlapping extra-articular features:
Mucosal inflammation: conjunctivitis, buccal ulceration,
urethritis, prostatitis, bowel ulceration
Pustular skin lesions and nail dystrophy
Anterior uveitis
Aortic root fibrosis (aortic incompetence, conduction
defects)
Erythema nodosum
Ankylosing spondylitis
Ankylosing spondylitis (AS) is characterised by a chronic
inflammatory arthritis predominantly affecting the
sacroiliac joints and spine, which can progress to bony
fusion of the spine. The onset is typically between the
ages of 20 and 30, with a male preponderance of about
3 : 1. In Europe, more than 90% of those affected are
HLA-B27-positive. The overall prevalence is less than
0.5% in most populations. Over 75% of patients are able
to remain in employment and enjoy a good quality of
life. Even if severe ankylosis develops, functional limita-
tion may not be marked as long as the spine is fused in
an erect posture.
Pathophysiology
Ankylosing spondylitis is thought to arise from an as yet
ill-defined interaction between environmental patho-
gens and the host immune system in genetically suscep-
tible individuals. Increased faecal carriage of Klebsiella
aerogenes occurs in patients with established AS and may
relate to exacerbation of both joint and eye disease.
Wider alterations in the human gut microbial environ-
ment are increasingly implicated, which could lead to
increased levels of circulating cytokines such as IL-23
that can activate enthesial or synovial T cells. The
HLA-B27 molecule itself is implicated through its
antigen-presenting function (it is a class I MHC mol-
ecule) or because of its propensity to form homodimers
that activate leucocytes. HLA-B27 molecules may also
misfold, causing increased endoplasmic reticulum
stress. This could lead to inflammatory cytokine release
by macrophages and dendritic cells, thus triggering
inflammatory disease.
Clinical features
The cardinal feature is low back pain and early morning
stiffness with radiation to the buttocks or posterior
thighs. Symptoms are exacerbated by inactivity and
relieved by movement. The disease tends to ascend
slowly, ultimately involving the whole spine, although
some patients present with symptoms of the thoracic
or cervical spine. As the disease progresses, the spine
becomes increasingly rigid as ankylosis occurs.
Secondary osteoporosis of the vertebral bodies
Seronegative spondyloarthropathies
25.65 Extra-articular features of
ankylosing spondylitis
• Anterior uveitis (25%) and conjunctivitis (20%)
• Prostatitis (80% men): usually asymptomatic
• Cardiovascular disease
Aortic incompetence
Mitral incompetence
Cardiac conduction defects
Pericarditis
• Amyloidosis
• Atypical upper lobe pulmonary fibrosis
frequently occurs, leading to an increased risk of verte-
bral fracture.
Early physical signs include a reduced range of
lumbar spine movements in all directions and pain on
sacroiliac stressing. As the disease progresses, stiffness
increases throughout the spine and chest expansion
becomes restricted. Spinal fusion varies in its extent and
in most cases does not cause a gross flexion deformity,
but a few patients develop marked kyphosis of the
dorsal and cervical spine that may interfere with forward
vision. This may prove incapacitating, especially when
associated with fixed flexion contractures of hips or
knees. Pleuritic chest pain aggravated by breathing is
common and results from costovertebral joint involve-
25
ment. Plantar fasciitis, Achilles tendinitis and tenderness
over bony prominences such as the iliac crest and greater
trochanter may all occur, reflecting inflammation at the
sites of tendon insertions (enthesitis).
Up to 40% of patients also have peripheral arthritis.
This is usually asymmetrical, affecting large joints such
as the hips, knees, ankles and shoulders. In about 10%
of cases, involvement of a peripheral joint may antedate
spinal symptoms, and in a further 10%, symptoms begin
in childhood, as in the syndrome of oligoarticular juve-
nile idiopathic arthritis.
Fatigue is a major complaint and may result from
both chronic interruption of sleep due to pain, and
chronic systemic inflammation with direct effects of
inflammatory cytokines on the brain. Acute anterior
uveitis is the most common extra-articular feature,
which occasionally precedes joint disease. Other extra-
articular features are occasionally observed but are rare
(Box 25.65). Disease activity in AS can be assessed by the
Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI), a questionnaire in which patients and their
physician rate severity of various symptoms (Box 25.66).
This is important in assessing eligibility for biological
treatment. The criteria for the diagnosis of classical AS
and axial spondyloarthropathy (SpA) are shown in Box
25.67. The criteria for axial SpA were developed to take
account of the fact that X-rays may be normal in patients
with early AS.
Investigations
In established AS, radiographs of the sacroiliac joint
show irregularity and loss of cortical margins, widening
of the joint space and subsequently sclerosis, joint space
narrowing and fusion. Lateral thoracolumbar spine
X-rays may show anterior ‘squaring’ of vertebrae due to
erosion and sclerosis of the anterior corners and perios-
titis of the waist. Bridging syndesmophytes may also be 1105
 RHEUMATOLOGY AND BONE DISEASE

25 seen. These are areas of calcification that follow the out-

ermost fibres of the annulus (Fig. 25.36). In advanced
25.67 Diagnostic criteria for ankylosing
spondylitis and axial spondyloarthritis
disease, ossification of the anterior longitudinal liga-
Axial spondyloarthritis Ankylosing spondylitis
ment and facet joint fusion may also be visible. The
combination of these features may result in the typical Imaging
‘bamboo’ spine (Fig. 25.37). Erosive changes may be seen Sacroiliitis on MRI only Bilateral sacroiliitis on X-ray,
in the symphysis pubis, the ischial tuberosities and even if changes are mild
peripheral joints. Osteoporosis and atlanto-axial disloca- Unilateral sacroiliitis on X-ray
tion can occur as late features. Patients with early disease if changes are definite
can have normal X-rays, and if clinical suspicion is high, History
MRI should be performed. This is much more sensitive Back pain > 3 mths which has Back pain > 3 mths
for detection of early sacroiliitis than X-ray (Fig. 25.38) four of the following improved by exercise and not
and can also detect inflammatory changes in the lumbar characteristics: relieved by rest
spine. 1. improved by exercise
2. not relieved by rest
3. insidious onset
4. night pain
25.66 Bath Ankylosing Spondylitis Disease 5. age at onset < 40
Activity Index Good response of back pain to
NSAID
Question Score
Family history of
1. How would you describe the overall level of fatigue 1–10 spondyloarthritis
or tiredness you have experienced? History of inflammatory bowel
2. How would you describe the overall level of neck, 1–10 disease
back or hip pain you have had? Clinical examination
3. How would you describe the overall level of pain 1–10 Arthritis Limitation of lumbar spine
and swelling you have had in joints other than the Enthesitis movement in sagittal and
neck, back or hip? Uveitis frontal planes
Dactylitis Chest expansion reduced
4. How would you describe the overall level of 1–10 Psoriasis
discomfort you have had from any areas tender to
touch or pressure? Investigations
HLA-B27-positive
5. How would you describe the overall level of 1–10 Elevated CRP
discomfort you have had from the time you wake up?
Axial spondyloarthritis is diagnosed when there is sacroiliitis
6. How long does your morning stiffness last from the 0 hr to on MRI plus one other feature on history, clinical examination
time you wake up? 2+ hrs or investigation. The diagnosis can also be made in patients
The patient is asked to complete each question. The score is who are HLA-B27-positive with two or more clinical features
calculated by taking the average of all 6 questions, where in the absence of sacroiliitis
duration of morning stiffness in minutes is coded in 12-minute Ankylosing spondylitis can be diagnosed when X-ray evidence
increments from none (1) to 120 (10). Online calculators are also of sacroiliitis occurs with one other feature on history or
available at http://basdai.com clinical examination

A B

Fig. 25.36 X-ray changes in spondyloarthropathies. A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow).
1106 B Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic/Reiter’s spondylitis (arrow).

Fig. 25.37 ‘Bamboo’ spine of severe late ankylosing spondylitis.
Note the symmetrical marginal syndesmophytes (arrows), sacroiliac joint
fusion and generalised osteopenia.
Fig. 25.38 MRI appearances in sacroiliitis. Coronal MRI short T1
inversion recovery (STIR) sequence showing bilateral sacroiliitis in early
ankylosing spondylitis. Bone marrow oedema (circles) is present around
both sacroiliac joints, which show irregularities due to erosions (arrows).
The ESR and CRP are usually raised in active disease
but may be normal. Testing for HLA-B27 can be helpful,
especially in patients with back pain suggestive of an
inflammatory cause, when other investigations have
yielded equivocal results. Autoantibodies such as RF,
ACPA and ANA are negative.
Management
The aims of management are to relieve pain and stiff-
ness, maintain a maximal range of skeletal mobility and
avoid the development of deformities. Education and
appropriate physical activity are the cornerstones of
management. Early in the disease, patients should be
taught to perform daily back extension exercises, includ-
ing a morning ‘warm-up’ routine, and to punctuate
Seronegative spondyloarthropathies
prolonged periods of inactivity with regular breaks.
Swimming is ideal exercise. Poor posture must be
avoided. NSAIDs and analgesics are often effective in
relieving symptoms and may alter the underlying course
of the disease. A long-acting NSAID at night is helpful
for alleviation of morning stiffness. Peripheral arthritis
can be treated with methotrexate or sulfasalazine, but
these drugs have no effect on axial disease. Anti-TNF
therapy should be considered in patients who are inad-
equately controlled on standard therapy with a BASDAI
score of ≥ 4.0 and a spinal pain score of ≥ 4.0. Anti-TNF
therapy frequently improves symptoms but has not been
shown to prevent ankylosis or alter natural history of
the disease. Other biological interventions using agents
developed for RA have been disappointing, suggesting
fundamental differences in disease pathogenesis.
Local corticosteroid injections can be useful for per-
sistent plantar fasciitis, other enthesopathies and periph-
eral arthritis. Oral corticosteroids may be required for
acute uveitis but do not help spinal disease. Severe hip,
knee or shoulder restriction may require surgery. Total
hip arthroplasty has largely removed the need for dif-
ficult spinal surgery in those with advanced deformity.
Reactive arthritis
Reactive arthritis (previously known as Reiter’s disease)
25
is predominantly a disease of young men, with a male
preponderance of 15 : 1. It is the most common cause
of inflammatory arthritis in men aged 16–35 but may
occur at any age. Between 1 and 2% of patients with
non-specific urethritis seen at genitourinary medicine
clinics have reactive arthritis (p. 415). Following an epi-
demic of Shigella dysentery, 20% of HLA-B27-positive
men developed reactive arthritis. Reactive arthritis may
present with the triad described in Box 25.68 but many
patients present with arthritis only.
Clinical features
The onset is typically acute, with an inflammatory
oligoarthritis that is asymmetrical and targets lower
limb joints, such as the knees, ankles, midtarsal and
MTP joints. It occasionally presents with single joint
25.68 Reiter’s disease
Classic triad*
• Non-specific urethritis • Reactive arthritis
• Conjunctivitis (~50%)
Additional extra-articular features
• Circinate balanitis • Nail dystrophy
(20–50%) • Buccal erosions (10%)
• Keratoderma
blennorrhagica (15%)
Precipitated by
• Bacterial dysentery, mainly Salmonella, Shigella,
Campylobacter or Yersinia
• Sexually acquired infection with Chlamydia
*Incomplete forms with just one or two of the classic triad are more
frequent than the full syndrome.
1107
 RHEUMATOLOGY AND BONE DISEASE
25 involvement and no clear history of an infectious trigger.
There may be considerable systemic disturbance, with
fever and weight loss. Achilles tendinitis or plantar fas-
ciitis may also be present. The first attack of arthritis is
usually self-limiting, but recurrent or chronic arthritis
develops in more than 60% of patients, and about 10%
still have active disease 20 years after the initial presen-
tation. Low back pain and stiffness are common and
15–20% of patients develop sacroiliitis. Spondylitis,
chronic erosive arthritis, recurrent acute arthritis and
uveitis are the major causes of long-term morbidity.
Several extra-articular features may occur (see
Box 25.68). Circinate balanitis starts as vesicles on the
coronal margin of the prepuce and glans penis, later
rupturing to form superficial erosions with minimal sur-
rounding erythema, some coalescing to give a circular
pattern. Lesions are often painless and may escape
notice. Keratoderma blennorrhagica begins as discrete
waxy, yellow-brown vesico-papules with desquamating
margins, occasionally coalescing to form large crusty
plaques. The palms and soles are particularly affected
but spread may occur to the scrotum, scalp and trunk.
These lesions are indistinguishable from pustular pso-
riasis. Nail dystrophy with subungual hyperkeratosis is
common and indistinguishable from psoriatic nail dys-
trophy. Mouth ulcers manifest as shallow red painless
patches on tongue, palate, buccal mucosa and lips,
lasting only a few days. Conjunctivitis may accompany
the first acute episode. Uveitis is rare with the first attack
but occurs in 30% of patients with recurring or chronic
arthritis.
Other complications are rare but include
aortic incompetence, conduction defects, pleuro-
pericarditis, peripheral neuropathy, seizures and
meningoencephalitis.
Investigations
The diagnosis is usually made clinically but joint aspira-
tion may be required to exclude crystal arthritis and
articular infection. Synovial fluid is leucocyte-rich and
may contain multinucleated macrophages (Reiter’s
cells). ESR and CRP are raised during an acute attack.
Urethritis may be confirmed in the ‘two-glass test’ by
demonstration of mucoid threads in the first-void speci-
men that clear in the second. High vaginal swabs may
reveal Chlamydia on culture. Except for post-Salmonella
arthritis, stool cultures are usually negative by the time
the arthritis presents, but serum agglutinin tests may
help confirm previous dysentery. RF, ACPA and ANA
are negative.
In chronic or recurrent disease, X-rays show
periarticular osteoporosis, joint space narrowing and
proliferative erosions. Another characteristic feature is
periostitis, especially of metatarsals, phalanges and
pelvis, and large, ‘fluffy’ calcaneal spurs. In contrast to
AS, radiographic sacroiliitis is often asymmetrical and
sometimes unilateral, and syndesmophytes are predom-
inantly coarse and asymmetrical, often extending
beyond the contours of the annulus (‘non-marginal’)
(see Fig. 25.36B). X-ray changes in the peripheral joints
and spine are identical to those in psoriasis.
Management
The acute attack should be treated with rest, oral NSAIDs
1108 and analgesics. Intra-articular steroids may be required
in patients with severe synovitis. Non-specific chlamy-
dial urethritis is usually treated with a short course of
doxycycline or a single dose of azithromycin, and this
may reduce the frequency of arthritis in sexually
acquired cases. Treatment with DMARDs should be con-
sidered for patients with persistent marked symptoms,
recurrent arthritis or severe keratoderma blennorrha-
gica. Anterior uveitis is a medical emergency requiring
topical, subconjunctival or systemic corticosteroids.
Psoriatic arthritis
Psoriatic arthritis (PsA) occurs in 7–20% of patients with
psoriasis and in up to 0.6% of the general population.
The onset is usually between 25 and 40 years of age.
Most patients (70%) have pre-existing psoriasis but
in 20% the arthritis predates the occurrence of skin
disease. Occasionally, the arthritis and psoriasis develop
synchronously.
Clinical features
The presentation is with pain and swelling affecting the
joints and entheses. Several patterns of joint involve-
ment are recognised but the course is generally one of
intermittent exacerbation followed by varying periods
of complete or near-complete remission. Destructive
arthritis and disability are uncommon, except in the case
of arthritis mutilans.
• Asymmetrical inflammatory oligoarthritis affects about
40% of patients and often presents abruptly with a
combination of synovitis and adjacent periarticular
inflammation. This occurs most characteristically in
the hands and feet, when synovitis of a finger or toe
is coupled with tenosynovitis, enthesitis and
inflammation of intervening tissue to give a
‘sausage digit’ or dactylitis (Fig. 25.39A). Large
joints, such as the knee and ankle, may also be
involved, sometimes with very large effusions.
• Symmetrical polyarthritis occurs in about 25% of
cases. It predominates in women and may strongly
resemble RA, with symmetrical involvement of
small and large joints in both upper and lower
limbs. Nodules and other extra-articular features
of RA are absent and arthritis is generally less
extensive and more benign. Much of the hand
deformity often results from tenosynovitis and soft
tissue contractures.
• Distal IPJ arthritis is an uncommon but characteristic
pattern affecting men more often than women. It
targets finger DIP joints and surrounding
periarticular tissues, almost invariably with
accompanying nail dystrophy (Fig. 25.39B).
• Psoriatic spondylitis presents a similar clinical picture
to AS but with less severe involvement. It may
occur alone or with any of the other clinical patterns
described above and is typically unilateral or
asymmetric in severity.
• Arthritis mutilans is a deforming erosive arthritis
targeting the fingers and toes that occurs in 5%
of cases of PsA. Prominent cartilage and bone
destruction results in marked instability. The
encasing skin appears invaginated and ‘telescoped’
(‘main en lorgnette’) and the finger can be pulled
back to its original length.

A Splints and prolonged rest should be avoided because
B
Fig. 25.39 Psoriatic arthropathy. A ‘Sausage’ middle finger of a
patient with psoriatic arthritis. B Typical distal interphalangeal joint
pattern with accompanying nail dystrophy (pitting and onycholysis).
Nail changes include pitting, onycholysis, subungual
hyperkeratosis and horizontal ridging. They are found
in 85% of those with PsA and only 30% of those with
uncomplicated psoriasis, and can occur in the absence
of skin disease. The characteristic rash of psoriasis
(p. 1286) may be widespread, or confined to the scalp,
natal cleft and umbilicus, where it is easily overlooked.
Conjunctivitis can occur, whereas uveitis is mainly con-
fined to HLA-B27-positive individuals with sacroiliitis
and spondylitis.
Investigations
The diagnosis is made on clinical grounds. Autoantibod-
ies are generally negative and acute phase reactants,
such as ESR and CRP, are raised in only a proportion of
patients with active disease. X-rays may be normal or
show erosive change with joint space narrowing. Fea-
tures that favour PsA over RA include the characteristic
distribution (see Fig 25.9, p. 1070) of proliferative ero-
sions with marked new bone formation, absence of peri-
articular osteoporosis and osteosclerosis. Imaging of the
axial skeleton often reveals features similar to those
in chronic reactive arthritis, with coarse, asymmetrical,
non-marginal syndesmophytes and asymmetrical sacro-
iliitis. MRI and ultrasound with power Doppler are
increasingly employed to detect synovial inflammation
and inflammation at the entheses.
Management
Therapy with NSAID and analgesics may be sufficient
to control symptoms in mild disease. Intra-articular
steroid injections can control synovitis in problem joints.
Connective tissue diseases
of the tendency to fibrous and bony ankylosis. Patients
with spondylitis should be prescribed the same exercise
and posture regime as in AS.
Therapy with DMARDs should be considered for
persistent synovitis unresponsive to conservative treat-
ment. Methotrexate is the drug of first choice since it
may also help skin psoriasis, but other DMARDs may
also be effective, including sulfasalazine, ciclosporin and
leflunomide. DMARD monitoring should take place
with particular attention to liver function since abnor-
malities are common in PsA. Hydroxychloroquine is
generally avoided, as it can cause exfoliative skin reac-
tions. Anti-TNF treatment should be considered for
patients with active synovitis who respond inadequately
to standard DMARDs. This is effective for both PsA and
psoriasis. Other biological treatments, such as ustekinu-
mab, are emerging, which target the IL-12/23 receptor.
Ustekinumab is highly effective in the treatment of pso-
riatic skin disease and is often effectve in PsA.
The retinoid acitretin (p. 1267) is effective for skin
lesions and, anecdotally, may also help arthritis, but it
is teratogenic so must be avoided in young women. It
also causes mucocutaneous side-effects, hyperlipidae-
mia, myalgias and extraspinal calcification. Photo-
chemotherapy with methoxypsoralen and long-wave
ultraviolet light (psoralen + UVA, PUVA) is primarily
used for skin disease, but can also help those with syn-
25
chronous exacerbations of inflammatory arthritis.
Enteropathic arthritis
An acute inflammatory oligoarthritis occurs in around
10% of patients with ulcerative colitis and 20% of those
with Crohn’s disease. It predominantly affects the large
lower limb joints (knees, ankles, hips) but wrists and
small joints of the hands and feet can also be involved.
The arthritis usually coincides with exacerbations of the
underlying bowel disease, and sometimes is accompa-
nied by aphthous mouth ulcers, iritis and erythema
nodosum. It improves with effective treatment of the
bowel disease, and can be cured by total colectomy in
patients with ulcerative colitis. Patients with inflamma-
tory bowel disease may also develop sacroiliitis (16%)
and AS (6%), which are clinically and radiologically
identical to classic AS. These can predate or follow the
onset of bowel disease and there is no correlation
between activity of the spondylitis and bowel disease.
The arthritis often remits with treatment of the bowel
disease but DMARD and biological treatment is occa-
sionally required.
CONNECTIVE TISSUE DISEASES
These share overlapping clinical features, characterised
by dysregulation of immune responses, autoantibody
production often directed at components of the cell
nucleus, and widespread tissue damage.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a rare disease
with a prevalence that ranges from about 0.03% in 1109
 RHEUMATOLOGY AND BONE DISEASE

25 Caucasians to 0.2% in Afro-Caribbeans. Some 90% of

affected patients are female and the peak age at onset is
between 20 and 30 years. Lupus is associated with con-
siderable morbidity and a five-fold increase in mortality
compared to age- and gender-matched controls, mainly
because of an increased risk of premature cardiovascular
disease.
Pathophysiology
The cause of SLE is incompletely understood but genetic
factors play an important role. There is a higher concord-
ance in monozygotic twins and the disease is strongly
associated with polymorphic variants at the HLA locus.
In a few instances, SLE is associated with inherited
mutations in complement components C1q, C2 and C4,
in the immunoglobulin receptor FcγRIIIb or in the DNA Fig. 25.40 Severe secondary Raynaud’s phenomenon leading to
digital ulceration.
exonuclease TREX1. Genome-wide association studies
have identified common polymorphisms near several
other genes that predispose to SLE, most of which are
involved in regulating immune cell function. From an
immunological standpoint, the characteristic feature of
SLE is autoantibody production. These autoantibodies
have specificity for a wide range of targets but many are
directed against antigens present within the cell or
within the nucleus. This has led to the hypothesis that
SLE may occur because of defects in apoptosis or in the
clearance of apoptotic cells, which causes inappropriate
exposure of intracellular antigens on the cell surface,
leading to polyclonal B- and T-cell activation and
autoantibody production. This is supported by the fact
that environmental factors that cause flares of lupus,
such as UV light and infections, increase oxidative stress
and cause cell damage. Whatever the underlying cause
of the autoantibody production, immune complex for-
mation is thought to be an important mechanism of
tissue damage in active SLE, leading to vasculitis and
organ damage.
Clinical features Fig. 25.41 Butterfly (malar) rash of systemic lupus
Symptoms such as fever, weight loss and mild lymph- erythematosus, sparing the nasolabial folds.
adenopathy may occur during flares of disease activity,
whereas others such as fatigue, malaise and fibromyalgia-
like symptoms can be constant and not particularly asso- Loss of the normal loop pattern, with capillary ‘fallout’
ciated with active inflammatory disease. and dilatation and branching of loops, supports connec-
Arthritis tive tissue disease.
Arthralgia is a common symptom, occurring in 90% of Skin
patients, and is often associated with early morning Rash is common in SLE and is classically precipitated by
stiffness. Tenosynovitis may also occur but clinically exposure to UV light. Three distinct types occur:
apparent synovitis with joint swelling is rare. Joint
• The classic butterfly facial rash (up to 20% of
deformities may occur (Jaccoud’s arthropathy) as the
patients). This is erythematous, raised and painful
result of tendon damage, but joint erosions do not occur.
or itchy, and occurs over the cheeks with sparing of
Raynaud’s phenomenon the nasolabial folds (Fig. 25.41).
Raynaud’s syndrome (p. 602) is common and may ante- • The subacute cutaneous lupus erythematosus
date other symptoms by months or years. A common (SCLE) rash, which is migratory, non-scarring and
presentation is Raynaud’s in combination with arthral- either annular or psoriaform.
gia or arthritis (Fig. 25.40). Raynaud’s associated with • The discoid lupus rash characterised by
SLE and other connective tissue disease needs to be dif- hyperkeratosis and follicular plugging, with
ferentiated from primary Raynaud’s, which is common scarring alopecia if it occurs on the scalp.
in healthy young women. Features in favour of second- Diffuse, usually non-scarring alopecia may also occur
ary Raynaud’s include age at onset of over 25 years, with active disease. Other skin manifestations include
absence of a family history of Raynaud’s, and occurrence periungual erythema (reflecting dilated capillary loops),
in a male. Examination of capillary nail-fold loops using vasculitis and livedo reticularis (Fig. 25.42), which is also
an ophthalmoscope (and oil placed on the skin) may a common feature of the antiphospholipid syndrome
1110 help distinguish primary from secondary Raynaud’s. (p. 1055).

Fig. 25.42 Livedo reticularis in systemic lupus erythematosus.
Kidney
Renal involvement is one of the main determinants of
prognosis, and regular monitoring of urinalysis and
blood pressure is essential. The typical renal lesion is a
proliferative glomerulonephritis (p. 498), characterised
by heavy haematuria, proteinuria and casts on urine
microscopy.
Cardiovascular
The most common manifestation is pericarditis. Myocar-
ditis and Libman–Sacks endocarditis can also occur. The
endocarditis is due to accumulation on the heart valves
of sterile fibrin containing vegetations, which is thought
to be a manifestation of hypercoagulability associated
with antiphospholipid antibodies. The risk of atheroscle-
rosis is greatly increased, as is the risk of stroke and
myocardial infarction. This is thought to be multifacto-
rial due to the adverse effects of inflammation on the
endothelium, chronic steroid therapy and the procoagu-
lant effects of antiphospholipid antibodies.
Lung
Lung involvement is common and most frequently
manifests as pleurisy or pleural effusion. Other features
include pneumonitis, atelectasis, reduced lung volume
and pulmonary fibrosis that leads to breathlessness. The
risk of thromboembolism is increased, especially in
patients with antiphospholipid antibodies.
Neurological
Fatigue, headache and poor concentration are common,
and often occur in the absence of laboratory evidence of
active disease. More specific features of cerebral lupus
include visual hallucinations, chorea, organic psychosis,
transverse myelitis and lymphocytic meningitis.
Haematological
Neutropenia, lymphopenia, thrombocytopenia or
haemolytic anaemia may occur, due to antibody-
mediated destruction of peripheral blood cells. The
degree of lymphopenia is a good guide to disease
activity.
Gastrointestinal
Mouth ulcers may occur and may or may not be painful.
Mesenteric vasculitis is a serious complication, which
can present with abdominal pain, bowel infarction or
perforation.
Connective tissue diseases
25.69 Revised American Rheumatism Association
criteria for systemic lupus erythematosus
Features Characteristics
Malar rash Fixed erythema, flat or raised, sparing the
nasolabial folds
Discoid rash Erythematous raised patches with adherent
keratotic scarring and follicular plugging
Photosensitivity Rash due to unusual reaction to sunlight
Oral ulcers Oral or nasopharyngeal ulceration, which
may be painless
Arthritis Non-erosive, involving two or more
peripheral joints
Serositis Pleuritis (history of pleuritic pain or rub, or
pleural effusion) or pericarditis (rub, ECG
evidence or effusion)
Renal disorder Persistent proteinuria > 0.5 g/day or
cellular casts (red cell, granular or tubular)
Neurological Seizures or psychosis, in the absence of
disorder provoking drugs or metabolic derangement
Haematological Haemolytic anaemia or leucopenia* (< 4 ×
disorder 109/L) or lymphopenia* (< 1 × 109/L) or
thrombocytopenia* (< 100 × 109/L) in the
absence of offending drugs
Immunological
disorder
Anti-DNA antibodies in abnormal titre or
presence of antibody to Sm antigen or
25
positive antiphospholipid antibodies
ANA disorder Abnormal titre of ANA by
immunofluorescence
A person has SLE if any 4 out of these 11 features are present
serially or simultaneously.
*On two separate occasions.
Investigations
The diagnosis is based on a combination of clinical fea-
tures and laboratory abnormalities. To fulfil the classifi-
cation criteria for SLE, at least 4 of the 11 factors shown
in Box 25.69 must be present or have occurred in the
past. Patients should be screened for ANA and antibod-
ies to extractable nuclear antigens, and have comple-
ment levels checked along with routine haematology
and biochemistry. Patients with active SLE almost
always test positive for ANA, but ANA-negative SLE
can very rarely occur in the presence of antibodies to
the Ro antigen. Anti-dsDNA antibodies are characteris-
tic of severe active SLE but only occur in around 30% of
cases. Similarly, patients with active disease tend to have
low levels of C3 and C4, but this may be the result of
inherited complement deficiency that predisposes to
SLE. Studies of other family members can help to dif-
ferentiate inherited deficiency from complement con-
sumption. A raised ESR, leucopenia and lymphopenia
are typical of active SLE, along with anaemia, haemo-
lytic anaemia and thrombocytopenia. CRP is often
normal in active SLE, except in the presence of serositis,
and an elevated CRP suggests coexisting infection.
Management
The therapeutic goals are to educate the patient about
the nature of the illness, to control symptoms and to 1111
 RHEUMATOLOGY AND BONE DISEASE
25 prevent organ damage. Patients should be advised to
avoid sun and UV light exposure and to employ sun
blocks (factor 25–50).
Mild to moderate disease
Patients with mild disease restricted to skin and joints
can sometimes be managed with analgesics, NSAID
and hydroxychloroquine (200–400 mg daily). Fre-
quently, however, corticosteroids are also necessary
(prednisolone 5–20 mg/day), often in combination with
immunosuppressants such as methotrexate, azathio-
prine or mycophenolate mofetil (MMF). Increased doses
of steroids may be required for flares in activity or com-
plications such as pleurisy or pericarditis. The mono-
clonal antibody belimumab, which targets the β-cell
growth factor BLyS, has recently been shown to be effec-
tive in patients with active SLE who have responded
inadequately to standard therapy.
Life-threatening disease
High-dose corticosteroids and immunosuppressants are
required for the treatment of renal, CNS and cardiac
involvement. A commonly used regimen is pulse
methylprednisolone (10 mg/kg IV), coupled with cyclo-
phosphamide (15 mg/kg IV), repeated at 2–3-weekly
intervals for six cycles. Cyclophosphamide may cause
haemorrhagic cystitis, but the risk can be minimised
by good hydration and co-prescription of mesna,
which binds its urotoxic metabolites. Because of the
risk of azoospermia and anovulation (which may be per-
manent), pre-treatment sperm or ova collection and
storage need to be considered prior to treatment with
cyclophosphamide.
Mycophenolate mofetil has been used successfully in
combination with high-dose steroids for renal involve-
ment in SLE, with results equivalent to those of pulse
cyclophosphamide but fewer adverse effects. The role of
belimumab in life-threatening SLE remains to be estab-
lished since clinical trials of this agent excluded patients
with renal and cerebral lupus.
Maintenance therapy
Following control of the acute episode, the patient
should be switched to oral immunosuppressive medica-
tion. A typical regimen is to start oral prednisolone in a
dose of 40–60 mg daily on cessation of pulse therapy,
gradually reducing to reach a target of 10–15 mg/day or
less by 3 months. Azathioprine (2–2.5 mg/kg/day),
methotrexate (10–25 mg/week) or MMF (2–3 g/day)
should also be prescribed. The long-term aim is to con-
tinue the lowest dose of corticosteroids and immuno-
suppressant that will maintain remission. Cardiovascular
risk factors, such as hypertension and hyperlipidaemia,
should be controlled and patients advised to stop
smoking.
Lupus patients with the antiphospholipid antibody
syndrome (p. 1055) who have had previous thrombosis
require life-long warfarin therapy.
Systemic sclerosis
Systemic sclerosis, or scleroderma, is a generalised dis-
order of connective tissue affecting the skin, internal
organs and vasculature. It is characterised by sclero-
1112 dactyly in combination with Raynaud’s and digital
Fig. 25.43 Systemic sclerosis. Hands showing tight, shiny skin,
sclerodactyly, flexion contractures of the fingers and thickening of the left
middle finger extensor tendon sheath.
ischaemia (Fig. 25.43). The peak age of onset is in the
fourth and fifth decades, and overall prevalence is 10–20
per 100 000, with a 4 : 1 female preponderance. It is sub-
divided into diffuse cutaneous systemic sclerosis (DCSS:
30% of cases) and limited cutaneous systemic sclerosis
(LCSS: 70% of cases). Many patients with LCSS have
features that are phenotypically grouped into the
‘CREST’ syndrome (Calcinosis, Raynaud’s, oEsophageal
involvement, Sclerodactyly and Telangiectasia). The
prognosis in DCSS is poor, with a 5-year survival of
approximately 70%. Features that associate with a poor
prognosis include older age, diffuse skin disease, pro-
teinuria, high ESR, a low TLCO (gas transfer factor for
carbon monoxide) and pulmonary hypertension.
Pathophysiology
The cause of systemic sclerosis is poorly understood.
There is evidence for a genetic component, and associa-
tions with alleles at the HLA locus have been found. The
disease occurs in all ethnic groups, and race may influ-
ence severity, since DCSS is significantly more common
in black women than white. Isolated cases have been
reported in which a systemic sclerosis-like disease has
been triggered by exposure to silica dust, vinyl chloride,
hypoxyresins and trichloroethylene. There is clear evi-
dence of immunological dysfunction: T lymphocytes,
especially those of the Th17 subtype, infiltrate the skin
and there is abnormal fibroblast activation, leading to
increased production of extracellular matrix in the
dermis, primarily type I collagen. This results in sym-
metrical thickening, tightening and induration of the
skin (sclerodactyly). Arterial and arteriolar narrowing
occurs due to intimal proliferation and vessel wall
inflammation. Endothelial injury causes release of vaso-
constrictors and platelet activation, resulting in further
ischaemia, which is thought to exacerbate the fibrotic
process.
Clinical features
Skin
Initially, there is non-pitting oedema of fingers and
flexor tendon sheaths. Subsequently, the skin becomes
shiny and taut, and distal skin creases disappear. This is
accompanied by erythema and tortuous dilatation of
capillary loops in the nail-fold bed, readily visible with

Fig. 25.44 Typical facial appearance in the CREST syndrome.
an ophthalmoscope or dissecting microscope (and oil
placed on the skin). The face and neck are usually
involved next, with thinning of the lips and radial fur-
rowing. In some patients, skin thickening stops at this
stage. Skin involvement restricted to sites distal to
the elbow or knee (apart from the face) is classified as
‘limited disease’ or CREST syndrome (Fig. 25.44).
Involvement proximal to the knee and elbow and on the
trunk is classified as ‘diffuse disease’.
Raynaud’s phenomenon
This is a universal feature and can precede other features
by many years. Involvement of small blood vessels in
the extremities may cause critical tissue ischaemia,
leading to skin ulceration over pressure areas, localised
areas of infarction and pulp atrophy at the fingertips.
Musculoskeletal features
Arthralgia, morning stiffness and flexor tenosynovitis
are common. Restricted hand function is due to skin
rather than joint disease and erosive arthropathy is
uncommon. Muscle weakness and wasting can occur
due to myositis.
Gastrointestinal involvement
Smooth muscle atrophy and fibrosis in the lower two-
thirds of the oesophagus lead to reflux with erosive
oesophagitis. Dysphagia and odynophagia may also
occur. Involvement of the stomach causes early satiety
and occasionally outlet obstruction. Recurrent occult
upper gastrointestinal bleeding may indicate a ‘water-
melon’ stomach (antral vascular ectasia), which occurs
in up to 20% of patients. Small intestine involvement
may lead to malabsorption due to bacterial overgrowth
and intermittent bloating, pain or constipation. Dilata-
tion of large or small bowel due to autonomic neu-
ropathy may cause pseudo-obstruction with nausea,
vomiting, abdominal discomfort and distension, often
worse after food.
Pulmonary involvement
This is a major cause of morbidity and mortality. Pulmo-
nary hypertension complicates long-standing disease
and is six times more prevalent in LCSS than in DCSS.
It presents with rapidly progressive dyspnoea (more
rapid than interstitial lung disease), right heart failure
and angina, often in association with severe digital
Connective tissue diseases
ischaemia. Fibrosing alveolitis mainly affects patients
with DCSS who have topoisomerase 1 antibodies.
Renal involvement
One of the main causes of death is hypertensive renal
crisis, characterised by rapidly developing malignant
hypertension and renal failure. Hypertensive renal crisis
is much more likely to occur in DCSS than in LCSS, and
in patients with topoisomerase 1 antibodies.
Investigations
Scleroderma is primarily a clinical diagnosis but various
laboratory abnormalities are characteristic. The ESR is
usually elevated and raised levels of IgG are common,
but CRP values tend to be normal unless there is severe
organ involvement or coexisting infection. ANA is posi-
tive in about 70%, and approximately 30% of patients
with DCSS have antibodies to topoisomerase 1 (Scl-70).
About 60% of patients with CREST syndrome have anti-
centromere antibodies (p. 1068).
Management
No treatments are available that halt or reverse the
fibrotic changes that underlie the disease. The focus of
management, therefore, is to ameliorate the effects of the
disease on target organs.
• Raynaud’s syndrome and digital ulcers. Raynaud’s
should be treated by avoidance of cold exposure
25
and use of mittens (heated mittens are available),
supplemented if necessary with calcium
antagonists. Intermittent infusions of prostacyclin
may benefit severe digital ischaemia. The endothelin
1 antagonist bosentan can be of value in promoting
healing of digital ulcers. If these become infected,
antibiotics may be required, but as these penetrate
tissues poorly in scleroderma, they need to be given
at higher doses for a longer duration than usual.
• Oesophageal reflux should be treated with proton
pump inhibitors and anti-reflux agents. Antibiotics
may be required for bacterial overgrowth
syndromes, and metoclopramide or domperidone
may help patients with symptoms of
pseudo-obstruction.
• Hypertension should be treated aggressively
with ACE inhibitors, even if renal impairment is
present.
• Joint involvement may be treated with analgesics
and/or NSAID. If synovitis is present,
immunosuppressants such as methotrexate can also
be of value.
• Pulmonary hypertension may be treated with
bosentan. In selected patients, heart–lung
transplantation may be considered. Corticosteroids
and cytotoxic drugs are indicated in patients who
have coexisting myositis or fibrosing alveolitis.
Mixed connective tissue disease
Mixed connective tissue disease (MCTD) is a condition
in which the clinical features of SLE, systemic sclerosis
and myositis may all occur in the same patient. It most
commonly presents with synovitis and oedema of the
hands, in combination with Raynaud’s phenomenon
and muscle pain or weakness. Most patients have 1113
 RHEUMATOLOGY AND BONE DISEASE

25 anti-ribonucleoprotein (RNP) antibodies, but these can

occur in SLE without overlap features. Management
focuses on treating the individual components of the
syndrome.
Sjögren’s syndrome
This is an autoimmune disorder of unknown cause,
characterised by lymphocytic infiltration of salivary and
lachrymal glands, leading to glandular fibrosis and exo-
crine failure. The typical age of onset is between 40 and
50, with a 9 : 1 female preponderance. The disease may
occur in isolation (primary Sjögren’s syndrome) or in
patients with other autoimmune diseases (secondary
Sjögren’s syndrome).
Clinical features
The eye symptoms, termed keratoconjunctivitis sicca,
are due to a lack of lubricating tears, which, in turn,
reflects inflammatory infiltration of the lacrimal glands.
Conjunctivitis and blepharitis are frequent, and may
lead to filamentary keratitis due to tenacious mucous
filaments binding to the cornea and conjunctiva. Oral
involvement manifests as a dry mouth and typically the
patient needs to sip water to swallow food. There is a
high incidence of dental caries. Other sites of extraglan-
dular involvement are listed in Box 25.70. The disease
is associated with a 40-fold increased lifetime risk of
lymphoma.
Investigations
The diagnosis can be established by the Schirmer tear
test, which measures tear flow over 5 minutes using
absorbent paper strips placed on the lower eyelid; a
normal result is more than 6 mm of wetting. Staining
with rose Bengal may show punctate epithelial abnor-
malities over the area not covered by the open eyelid. If
the diagnosis remains in doubt, it can be confirmed by
lip biopsy, which shows focal lymphocytic infiltrate of
the minor salivary glands. Most patients have an ele-
vated ESR and hypergammaglobulinaemia, and one or
more autoantibodies, including ANA and RF. Anti-Ro
and anti-La antibodies are commonly present (see Box
25.11, p. 1068).
Management
No treatments that have disease-modifying effects have
yet been identified and management is symptomatic.
Lachrymal substitutes, such as hypromellose, should be
used during the day in combination with more viscous
lubricating ointment at night. Soft contact lenses can be
useful for corneal protection in patients with filamentary
keratitis, and occlusion of the lachrymal ducts is occa-
sionally needed. Artificial saliva and oral gels can be
tried for xerostomia but are often not effective. Stimula-
tion of saliva flow by sugar-free chewing gum or loz-
enges may be helpful. Adequate post-prandial oral
hygiene and prompt treatment of oral candidiasis are
essential. Vaginal dryness is treated with lubricants such
as K-Y jelly. Extraglandular and musculoskeletal mani-
festations may respond to steroids, and if so, immuno-
suppressive drugs can be added for their steroid-sparing
effect. Fatigue is difficult to treat; this is usually due to
non-restorative sleep (often because of xerostomia) and
is unresponsive to steroids. Immunosuppression does
not improve sicca symptoms. If lymphadenopathy or
salivary gland enlargement develops, biopsy should be
performed to exclude malignancy.

Polymyositis and dermatomyositis

25.70 Features of Sjögren’s syndrome
Risk factors
• Age of onset 40–60
• Female > male
Common clinical features
• Keratoconjunctivitis sicca
• Xerostomia
• Salivary gland enlargement
Less common features
• Low-grade fever
• Interstitial lung disease
• Anaemia, leucopenia
• Thrombocytopenia
• Cryoglobulinaemia
• Vasculitis
Autoantibodies frequently detected
• RF
• ANA
• SS-A (anti-Ro)
Associated autoimmune disorders
• SLE
• Progressive systemic
sclerosis
1114
• HLA-B8/DR3
• Non-erosive arthritis
• Raynaud’s phenomenon
• Fatigue
• Peripheral neuropathy
• Lymphadenopathy
• Lymphoreticular lymphoma
• Glomerulonephritis
• Renal tubular acidosis
• SS-B (anti-La)
• Gastric parietal cell
• Thyroid
• Primary biliary cirrhosis
• Chronic active hepatitis
• Myasthenia gravis
Polymyositis and dermatomyositis are related disorders
that are characterised by an inflammatory process affect-
ing skeletal muscle. In dermatomyositis, characteristic
skin changes also occur. Both diseases are rare, with an
incidence of 2–10 cases per million/year. They can occur
in isolation or in association with other autoimmune
diseases, such as SLE, systemic sclerosis and Sjögren’s
syndrome. The cause is unknown, although there is evi-
dence for a genetic contribution.
Clinical features
The typical presentation of polymyositis is with
symmetrical proximal muscle weakness, usually affect-
ing the lower limbs more than the upper. The onset
is usually between 40 and 60 years of age and is typi-
cally gradual, over a few weeks. Myositis is usually
widespread but focal disease can also occur. Affected
patients report difficulty rising from a chair, climbing
stairs and lifting, sometimes in combination with
muscle pain. Systemic features of fever, weight loss
and fatigue are common. Respiratory or pharyngeal
muscle involvement can lead to ventilatory failure or
aspiration that requires urgent treatment. Interstitial
lung disease occurs in up to 30% of patients and is
strongly associated with the presence of antisynthetase
(Jo-1) antibodies.

Fig. 25.45 Typical eyelid appearance in dermatomyositis. Note the
oedema and telangiectasia.
Fig. 25.46 Muscle biopsy from a patient with inflammatory
myositis. The sample shows an intense inflammatory cell infiltrate in
an area of degenerating and regenerating muscle fibres.
Dermatomyositis presents similarly but in combina-
tion with characteristic skin lesions. These include
Gottron’s papules, which are scaly, erythematous or vio-
laceous, psoriaform plaques occurring over the extensor
surfaces of PIP and DIP joints, and a heliotrope rash that
is a violaceous discoloration of the eyelid in combination
with periorbital oedema (Fig. 25.45). Similar rashes
occur on the upper back, chest and shoulders (‘shawl’
distribution). Periungual nail-fold capillaries are often
enlarged and tortuous. There is about a threefold
increased risk of malignancy in patients with dermato-
myositis and polymyositis. This may be apparent at the
time of presentation, but the risk remains increased for
at least 5 years following diagnosis.
Investigations
Muscle biopsy is the pivotal investigation and shows
the typical features of fibre necrosis, regeneration and
inflammatory cell infiltrate (Fig. 25.46). Occasionally,
however, a biopsy may be normal, particularly if myosi-
tis is patchy. In such cases, MRI is used to identify areas
of abnormal muscle for biopsy. Serum levels of CK are
usually raised and are a useful measure of disease activ-
ity, although a normal CK does not exclude the diagno-
sis, particularly in juvenile myositis. EMG can confirm
the presence of myopathy and exclude neuropathy.
Vasculitis
Screening for underlying malignancy should be under-
taken routinely, and should include CT of chest/
abdomen/pelvis, upper and lower gastrointestinal
endoscopy, and mammography in women.
Management
Oral corticosteroids (prednisolone 1 mg/kg daily) are
the mainstay of initial treatment, but high-dose intra-
venous methylprednisolone (1 g/day for 3 days) may be
required in patients with respiratory or pharyngeal
weakness. If there is a good response, steroids should be
reduced by approximately 25% per month to a mainte-
nance dose of 5–7.5 mg. Although most patients respond
well to corticosteroids, many need additional immuno-
suppressive therapy. Azathioprine and methotrexate are
the agents of first choice, but ciclosporin, cyclophospha-
mide, tacrolimus or MMF can be used as alternatives.
Intravenous immunoglobulin may be effective in refrac-
tory cases. Relapses may occur in association with a
rising CK, and indicate the need for additional therapy.
If the patient relapses or fails to respond to treatment,
this may be due to steroid-induced myopathy. A further
biopsy should be performed and may show type 2 fibre
atrophy in steroid-induced myopathy, as opposed to
necrosis and regeneration in active myositis.
Inclusion body myositis 25
This is an inflammatory disease of muscle of unknown
cause with a genetic component, which is associated
with the accumulation of abnormal protein aggregates
in affected tissue. It presents with muscle weakness in
those over the age of 40 and is more common in men.
Although proximal weakness does occur, distal involve-
ment is more usual and may be asymmetrical. Investiga-
tion is the same as for polymyositis (p. 1115) and
typically reveals a slightly elevated CK and both myo-
pathic and neurogenic changes on EMG. Muscle biopsy
shows abnormal fibres containing rimmed vacuoles
and filamentous inclusions in the nucleus and cyto-
plasm. Treatment can be tried with high-dose cortico-
steroids, immunosuppressants and immunoglobulin, as
described for polymyositis, but the therapeutic response
is often poor.
VASCULITIS
These are a heterogeneous group of diseases character-
ised by inflammation and necrosis of blood-vessel walls,
with associated damage to skin, kidney, lung, heart,
brain and gastrointestinal tract. There is a wide spec-
trum of involvement and disease severity, ranging from
mild and transient disease affecting only the skin, to
life-threatening fulminant disease with multiple organ
failure. Principal sites of involvement for the main types
of vasculitis are summarised in Figure 25.47. The clinical
features result from a combination of local tissue ischae-
mia (due to vessel inflammation and narrowing) and the
systemic effects of widespread inflammation. Systemic
vasculitis should be considered in any patient with
fever, weight loss, fatigue, evidence of multisystem
involvement, rashes, raised inflammatory markers and
abnormal urinalysis (Box 25.71). 1115
 RHEUMATOLOGY AND BONE DISEASE

25 Behçet’s syndrome
Giant cell arteritis

Polyangiitis with
granulomatosis
Takayasu’s arteritis

Kawasaki disease

Churg–Strauss
syndrome
Microscopic
polyangiitis
Polyarteritis nodosa
Cryoglobulinaemic
vasculitis
Henoch-Schönlein
Behçet’s syndrome purpura

Fig. 25.47 Types of vasculitis. The anatomical

targets of different forms of vasculitis are shown.

arthralgia and weight loss. The vessels most commonly

25.71 Clinical features of systemic vasculitis affected are the aorta and carotid, ulnar, brachial,
radial and axillary arteries. Clinical examination may
Systemic
reveal loss of pulses, bruits, hypertension and aortic
• Malaise • Weight loss with arthralgia incompetence. Investigation will identify an acute phase
• Fever and myalgia response and normocytic, normochromic anaemia, but
• Night sweats the diagnosis is based on angiography, which reveals
Rashes coarctation, occlusion and aneurysmal dilatation. The
• Palpable purpura • Ulceration distribution of involvement is classified into four types:
• Pulp infarcts • Livedo reticularis • type 1: localised to the aorta and its branches
• type 2: localised to the descending thoracic and
Ear, nose and throat
abdominal aorta
• Epistaxis • Deafness • type 3: combines features of 1 and 2
• Recurrent sinusitis • type 4: involves the pulmonary artery.
Respiratory Treatment is with high-dose steroids and immuno-
• Haemoptysis • Poorly controlled asthma suppressants, as described for SLE. With appropriate
• Cough treatment, the 5-year survival is 83%.
Gastrointestinal
• Abdominal pain (due to • Mouth ulcers
mucosal inflammation or • Diarrhoea Kawasaki disease
enteric ischaemia)
Neurological Kawasaki disease is a vasculitis that mostly affects the
coronary vessels. It presents as an acute systemic disor-
• Sensory or motor neuropathy
der, usually affecting children under 5 years. It occurs
mainly in Japan and other Asian countries, such as
China and Korea, but other ethnic groups may also be
affected. Presentation is with fever, generalised rash,
Takayasu’s disease including palms and soles, inflamed oral mucosa and
conjunctival injection resembling a viral exanthem. The
Takayasu’s disease predominantly affects the aorta, its cause is unknown but is thought to be the result of
major branches and occasionally the pulmonary arteries. an abnormal immune response to an infectious trigger.
The typical age at onset is between 25 and 30 years, with Cardiovascular complications include coronary arteritis,
an 8 : 1 female preponderance. It has a worldwide leading to myocardial infarction, transient coronary
distribution but is most common in Asia. Takayasu’s is dilatation, myocarditis, pericarditis, peripheral vascular
characterised by granulomatous inflammation of the insufficiency and gangrene. Treatment is with aspirin
vessel wall, leading to vessel occlusion or weakening (5 mg/kg daily for 14 days) and intravenous gamma-
1116 of the vessel wall. It presents with claudication, fever, globulin (400 mg/kg daily for 4 days).

Fig. 25.48 Rash of systemic vasculitis (palpable purpura).
Polyarteritis nodosa
Polyarteritis nodosa has a peak incidence between the
ages of 40 and 50, with a male preponderance of 2 : 1. The
annual incidence is around 2/1 000 000. Hepatitis B is an
important risk factor, and the incidence is 10 times
higher in the Inuit of Alaska, in whom hepatitis B infec-
tion is endemic. Presentation is with fever, myalgia,
arthralgia and weight loss, in combination with mani-
festations of multisystem disease. The most common
skin lesions are palpable purpura (Fig. 25.48), ulceration,
infarction and livedo reticularis (see Fig. 25.42, p. 1111).
Pathological changes comprise necrotising inflamma-
tion and vessel occlusion, and in 70% of patients, arteri-
tis of the vasa nervorum leads to neuropathy, which is
typically symmetrical and affects both sensory and
motor function. Severe hypertension and/or renal
impairment may occur due to multiple renal infarctions,
but glomerulonephritis is rare (in contrast to micro-
scopic polyangiitis). The diagnosis is confirmed by angi-
ography, which shows multiple aneurysms and smooth
narrowing of mesenteric, hepatic or renal systems, or by
muscle or sural nerve biopsy, which reveals the histo-
logical changes above. Treatment is with high-dose ster-
oids and immunosuppressants, as described for SLE.
Giant cell arteritis and polymyalgia
rheumatica
Giant cell arteritis (GCA) is a granulomatous arteritis
that predominantly affects medium-sized arteries in the
head and neck. It is commonly associated with poly-
myalgia rheumatica (PMR), which presents with sym-
metrical muscle pain and stiffness affecting the shoulder
and pelvic girdles. Since many patients with GCA have
symptoms of PMR, and many patients with PMR go on
to develop GCA if untreated, many rheumatologists
consider them to be different manifestations of the same
Vasculitis
25.72 Conditions that can mimic
polymyalgia rheumatica
• Fibromyalgia • Inflammatory myopathy
• Hypothyroidism (particularly inclusion body
• Cervical spondylosis myositis, p. 1115)
• RA • Malignancy
• Systemic vasculitis
underlying disorder. Both diseases are rare under the
age of 60 years. The average age at onset is 70, with a
female preponderance of about 3 : 1. The overall preva-
lence is about 20 per 100 000 in those over the age of
50 years.
Clinical features
The cardinal symptom of GCA is headache, which is
often localised to the temporal or occipital region and
may be accompanied by scalp tenderness. Jaw pain
develops in some patients, brought on by chewing or
talking, due to ischaemia of the masseter muscles. Visual
disturbance can occur and a catastrophic presentation is
with blindness in one eye due to occlusion of the poste-
rior ciliary artery. On fundoscopy, the optic disc may
appear pale and swollen with haemorrhages, but these
changes may take 24–36 hours to develop and the fundi 25
may initially appear normal. Other visual symptoms
include loss of visual acuity, reduced colour perception
and papillary defects. Rarely, neurological involvement
may occur, with transient ischaemic attacks, brainstem
infarcts and hemiparesis.
The cardinal features of PMR are symmetrical muscle
pain and stiffness affecting the shoulder and pelvic
girdles. Constitutional symptoms, such as weight loss,
fatigue, malaise and night sweats, are common. The
onset of symptoms is usually fairly sudden over a few
days, but may be more insidious. On examination, there
may be stiffness and painful restriction of active shoul-
der movement but passive movements are preserved.
Muscles may be tender to palpation but weakness and
muscle-wasting are absent. Other conditions that mimic
PMR are shown in Box 25.72.
Investigations
The typical laboratory abnormality is an elevated ESR,
often with a normochromic, normocytic anaemia. CRP
may also be elevated and in some cases this precedes
elevation of the ESR. Rarely, PMR and GCA can present
with a normal ESR. The diagnosis is usually based on a
combination of the typical clinical features, raised ESR
and prompt response to steroid. However, if there is
doubt concerning the diagnosis of GCA, a temporal
artery biopsy may be undertaken. Characteristic biopsy
findings are fragmentation of the internal elastic lamina
with necrosis of the media in combination with a mixed
inflammatory cell infiltrate. Whilst a positive biopsy is
helpful, a negative biopsy does not exclude the diagno-
sis because the lesions are focal. Ultrasound or arteriog-
raphy may be used to help guide the biopsy.
Management
Corticosteroids are the treatment of choice and should
be commenced urgently in suspected GCA because of
the risk of visual loss (Box 25.73). Response to treatment 1117
 RHEUMATOLOGY AND BONE DISEASE
25 25.73 Emergency management of
giant cell arteritis
• Take blood for ESR and CRP
• Commence prednisolone 40–60 mg daily
• Review patient in 3–4 days
• Continue steroids in patients whose symptoms have resolved,
with gradual reduction in dose
• Organise temporal artery biopsy in patients with poor or
equivocal response
is dramatic, such that symptoms will have completely
resolved within 48–72 hours of starting corticosteroid
therapy in virtually all patients. It is customary to use
higher doses in GCA (60–80 mg prednisolone) than in
PMR (15–30 mg), although the evidence base for this is
weak. In both conditions the steroid dose should be
progressively reduced, guided by symptoms and ESR,
with the aim of reaching a dose of 10–15 mg by about
8 weeks. Thereafter, the rate of reduction should be
slower – by 1 mg per month – until an acceptable dose
is achieved (5–7.5 mg daily). If symptoms recur, the dose
should be increased to that which previously controlled
the symptoms, and reduction attempted again in another
few weeks. Most patients need steroids for an average
of 12–24 months. Some patients also require steroid-
sparing agents, such as methotrexate or azathioprine, if
they require a maintenance dose of prednisolone of
more than 7.5 mg daily. Prophylaxis against osteoporo-
sis should be given in patients with low BMD.
Antineutrophil cytoplasmic
antibody-associated vasculitis
Antineutrophil cytoplasmic antibody (ANCA)-associ-
ated vasculitis is a life-threatening disorder character-
ised by inflammatory infiltration of small blood vessels,
fibrinoid necrosis and the presence of circulating anti-
bodies to ANCA. The combined incidence is about 10–
15/1 000 000. Two subtypes are recognised. Microscopic
polyangiitis (MPA) is a necrotising small-vessel vasculi-
tis found with rapidly progressive glomerulonephritis,
often in association with alveolar haemorrhage. Cutane-
ous and gastrointestinal involvement is common and
other features include neuropathy (15%) and pleural
effusions (15%). Patients are usually myeloperoxidase
(MPO) antibody-positive. In granulomatosis with poly-
angiitis (also known as Wegener’s granulomatosis
(WG)), the vasculitis is characterised by granuloma for-
mation, mainly affecting the nasal passages, airways and
kidney. A minority of patients present with glomerulo-
nephritis. The most common presentation of WG is with
epistaxis, nasal crusting and sinusitis, but haemoptysis
and mucosal ulceration may also occur. Deafness may be
a feature due to inner ear involvement, and proptosis
may occur because of inflammation of the retro-orbital
tissue (Fig. 25.49). This causes diplopia due to entrap-
ment of the extra-ocular muscles, or loss of vision due to
optic nerve compression. Disturbance of colour vision is
an early feature of optic nerve compression. Untreated
nasal disease ultimately leads to destruction of bone and
1118 cartilage. Migratory pulmonary infiltrates and nodules
Fig. 25.49 Eye involvement in granulomatosis with polyangiitis.
occur in 50% of patients. Patients with WG are usually
proteinase-3 (PR3) antibody-positive.
Patients with active disease usually have a leuco-
cytosis with an elevated CRP and ESR, in association
with raised ANCA levels. Complement levels are usually
normal or slightly elevated. Imaging of the upper
airways or chest with MRI can be useful in localising
abnormalities but, where possible, the diagnosis should
be confirmed by biopsy of the kidney or lesions in the
sinuses and upper airways.
Management is with high-dose steroids and
cyclophosphamide, as described for SLE, followed
by maintenance therapy with lower-dose steroids and
azathioprine, methotrexate or mycophenolate mofetil
(MMF). Rituximab in combination with high-dose ster-
oids is equally effective as oral cyclophosphamide at
inducing remission in ANCA-associated vasculitis. Both
MPA and WG have a tendency to relapse, and patients
must be followed on a regular and long-term basis to
check for clinical signs of recurrence. Measurements of
ESR, CRP and levels of ANCA antibodies are useful in
monitoring disease activity.
Churg–Strauss syndrome
Churg–Strauss syndrome (CSS) is a small-vessel vascu-
litis with an incidence of about 1–3 per 1 000 000; it is
associated with eosinophilia. Some patients have a pro-
dromal period for many years, characterised by allergic
rhinitis, nasal polyposis and late-onset asthma that is
often difficult to control. The typical acute presentation
is with a triad of skin lesions (purpura or nodules),
asymmetric mononeuritis multiplex and eosinophilia.
Pulmonary infiltrates and pleural or pericardial effu-
sions due to serositis may be present. Up to 50% of
patients have abdominal symptoms provoked by
mesenteric vasculitis. Patients with active disease have
raised levels of ESR and CRP and an eosinophilia.
Although antibodies to MPO or PR3 can be detected in
up to 60% of cases, CSS is considered to be a distinct
disorder from the other ANCA-associated vasculitides.
Biopsy of an affected site reveals a small-vessel vascu-
litis with eosinophilic infiltration of the vessel wall.
Management is with high-dose steroids and cyclophos-
phamide, followed by maintenance therapy with low-
dose steroids and azathioprine, methotrexate or MMF.
 RHEUMATOLOGY AND BONE DISEASE
25 DISEASES OF BONE
Osteoporosis
Osteoporosis is the most common bone disease and
affects millions of people worldwide. Fractures related
to osteoporosis are estimated to affect around 30% of
women and 12% of men in developed countries, and are
a major public health problem. In the UK alone, fractures
are sustained by over 250 000 individuals annually, with
treatment costs of about £1.75 billion. Osteoporotic frac-
tures can affect any bone, but the most common sites are
the forearm (Colles fracture), spine (vertebral fracture)
and hip (Fig. 25.51). Of these, hip fractures are the most
serious. Their immediate mortality is about 12% and
there is a continued increase in mortality of about 20%
when compared with age-matched controls. Treatment
of hip fracture accounts for the majority of the health-
care costs associated with osteoporosis.
The defining feature of osteoporosis is reduced bone
density, which causes a micro-architectural deteriora-
tion of bone tissue and leads to an increased risk of
fracture. The prevalence of osteoporosis increases
with age, reflecting the fact that bone density declines
with age, especially in women (Fig. 25.52). The age-
related decline in bone mass is accompanied by an
increased risk of fractures (Fig. 25.53). This is due in
part to the fall in bone density, but more importantly,
to the increased risk of falling, which increases with age
(p. 172).
Pathophysiology
Osteoporosis occurs because of a defect in attaining peak
bone mass and/or because of accelerated bone loss. In
normal individuals, bone mass increases during skeletal
growth to reach a peak between the ages of 20 and
40 years but falls thereafter (see Fig. 25.52). In women
there is an accelerated phase of bone loss after the meno-
pause due to oestrogen deficiency, which causes uncou-
pling of bone resorption and bone formation, such that
the amount of bone removed by osteoclasts exceeds the
rate of new bone formation by osteoblasts. Age-related
bone loss is a distinct process that accounts for the
gradual bone loss that occurs with advancing age in both
genders. Bone resorption is not particularly increased
but bone formation is reduced and fails to keep pace
with bone resorption. Accumulation of fat in the bone
marrow space also occurs because of an age-related
decline in the ability of bone marrow stem cells to
A B
1120 Fig. 25.51 Osteoporotic fractures: X-rays. A Wrist (Colles fracture). B Spine. C Hip.
differentiate into osteoblasts and an increase in their
ability to differentiate into adipocytes.
Peak bone mass and bone loss are regulated by
both genetic and environmental factors. Genetic factors
account for up to 80% of the population variance in peak
bone mass and other determinants of fracture risk, such
as bone turnover and bone size. Polymorphisms have
been identified in several genes that contribute to the
pathogenesis of osteoporosis and many of these are in
the RANK and Wnt signalling pathways, which play a
critical role in regulating bone turnover (see Fig. 25.2,
p. 1061). However, these account for only a small propor-
tion of the genetic contribution to osteoporosis and many
additional genetic variants remain to be discovered.
Environmental factors, such as exercise and calcium
intake during growth and adolescence, are important in
maximising peak bone mass and in regulating rates of
post-menopausal bone loss. Smoking has a detrimental
effect on bone mineral density (BMD) and is associated
with an increased fracture risk, partly because female
smokers have an earlier menopause than non-smokers.
Heavy alcohol intake is a recognised cause of osteoporo-
sis and fractures, but moderate intake does not substan-
tially alter risk.
Post-menopausal osteoporosis
This is the most common cause of osteoporosis because
of the effects of oestrogen deficiency, as described above.
Early menopause (below the age of 45 years) is a particu-
larly important risk factor.
Male osteoporosis
Osteoporosis is less common in men and a secondary
cause can be identified in about 50% of cases. The
most common are hypogonadism, corticosteroid use
(see below) and alcoholism. In hypogonadism, the
pathogenesis is as described for post-menopausal osteo-
porosis, as testosterone deficiency results in an increase
in bone turnover and uncoupling of bone resorption
from bone formation. Genetic factors are probably
important in the 50% of cases with no identifiable cause.
Corticosteroid-induced osteoporosis
This is an important cause of osteoporosis that relates to
dose and duration of corticosteroid therapy. Although
there is no ‘safe’ dose of corticosteroid, the risk increases
when the dose of prednisolone exceeds 7.5 mg daily and
is continued for more than 3 months. Corticosteroids
have adverse effects on calcium metabolism and bone
cell function. A key abnormality is reduced bone
C
 Diseases of bone

A
+1.0
25.75 Secondary causes of osteoporosis and
osteoporotic fractures
Endocrine disease
Bone density T-score
0
Normal • Hypogonadism • Hyperparathyroidism
–1.0
• Hyperthyroidism • Cushing’s syndrome
Inflammatory disease
Osteopenia
–2.0 • Inflammatory bowel disease • RA
• Ankylosing spondylitis
–3.0 Osteoporosis Drugs
• Corticosteroids • Thiazolidinediones
• Gonadotrophin-releasing • Sedatives
0 20 40 60 80 hormone (GnRH) agonists • Anticonvulsants
• Aromatase inhibitors • Alcohol intake > 3 U/day
B • Thyroxine over-replacement • Heparin
Gastrointestinal disease
• Malabsorption • Chronic liver disease
Lung disease
• Chronic obstructive • Cystic fibrosis
pulmonary disease
Normal Osteoporosis Miscellaneous
Fig. 25.52 Changes in bone mass and microstructure with age. • Myeloma • Systemic mastocytosis
A Changes in bone mass with age in men (blue line) and women (red • Homocystinuria • Immobilisation
line). B Scanning electron micrographs of normal bone (left) and Body mass index < 18
25
• Anorexia nervosa* •
osteoporotic bone (right). • Highly trained athletes* • Heavy smokers
• HIV infection • Autoantibodies to
Women Men • Gaucher’s disease osteoprotegerin (OPG)
Fractures/100000 person-years

3000
Hip
Spine *Hypogonadism also plays a role in osteoporosis associated with these
Wrist conditions.
2000

1000 hyperparathyroidism causes bone loss because sus-

40 50 60 70 80 90 40 50 60 70 80
Age (years)
Fig. 25.53 Relationship between age and the incidence of
osteoporotic fractures. Changes in the incidence of wrist fractures,
vertebral fractures and hip fractures with age.
formation due to a direct inhibitory effect on osteoblast
function and steroid-induced osteoblast and osteocyte
apoptosis. Corticosteroids also inhibit intestinal calcium
absorption and cause a renal leak of calcium, and this
tends to reduce serum calcium, leading to secondary
hyperparathyroidism with increased osteoclastic bone
resorption. Hypogonadism may also occur with high-
dose steroids.
Pregnancy-associated osteoporosis
This is a rare condition that typically presents with back
pain and multiple vertebral fractures during the second
or third trimester. The cause is unknown but may relate
to an exaggeration of the bone loss that normally occurs
during pregnancy, in patients with pre-existing low
bone mass.
Other causes
Osteoporosis can occur as a complication of many
diseases and drug treatments (Box 25.75). Primary
tained elevation in PTH increases bone turnover, and
bone formation cannot keep pace with resorption. A
similar mechanism operates in thyrotoxicosis, driven
90 by raised levels of thyroid hormones. Cushing’s disease
Age (years) is a rare cause, identical in mechanism to corticosteroid-
induced osteoporosis. Anorexia nervosa causes osteo-
porosis through calcium deficiency, low body weight
and hypogonadism, whereas malabsorption predis-
poses to it through malnutrition, calcium and vitamin
D deficiency and consequent secondary hyperpara-
thyroidism. Chronic HIV infection predisposes to osteo-
porosis because of low body weight, chronic immune
activation and antiretroviral therapy. Inflammatory dis-
eases increase bone resorption and suppress bone for-
mation through release of pro-inflammatory cytokines
such as IL-1 and TNF, and increased expression of
RANK by lymphocytes. Similar mechanisms operate in
certain cancers, which release a variety of bone-resorbing
factors, including TNF, lymphotoxin and parathyroid
hormone-related protein (PTHrP). Gaucher’s disease
(p. 451) and systemic mastocytosis also cause release
of bone resorbing factors. Thiazolidinediones such
as rosiglitazone inhibit osteoblast differentiation and
promote adipocyte differentiation in the bone marrow,
leading to reduced bone formation and bone loss.
Aromatase inhibitors cause osteoporosis by reducing
peripheral conversion of adrenal androgens to oestro-
gen, whereas gonadotrophin-releasing hormone ago-
nists do so by causing hypogonadism. 1121
 RHEUMATOLOGY AND BONE DISEASE

25 Clinical features
Patients with osteoporosis are asymptomatic until a frac-
with an elevated 10-year fracture risk as defined by a
fracture risk assessment tool (websites listed on p. 1135).
Figure 25.54 provides an algorithm for the investigation
ture occurs. Osteoporotic spinal fracture may present
of patients with suspected osteoporosis based on clinical
with acute back pain or gradual onset of height loss and
risk factors, fracture risk assessment and DEXA.
kyphosis with chronic pain. The pain of acute vertebral
A history should be taken to identify any predispos-
fracture can occasionally radiate to the anterior chest or
ing causes, such as early menopause, excessive alcohol
abdominal wall and be mistaken for a myocardial infarc-
intake, smoking and corticosteroid therapy. Signs of
tion or intra-abdominal pathology, but worsening of
endocrine disease, neoplasia and inflammatory disease
pain by movement and local tenderness both suggest
should be sought on clinical examination. A falls history
vertebral fracture. Peripheral osteoporotic fractures
should be taken and a ‘get up and go’ test performed,
present with local pain, tenderness and deformity, often
especially in older patients (p. 167). Renal function, liver
after an episode of minimal trauma. In patients with hip
function, thyroid function, immunoglobulins and ESR,
fracture, the affected leg is shortened and externally
with screening for coeliac disease (anti-tissue trans-
rotated. Many patients present with incidental osteo-
glutaminase (tTG) antibodies), should be performed.
penia on an X-ray performed for other reasons.
Serum 25(OH) vitamin D and PTH measurements are
Investigations useful to exclude vitamin D deficiency and secondary
hyperparathyroidism. Primary hyperparathyroidism
The pivotal investigation is dual energy X-ray absorptio-
should be suspected if hypercalcaemia is present
metry (DEXA) at the lumbar spine and hip (see Fig. 25.8,
(p. 769). Levels of sex hormones and gonadotrophins
p. 1066). This should be considered in patients with clini-
should be measured in men with osteoporosis and
cal risk factors for osteoporosis (Box 25.76), and those
women under the age of 50. Transiliac bone biopsy is
sometimes required in early-onset osteoporosis of
unknown cause or when coexisting osteomalacia is
25.76 Indications for bone densitometry suspected.

• Low trauma fracture age > 50 years*

• Clinical features of osteoporosis (height loss, kyphosis) Management
• Osteopenia on plain X-ray The aim of treatment is to reduce the risk of fracture
• Corticosteroid therapy (> 7.5 mg prednisolone daily for and this can be achieved by a combination of non-
> 3 mths) pharmacological and pharmacological approaches.
• Family history of hip fracture
• Low body weight (BMI < 18) Non-pharmacological interventions
• Early menopause (< 45 yrs)
• Diseases associated with osteoporosis Advice on smoking cessation, moderation of alcohol
• Increased fracture risk on risk factor analysis (FRAX or intake, adequate dietary calcium intake and exercise
QFracture) should be given. Those with recurrent falls or unsteadi-
• Assessing response of osteoporosis to treatment ness on a ‘get up and go’ test should be referred to a
multidisciplinary falls prevention team (p. 172). Hip
*Defined as a fracture that occurs as the result of a fall from standing protectors can reduce the risk of hip fracture in selected
height or less.
patients but adherence is often poor.

Clinical risk factors Fragility fracture

+ fracture risk assessment* age > 50

Low risk Moderate or high risk

Reassure Measure BMD

at spine and hip

Normal Osteopenia Osteoporosis

(T-score > −1.0) (T-score −1.5 to −2.5) (T-score < –2.5)

Lifestyle advice Lifestyle advice

Reassure and reassess and drug
after 2–5 years treatment

Fig. 25.54 Algorithm for the investigation of patients with suspected osteoporosis. *Using FRAX® or QFracture (see Further information,
1122 p. 1135). (BMD = bone mineral density)

Drug treatment
Several drugs have been shown to reduce the risk of
osteoporotic fractures in randomised controlled trials.
Their effects on vertebral and non-vertebral fracture are
also summarised in Box 25.77.
Drug treatment should be considered in patients
with BMD T-score values below −2.5 or below −1.5 in
corticosteroid-induced osteoporosis, because there is
evidence that fractures occur at a higher BMD value in
steroid users and that drugs prevent fracture in patients
with T-scores at this level. Treatment should also be
considered in patients with vertebral fractures, irre-
spective of BMD, unless they resulted from significant
trauma.
Bisphosphonates
Bisphosphonates inhibit bone resorption by binding to
hydroxyapatite crystals on the bone surface. When
osteoclasts attempt to resorb bone that contains bisphos-
phonate, the drug is released within the cell, where it
inhibits key signalling pathways that are essential for
osteoclast function. Although bisphosphonates prima-
rily target the osteoclast, bone formation is also sup-
pressed because of coupling between bone formation
and bone resorption and an inhibitory effect on osteo-
blasts. However, the balance of effect on bone turnover
is favourable, resulting in a gain in bone density due
partly to increased mineralisation of bone. Bisphospho-
nate treatment typically leads to an increase in spine
BMD of about 5–8% and in hip BMD of 2–4% during the
first 3 years of treatment and plateaus thereafter.
Alendronic acid is the bisphosphonate used most fre-
quently. It reduces risk of vertebral fractures by 40% and
non-vertebral fractures by about 25% in postmenopausal
women with osteoporosis. Risedronate is an alternative
with similar efficacy, but may be better tolerated in
patients with a history of gastrointestinal upset. Both
drugs are effective in the treatment of corticosteroid-
induced osteoporosis. They can also be used to treat
25.77 Effects of drugs on the risk of osteoporotic fractures
Drug Regimen
Alendronic acid 70 mg/wk orally
Risedronate 35 mg/wk orally
Ibandronate 150 mg/mth orally
3 mg 3-monthly IV
Zoledronic acid 5 mg annually IV
Denosumab 60 mg 6-monthly SC
Strontium ranelate 2 g daily orally
Hormone replacement therapy Various preparations
PTH 1-34 20 μg/day SC
PTH 1-84 100 μg/day SC
Raloxifene 60 mg/day orally
Tibolone 1.25 mg/day orally
Calcium/vitamin D 500 mg calcium and
800 U vitamin D orally
(+ effective, – not effective; +/– equivocal results, or efficacy based on post-hoc subgroup analysis of clinical trials.)
Diseases of bone
male osteoporosis but neither has been shown to prevent
non-vertebral fractures in men. Ibandronate is some-
times used but the evidence for prevention of non-
vertebral fractures is less robust. Zoledronic acid is
effective in the treatment of post-menopausal osteoporo-
sis, corticosteroid-induced osteoporosis and osteoporo-
sis in men. It reduces the risk of vertebral fracture by
about 75% with similar effects to alendronic acid on non-
vertebral fractures. It is especially useful for secondary
prevention of fractures in elderly patients with hip frac-
ture and reduces mortality in this group, being the only
treatment that has been shown to modify this. Etidro-
nate reduces the risk of vertebral fracture but the effects
on non-vertebral fracture are less robust than those of
other bisphosphonates. It is now seldom used.
Oral bisphosphonates are poorly absorbed from the
gastrointestinal tract and should be taken on an empty
stomach with plain water; no food should be eaten
for 30–45 minutes after administration. Upper gastro-
intestinal upset occurs in about 5% so oral bisphospho-
nates should be used with caution in patients with
existing gastro-oesophageal reflux disease. They should
be avoided in patients with oesophageal stricture or
achalasia, since tablets may stick in the oesophagus,
causing ulceration and perforation. The most common
adverse effect with intravenous bisphosphonates is a
transient influenza-like illness characterised by fever,
malaise, anorexia and generalised aches, which occurs
25
24–48 hours after administration. This is self-limiting but
can be treated with paracetamol or NSAID if necessary.
It predominantly occurs after the first exposure and tol-
erance develops thereafter. Other adverse effects are
shown in Box 25.78. Osteonecrosis of the jaw (ONJ) is
characterised by the presence of necrotic bone in the
mandible or maxilla, typically occurring after tooth
extraction when the socket fails to heal. Most ONJ cases
have occurred in cancer patients with coexisting mor-
bidity, such as infection and diabetes, who have received
high doses of intravenous bisphosphonates; this compli-
cation is very rare in patients who are treated with the
Vertebral fracture Non-vertebral fracture Hip fracture
+ + +
+ + +
+ +/– –
+ + +
+ + +
+ + +/–
+ + +
+ + –
+ – –
+ – –
+ + –
– +/– –
1123
 RHEUMATOLOGY AND BONE DISEASE
25 25.78 Adverse effects of bisphosphonates
Common
• Upper gastrointestinal intolerance (oral)
• Acute phase response (intravenous)
Less common
• Atrial fibrillation (intravenous zoledronic acid)
• Renal impairment (intravenous zoledronic acid)
• Atypical subtrochanteric fractures
Rare
• Uveitis
• Osteonecrosis of the jaw
dose regimes used in osteoporosis. None the less, all
patients receiving bisphosphonates for any reason
should be advised to pay attention to good oral hygiene.
There is no evidence that temporarily stopping medica-
tion in patients undergoing tooth extraction is necessary
or alters the occurrence of ONJ. Atypical subtrochanteric
fractures have been described in patients who have
received long-term bisphosphonates, and may be the
result of over-suppression of normal bone remodelling.
In the vast majority, the benefits of bisphosphonate
therapy far outweigh the risks, but it is important that
treatment is targeted to patients with low BMD who are
most likely to benefit.
Denosumab
Denosumab is a monoclonal antibody that neutralises
the effects of RANKL (see Figure 25.2, p. 1061); it is
administered by subcutaneous injection every 6 months
in the treatment of osteoporosis. It is a powerful inhibi-
tor of bone resorption and reduces the risk of hip frac-
tures by 40%, vertebral fractures by 70% and other
non-vertebral fractures by 20%. It has few adverse effects
but there are isolated reports of ONJ with long-term use.
Unlike bisphosphonates, its duration of action is short
and it must be administered on a long-term basis to
maintain its effect on bone mass and bone turnover.
Calcium and vitamin D
Calcium and vitamin D have limited efficacy in the
prevention of osteoporotic fractures when given in
isolation but are widely used as an adjunct to other
treatments, most often as combination preparations con-
taining 500 mg calcium and 800 U vitamin D. They are
of greatest value in preventing fragility fractures in
elderly or institutionalised patients who are at high risk
of calcium and vitamin D deficiency (Box 25.79).
Strontium ranelate
Strontium ranelate reduces vertebral fracture risk by
about 50% after 3 years and non-vertebral fracture risk
by 12%. The mechanism of action is poorly understood.
It has a weak inhibitory effect on bone resorption, stimu-
lates biochemical markers of bone formation and is
incorporated within hydroxyapatite crystals in place of
calcium. Large changes in BMD (12%) occur, although
this is partly an artefact due to substitution of strontium
for calcium in bone mineral. The most common adverse
effect is diarrhoea. Strontium is contraindicated in
1124 patients with cardiovascular disease due to an increased
25.79 Osteoporosis in old age
• Bone loss: due to increased bone turnover, with an
age-related defect switch in differentiation of bone marrow
stromal cells to form adipocytes as opposed to osteoblasts.
• Fractures due to osteoporosis: common cause of morbidity
and mortality, although fracture healing is not delayed by age.
• Recurrent fractures: those who suffer a fragility fracture are
at increased risk of further fracture, so should be
investigated for osteoporosis and treated if this is confirmed.
• Falls: risk factors for falls (such as visual and neuromuscular
impairments) are independent risk factors for hip fracture in
elderly women, so intervention to prevent falls is as
important as treatment of osteoporosis (p. 172).
• Intravenous zoledronic acid: reduces mortality and
subsequent fracture in elderly patients with hip fractures.
• Calcium and vitamin D: reduce the risk of fractures in those
who are housebound or living in care homes.
risk of myocardial infarction. There is also an increased
risk of venous thrombosis. Rarely, a severe rash occurs,
and this is an indication to stop treatment.
Parathyroid hormone
PTH is an anabolic agent that works by stimulating new
bone formation. The most widely used preparation is the
1-34 fragment of PTH (teriparatide) given by single daily
subcutaneous injection of 20 μg. Teriparatide increases
BMD by 10% or more in osteoporotic subjects and
reduces risk of vertebral fractures by about 65% and
non-vertebral fractures by 50%. It is also effective in
corticosteroid-induced osteoporosis and appears supe-
rior to alendronate in terms of BMD gain and vertebral
fracture reduction. It is also effective in male osteoporo-
sis. PTH is expensive and is usually reserved for patients
with severe osteoporosis (BMD T-score of −3.5 to −4.0 or
below) and those who have failed to respond adequately
to other treatments. The recommended duration of treat-
ment is 24 months, after which patients should receive
an antiresorptive drug, such as a bisphosphonate, to
maintain the increase in BMD. Teriparatide should not
be administered at the same time as bisphosphonates, as
this blunts the anabolic effect. In patients who are being
treated with teriparatide because of failure to respond,
existing treatments should be stopped. The 1-84 frag-
ment of PTH acts in a similar way to teriparatide but the
evidence for prevention of non-vertebral fracture is less
robust.
Hormone replacement therapy,
raloxifene and tibolone
Cyclical HRT with oestrogen and progestogen prevents
post-menopausal bone loss and reduces the risk of ver-
tebral and non-vertebral fractures in post-menopausal
women. It is primarily indicated for the prevention of
osteoporosis in women with an early menopause
(p. 760) and for treatment of women with osteoporosis
in their early fifties who have troublesome menopausal
symptoms. HRT should be avoided in older women
with established osteoporosis because it significantly
increases the risk of breast cancer and cardiovascular
disease. Raloxifene acts as a partial agonist at oestrogen
receptors in bone and liver but as an antagonist in breast
and endometrium, and is classified as a selective
oestrogen receptor modulator (SERM). It results in a

modest increase in BMD (2%) and a 40% reduction in
vertebral fractures, but does not influence the risk of
non-vertebral fracture and can provoke muscle cramps
and worsen hot flushes. It increases the risk of VTE to a
similar extent as HRT but reduces the risk of breast
cancer; it does not influence the risk of cardiovascular
disease. Bazedoxifene is a related SERM that has similar
effects to raloxifene. Tibolone is a steroid that has partial
agonist activity at oestrogen, progestogen and androgen
receptors. It has similar effects on BMD to raloxifene and
has been found to prevent vertebral and non-vertebral
fractures in post-menopausal osteoporosis. Treatment is
associated with a slightly increased risk of stroke but a
reduced risk of breast cancer.
Other drugs
Calcitonin is an osteoclast inhibitor that has weak anti-
fracture efficacy but is no longer used in the treatment
of osteoporosis because of concerns about an increased
risk of cancer with long-term use. It is occasionally used
(unlicensed) in the short-term treatment of patients with
acute vertebral fracture, when it is given by subcutane-
ous or intramuscular injection (100–200 U daily). Calci-
triol (1,25(OH)2D3), the active metabolite of vitamin D,
is licensed for treatment of osteoporosis, but it is seldom
used since the data on fracture prevention are less robust
than for other agents.
Duration of therapy and
monitoring response
Oral bisphosphonates are usually given on a long-term
basis for osteoporosis with periodic review of the
continued need for therapy at 5-yearly intervals. The
evidence base on duration of treatment is limited. Alen-
dronate and risedronate appear to be safe and effective
for up to 10 years in most patients, although one ran-
domised trial with alendronate showed that overall frac-
ture rates were similar in those given 5 years’ therapy as
opposed to 10. Studies with intravenous zoledronic acid
have shown that 3 years’ treatment give equal protection
from fractures as 6 years’ treatment. Other drug treat-
ments, such as HRT, raloxifene and denosumab, need to
be given continuously for a beneficial effect. The optimal
duration of treatment for strontium has not been estab-
lished. For anabolic drugs such as PTH, a 2-year course
of treatment is given and followed by long-term anti-
resorptive therapy.
The response to drug treatment can be assessed by
repeating BMD measurements after 2–3 years. However,
changes in BMD do not predict anti-fracture efficacy
well and there is little evidence that monitoring by BMD
or markers improves adherence. It may, however, reas-
sure the patient that the treatment is working. Since the
precision of spine BMD (approximately 1%) is better
than hip (approximately 2.5%), spine BMD is best for
monitoring. To be sure that a change has occurred, about
twice the precision (about 2% for spine, 5% for hip) is
required. This means that, under normal circumstances,
at least 2 years should have elapsed before a repeat scan
is performed. Biochemical markers of bone turnover,
such as N-telopeptide (NTX), respond more quickly
than BMD and can be used to assess adherence, but the
correlation with anti-fracture efficacy is modest. Treat-
ment response can also be established by measuring
change in patient height (to assess progression of
Diseases of bone
vertebral osteoporosis) and documenting the occurrence
of clinical fractures.
Surgery
Orthopaedic surgery is frequently required to reduce
and stabilise osteoporotic fractures. Patients with intra-
capsular fracture of the femoral neck generally require
hemi-arthroplasty or total hip replacement in view of the
high risk of avascular necrosis.
Vertebroplasty and kyphoplasty
Vertebroplasty (VP) is sometimes used in the treatment
of painful vertebral compression fractures. It involves
injecting methyl methacrylate (MMA) into the affected
vertebral body. Although VP has been found to give
better pain relief than medical therapy in the short term,
recent randomised controlled trials that compared VP
with a sham procedure showed no benefit (Box 25.80),
indicating that the reduction in pain may be a placebo
response. Kyphoplasty (KP) is used under similar cir-
cumstances but in this case a needle is introduced into
the affected vertebral body and a balloon is inflated,
which is then filled with MMA. This procedure is more
effective than medical treatment at relieving pain in the
short term, with results similar to VP. The effects of KP
have not so far been compared with a sham procedure.
Both procedures are generally safe but serious adverse
effects include spinal cord compression, and fat embolus
25
may occur.
25.80 Vertebroplasty in painful vertebral
fractures
‘Meta-analysis of individual patient data from two placebo
controlled trials of vertebroplasty showed no advantage of active
treatment over a sham procedure.’
• Staples MP, et al BMJ 2011; 343:d3952.
Management of recurrent fracture
Since the treatments for osteoporosis are incompletely
effective at preventing fracture, it is not uncommon to
encounter patients who suffer recurrent fractures whilst
on treatment. In these circumstances it is useful
to perform DEXA to determine whether BMD has
increased, provided that sufficient time has elapsed to
assess this (see above). If BMD has increased, then treat-
ment should be continued. If there has been no BMD
response or significant bone loss has occurred, the
patient should be questioned about adherence and
asked if the treatment is being taken correctly. This
is particularly important with oral bisphosphonates,
where absorption is poor and is inhibited by food. If the
patient appears to be taking the medication correctly
and significant bone loss has occurred, then a different
treatment should be considered.
Osteomalacia and rickets
These conditions are characterised by defective miner-
alisation of bone due to vitamin D deficiency, resistance
to the effects of vitamin D or hypophosphataemia.
Osteomalacia describes a syndrome in adults of defec-
tive bone mineralisation, bone pain, increased bone 1125
 RHEUMATOLOGY AND BONE DISEASE

25 25.81 Causes of osteomalacia and rickets

Cause
Vitamin D deficiency
Classical
Gastrointestinal disease
Failure of 1,25 vitamin D synthesis
Chronic renal failure
Vitamin D-resistant rickets type I
(autosomal recessive)
Vitamin D receptor defects
Vitamin D-resistant rickets type II
(autosomal recessive)
Defects in phosphate and pyrophosphate metabolism
Hypophosphataemic rickets (X-linked
dominant)
Autosomal dominant
hypophosphataemic rickets
Autosomal recessive
hypophosphataemic rickets
Tumour-induced hypophosphataemic
osteomalacia
Hypophosphatasia
Iatrogenic and other
Bisphosphonate therapy
Aluminium
Fluoride
Predisposing factor
Lack of sunlight exposure and poor diet
Malabsorption
Hyperphosphataemia and kidney
damage
Loss-of-function mutations in renal
25(OH)D 1α-hydroxylase enzyme
Loss-of-function mutations in vitamin D
receptor
Mutations in PHEX
Mutation in FGF23
DMP1 mutation
Ectopic production of FGF23 by tumour
Mutations in bone-specific alkaline
phosphatase
High-dose etidronate/pamidronate
Use of aluminium-containing phosphate
binders or aluminium in dialysis fluid
High fluoride in water
Mechanism
Reduced cholecalciferol synthesis in the skin/low
levels of vitamin D in diet
Malabsorption of dietary vitamin D and calcium
Impaired conversion of 25(OH)D3 to 1,25(OH)2D3
Impaired conversion of 25(OH)D3 to 1,25(OH)2D3
Impaired response to 1,25(OH)2D3
Increased FGF23 production (mechanism unclear)
Mutant FGF23 is resistant to degradation
Increased production of FGF23
Local deficiency of DMP1 inhibits mineralisation
Over-production of FGF23
Inhibition of bone mineralisation due to
accumulation of pyrophosphate in bone
Drug-induced impairment of mineralisation
Aluminium-induced impairment of mineralisation
Fluoride inhibits mineralisation

fragility and fractures. Rickets is the equivalent syn-
drome in children and is characterised by enlargement
of the growth plate and bone deformity. The disease
remains prevalent in frail older people who have a poor
diet and limited sunlight exposure, and in some Muslim
women who live in northern latitudes. There are four
main causes of osteomalacia and rickets (Box 25.81).
Vitamin D deficiency
The most common cause of osteomalacia and rickets is
vitamin D deficiency, which can result from either lack
of sunlight exposure, from which the majority of vitamin
D is derived; dietary deficiency (Fig. 25.55); or malab-
sorption of vitamin D in patients with gastrointestinal
disease.
Pathophysiology
The source of vitamin D and pathways involved in
regulating its metabolism are shown in Figure 25.55. In
normal individuals, vitamin D (also known as cholecal-
ciferol) comes from two sources: about 70% is made in
the skin from 7-dehydrocholesterol under the influence
of ultraviolet light, whereas the remaining 30% is
derived from the diet. On entering the circulation,
vitamin D is hydroxylated in the liver to form 25(OH)
vitamin D and this is further hydroxylated in the kidney
to form 1,25(OH)2D, the biologically active metabolite.
The 1,25(OH)2D primarily acts on the gut to increase
intestinal calcium absorption but also acts on the
skeleton to stimulate bone remodelling. Synthesis of
1126 1,25(OH)2D is regulated by a negative feedback loop
orchestrated by the parathyroid glands. When vitamin
D levels fall – for example, as the result of reduced sun-
light exposure or dietary lack – 25(OH)D and 1,25(OH)2D
levels also fall, resulting in a reduction in calcium
absorption from the gut. This causes serum calcium
levels to fall, and this is detected by calcium-sensing
receptors on the parathyroid chief cells, which respond
by secreting parathyroid hormone (PTH). The raised
levels of PTH restore calcium levels to normal by stimu-
lating production of 1,25(OH)2D, reducing renal calcium
excretion and increasing bone resorption. Renal phos-
phate excretion also increases, lowering serum phos-
phate levels. Initially, these changes are effective in
maintaining normal levels of serum calcium but, with
prolonged vitamin D deficiency, reserves of 25(OH)D
become progressively depleted (through increased
conversion of 25(OH)D to 1,25(OH)2D), leading to
hypocalcaemia and hypocalcaemia with progressive
demineralisation of the skeleton and the clinical syn-
dromes of osteomalacia and rickets.
Clinical features
Vitamin D deficiency in children causes delayed devel-
opment, muscle hypotonia, craniotabes (small unossi-
fied areas in membranous bones of the skull that yield
to finger pressure with a cracking feeling), bossing of the
frontal and parietal bones and delayed anterior fonta-
nelle closure, enlargement of epiphyses at the lower end
of the radius, and swelling of the rib costochondral junc-
tions (‘rickety rosary’). Osteomalacia in adults presents
insidiously. Mild osteomalacia can be asymptomatic or
 Diseases of bone

Sunlight
Calcium-sensing Parathyroids
Oral Parathyroid receptor
intake chief cell
Ca2+
–ve Ca2+
Ca2+ –ve feedback
PTH
Skin secretory
granules PTH

~30% ~70%
PTH
Vitamin D Kidney Bone
Liver

Vitamin D 25(OH)
25-hydroxylase 25(OH) 1,25(OH) 2
vitamin D vitamin D vitamin D
(inactive) 1α-hydroxylase (active)

Gut

Serum Serum
phosphate↓ calcium↑

Fig. 25.55 Vitamin D metabolism. There is close interaction between vitamin D, serum calcium and parathyroid hormone (PTH). See text for details. 25
present with fractures and mimic osteoporosis. More A
severe osteomalacia presents with muscle and bone
pain, general malaise and fragility fractures. Proximal
muscle weakness is prominent and the patient may walk
with a waddling gait and struggle to climb stairs or get
out of a chair. There may be bone and muscle tenderness
on pressure and focal bone pain can occur due to fissure
fractures of the ribs and pelvis.
Investigations
The diagnosis can usually be made on a biochemical
screen with measurement of serum 25(OH)D and PTH.
Typically, serum ALP levels are raised, 25(OH)D levels
are low or undetectable, and PTH is elevated. Serum
B
calcium and phosphate levels may also be low but
normal values do not exclude the diagnosis. X-rays are
normal until advanced disease, when focal radiolucent
areas (pseudofractures or Looser’s zones) may be seen
in ribs, pelvis and long bones (Fig. 25.56A). Radiographic
osteopenia is common and the presence of vertebral
crush fractures may cause confusion with osteoporosis.
In children, there is thickening and widening of the
epiphyseal plate. Radionuclide bone scan can show
multiple hot spots in the ribs and pelvis at the site of
fractures and the appearance may be mistaken for Fig. 25.56 Osteomalacia. A X-ray of the pelvis showing Looser’s
metastases. Where there is doubt, the diagnosis can be zones (arrow). B Photomicrograph of bone biopsy from osteomalacic
confirmed by bone biopsy, which shows the pathogno- patient showing thick osteoid seams (stained light blue) that cover almost
monic features of increased thickness and extent of all of the bone surface. Calcified bone is stained dark blue.
osteoid seams (Fig. 25.56B).
Management fall to within the reference range as the bone disease
Osteomalacia and rickets respond promptly to treatment heals. After 3–4 months, treatment can generally be
with vitamin D (250–1000 μg daily), with rapid clinical stopped or the dose of vitamin D reduced to a mainte-
improvement, an elevation in serum 25(OH)D and a nance level of 10–20 μg of cholecalciferol daily, except in
reduction in PTH. Serum ALP levels sometimes rise ini- patients with underlying disease such as malabsorption,
tially as mineralisation of bone increases, but eventually in whom higher doses may be required. 1127
 RHEUMATOLOGY AND BONE DISEASE
25 Vitamin D-resistant rickets
The term vitamin D-resistant rickets (VDRR) describes
osteomalacia and rickets caused by:
• inactivating mutations in the 25-hydroxyvitamin D
1α-hydroxylase (CYP27B1) enzyme, which converts
25(OH)D to the active metabolite 1,25(OH)2D3 (type
I VDRR)
• inactivating mutations in the vitamin D receptor,
which impair its ability to activate transcription
(type II VDRR).
Clinical features are similar to those of infantile rick-
ets and the diagnosis is usually first suspected when the
patient fails to respond to vitamin D supplementation.
Since both are recessive disorders, consanguinity is com-
mon but there may or may not be a positive family his-
tory. Biochemical features of type I disease are similar to
vitamin D deficiency, except that levels of 25(OH)D are
normal. In type II disease, 25(OH)D is normal but PTH
and 1,25(OH)2D3 values are raised. Type I can be treated
with the active vitamin D metabolites, 1α-hydroxyvitamin
D (1–2 μg daily, orally) or 1,25 dihydroxyvitamin D
(0.25–1.5 μg daily, orally), with or without calcium sup-
plements, depending upon the patient’s diet. Type II
VDRR is extremely difficult to treat but sometimes
responds partially to very high doses of active vitamin D
metabolites and calcium and phosphate supplements.
Renal rickets and osteomalacia
Osteomalacia and rickets occur in patients with chronic
renal failure due to defects in synthesis of renal
1,25(OH)2D3 or due to over-aggressive treatment with
oral phosphate binders. Pathogenesis and management
are discussed on page 486.
Hypophosphataemic rickets
and osteomalacia
Rickets and osteomalacia can occur as the result of
inherited or acquired defects in renal tubular phosphate
reabsorption, and rarely in patients with tumours that
secrete phosphaturic substances (see Box 25.81).
Pathophysiology
Circulating levels of FGF23 play a critical role in regulat-
ing serum phosphate by modulating expression of
sodium-dependent phosphate transporters in the
kidney, which are responsible for renal tubular phos-
phate reabsorption. Osteocytes are the main source of
FGF23 and levels of expression are regulated by the
proteins DMP1 and PHEX, which are also produced by
osteocytes (see Fig. 25.2, p. 1061). Inherited mutations
affecting these proteins are summarised in Box 25.81
and account for most cases of hypophosphataemic
rickets. Acquired hypophosphataemic rickets is mostly
caused by over-production of FGF23 by tumours.
Clinical features and diagnosis
The hereditary disorders usually present in childhood
with rickets. The diagnosis is made on the basis of the
early age at onset and the presence of hypophosphat-
aemia with renal phosphate wasting, in the absence of
vitamin D deficiency. Molecular diagnosis can define the
causal mutation. Tumour-induced hypophosphataemic
osteomalacia presents with severe, rapidly progressive
1128 symptoms in patients with no obvious predisposing
factor for osteomalacia. Strenuous efforts should be
made to identify the underlying, usually occult tumour
with whole-body MRI or CT.
Management
Treatment is with phosphate supplements (1–4 g daily)
and active metabolites of vitamin D (1α-hydroxyvitamin
D, 1–2 μg daily, or 1,25 dihydroxyvitamin D, 0.25–1.5 μg
daily) to promote intestinal calcium and phosphate
absorption. The aim is to ameliorate symptoms, restore
normal growth, maintain serum phosphate levels within
the reference range and normalise ALP levels. Levels
of calcium, phosphate, ALP and renal function should
be monitored. Tumour-induced osteomalacia can be
managed in the same way but ideally should be treated
with surgical excision of the tumour since this is
curative.
Hypophosphatasia
Hypophosphatasia is an autosomal recessive disorder
caused by inactivating mutations in the TNALP gene
that impair ALP function, resulting in accumulation of
pyrophosphate and inhibition of bone mineralisation.
Chondrocalcinosis may also occur. The diagnosis
should be suspected in osteomalacic patients with low
or undetectable levels of serum ALP but normal levels
of calcium, phosphate, PTH and vitamin D metabolites.
Medical treatment with injections of recombinant ALP
has recently been introduced with promising results.
Other causes of osteomalacia
These are summarised in Box 25.81. Aluminium intoxi-
cation is now rare due to reduced use of aluminium-
containing phosphate binders and removal of aluminium
from the water supplies used in dialysis. If aluminium
intoxication is suspected, the diagnosis can be confirmed
by demonstration of aluminium at the calcification front
in a bone biopsy. Osteomalacia due to bisphosphonates
has mostly been described in patients with Paget’s
disease receiving etidronate and high-dose pamidro-
nate. It is usually asymptomatic and healing occurs
when treatment is stopped. Excessive fluoride intake
causes osteomalacia due to direct inhibition of minerali-
sation and is common in parts of the world where there
is a high fluoride content in drinking water. The condi-
tion reverses when fluoride intake is reduced.
Paget’s disease of bone
Paget’s disease of bone (PDB) is a common condition
characterised by focal areas of increased and disorgan-
ised bone remodelling. It mostly affects the axial skele-
ton, and bones that are commonly involved include the
pelvis, femur, tibia, lumbar spine, skull and scapula. It
is seldom diagnosed before the age of 40, but gradually
increases in incidence thereafter to affect up to 8% of the
UK population by the age of 85. The disease is common
in Caucasians from north-west and southern Europe but
is rare in Scandinavians, Asians, Chinese and Japanese.
These ethnic differences persist after migration, support-
ing the importance of genetic factors in the aetiology, but
the incidence of PDB has fallen in some countries over
the past 25 years, suggesting that environmental triggers
also play a role.

Pathophysiology
The primary abnormality is increased osteoclastic bone
resorption, accompanied by marrow fibrosis, increased
vascularity of bone and increased osteoblast activity.
Bone in PDB is architecturally abnormal and has reduced
mechanical strength. Osteoclasts in PDB are increased in
number, are unusually large and contain characteristic
nuclear inclusion bodies. Genetic factors are important
and mutations in the SQSTM1 gene are a common cause
of classical PDB. The presence of nuclear inclusion
bodies in osteoclasts has fuelled speculation that PDB
might be caused by a slow virus infection with measles
or distemper but the evidence is conflicting. Biomechani-
cal factors may help determine the pattern of involve-
ment, since PDB often starts at sites of muscle insertions
into bone and, in some cases, localises to bones or limbs
that have been subjected to repetitive trauma or overuse.
Involvement of subchondral bone can compromise the
joint and predispose to OA (‘Pagetic arthropathy’).
Clinical features
The classic presentation is with bone pain, deformity,
deafness and pathological fractures, but many patients
are asymptomatic and diagnosed from an abnormal
X-ray or blood test performed for another reason. Cli-
nical signs include bone deformity and expansion,
increased warmth over affected bones, and pathological
fracture. Bone deformity is most evident in weight-
bearing bones such as the femur and tibia, but when
the skull is affected the patient may complain that hats
no longer fit due to cranial enlargement. Neurological
problems, such as deafness, cranial nerve defects, nerve
root pain, spinal cord compression and spinal stenosis,
are recognised complications due to enlargement of
affected bones and encroachment upon the spinal cord
and nerve foraminae. Surprisingly, deafness seldom
results from compression of the auditory nerve, but is
conductive due to osteosclerosis of the temporal bone.
The increased vascularity of Pagetic bone makes opera-
tive procedures difficult and, in extreme cases, can
A B
Fig. 25.57 Paget’s disease. A Isotope bone scan from a patient with Paget’s disease, illustrating the intense tracer uptake and deformity of the
affected femur. B The typical radiographic features with expansion of the femur, alternating areas of osteosclerosis and radiolucency of the trochanter,
and pseudofractures breaching the bone cortex (arrows).
Diseases of bone
precipitate high-output cardiac failure in elderly patients
with limited cardiac reserve. Osteosarcoma is a rare but
serious complication that presents with subacute onset
of increasing pain and swelling of an affected site.
Investigations
The characteristic features are an elevated serum ALP
and bone expansion on X-ray, with alternating areas of
radiolucency and osteosclerosis (Fig. 25.57B). ALP is
normal in about 5% of cases, usually because of mono-
stotic involvement. Radionuclide bone scanning is useful
to define the presence and extent of disease (Fig. 25.57A).
If the bone scan is positive, X-rays should be taken of an
affected bone to confirm the diagnosis. Bone biopsy is
not usually required but may help to exclude osteo-
sclerotic metastases in cases of diagnostic uncertainty.
Management
The main indication for treatment with inhibitors of bone
resorption is bone pain thought to be due to increased
metabolic activity (Box 25.82). It is often difficult to dif-
ferentiate this from pain due to complications such as
bone deformity, nerve compression symptoms and OA.
If there is doubt, it can be worthwhile giving a therapeu-
tic trial of antiresorptive therapy to determine whether
the symptoms improve. A positive response indicates
that the pain was due to increased metabolic activity.
The aminobisphosphonates pamidronate, zoledronate 25
and risedronate are more effective than simple bisphos-
phonates such as etidronate and tiludronate at suppress-
ing bone turnover in PDB, but their effects on pain are
similar. Although bisphosphonates suppress bone turn-
over in PDB, there is no evidence to show that they alter
the natural history or prevent complications. Calcitonin
can be used as an alternative but is less convenient to
administer and more expensive. Repeated courses of
bisphosphonates or calcitonin can be given if symptoms
recur. If symptoms do not respond to antiresorptive
therapy, it is likely that the pain is due to a complication
of the disease and this should be managed according to
the principles described on page 1085.
1129
 RHEUMATOLOGY AND BONE DISEASE

25 25.82 Medical management of Paget’s disease

Inhibitory
effect on
Route of bone
Drug administration Dose turnover
Etidronate Oral 400 mg daily +
for 3–6 mths
Tiludronate Oral 400 mg daily +
for 3–6 mths
Risedronate Oral 30 mg daily ++
for 2 mths
Pamidronate IV 1–3 × 60 mg ++
Zoledronic IV 1 × 5 mg +++
acid
Calcitonin SC 100–200 U +
3 times
weekly for
2–3 mths

+ moderately effective; ++ effective; +++ highly effective.

Fig. 25.58 Reflex sympathetic dystrophy. Isotope bone scan showing
increased uptake in femoral condyle.

Other bone diseases

Reflex sympathetic
dystrophy syndrome
Reflex sympathetic dystrophy syndrome (RSDS), or
algodystrophy, presents with gradual onset of severe
pain, swelling and local tenderness, usually affecting a
limb extremity. It is characterised by localised osteo-
porosis of the affected limb and evidence of regional
autonomic dysfunction, such as abnormal sweating,
colour and temperature change. It is commonly trig-
gered by fracture, occurring in up to 25% of patients
with Colles fracture. It can also associate with soft tissue
injury, pregnancy and intercurrent illness, or can
develop spontaneously. The cause is unknown but over-
activity of the sympathetic nervous system is thought to
be responsible for many of its features.
The diagnosis is clinical but supported by patchy
osteoporosis of the affected bone on X-ray, by a local
increase in isotope uptake on bone scanning (Fig. 25.58),
or by marrow oedema on MRI. The differential diagno-
sis includes infection and malignancy. Usually, the diag-
nosis of RSD is clear on clinical grounds and by the
absence of an acute phase response or other systemic
features of malignancy, but a biopsy of the affected site
can be undertaken if necessary and typically shows local
osteopenia only.
The aims of treatment are to control pain and encour-
age mobilisation. Analgesics, NSAID, antineuropathic
agents, calcitonin, corticosteroids, β-adrenoceptor ant-
agonists (β-blockers), sympathectomy and bisphospho-
nates have all been tried, but none is particularly
effective. Although some cases resolve with time, many
have persistent symptoms and fail to regain normal
function.
Osteonecrosis
Osteonecrosis describes death of bone due to impair-
1130 ment of its blood supply. The most commonly affected
sites are the femoral head, humeral head and femoral
condyles. In some cases, the condition occurs as the
result of direct trauma that interrupts the blood supply
to the affected bone. This is the reason for osteonecrosis
of the femoral head in patients with subtrochanteric
fractures of the femoral neck, and patients with throm-
bophilia and haemoglobinopathies such as sickle cell
disease. Other important predisposing factors include
high-dose corticosteroid treatment, alcohol excess, SLE
and radiotherapy, but in many of these conditions, the
pathophysiology is poorly understood. The presentation
is with pain localised to the affected site, which is exac-
erbated by weight-bearing. The diagnosis can be con-
firmed by MRI, which shows evidence of subchondral
necrotic bone and bone marrow oedema. X-rays are
normal in the early stages but later may show evidence
of osteosclerosis and deformity of the affected bone.
There is no specific treatment. Management should
focus on controlling pain and encouraging mobilisation
(p. 1085). Symptoms often improve spontaneously with
time but joint replacement may be required in patients
who have persisting pain in association with significant
structural damage to the affected joint.
Scheuermann’s osteochondritis
This disorder predominantly affects adolescent boys,
who develop a dorsal kyphosis in association with
irregular radiographic ossification of the vertebral end
plates. It has a strong genetic component and may be
inherited in an autosomal dominant manner. Most
patients are asymptomatic but back pain, aggravated
by exercise and relieved by rest, may occur. Excessive
exercise and heavy manual labour before epiphyseal
fusion has occurred may aggravate symptoms. Man-
agement consists of advice to avoid excessive activity,
and protective postural exercises. Rarely, corrective
surgery may be required if there is severe deformity.
During adulthood, Scheuermann’s osteochondritis can
sometimes be complicated by the development of

secondary OA, which may cause back pain. Occasion-
ally, the vertebral deformity and kyphosis can be mis-
taken for osteoporotic vertebral fractures during adult
life, but this can be excluded by DEXA examination,
which typically shows normal or raised BMD values in
Scheuermann’s disease.
Polyostotic fibrous dysplasia
This is an acquired disorder caused by mutations in the
GNAS1 gene, characterised by focal or multifocal bone
pain, bone deformity and expansion, and pathological
fractures. Associated features include endocrine dys-
function, especially precocious puberty, and café-au-lait
skin pigmentation (McCune–Albright syndrome). The
diagnosis is made by imaging, which shows focal, pre-
dominantly osteolytic lesions and bone expansion
on X-ray, and focal increased uptake on bone scan.
The condition can resemble Paget’s disease of bone but
the earlier age of onset and pattern of involvement
are usually distinctive. Management is symptomatic.
Surgery is sometimes required for treatment of fracture
and deformity. Very rarely, malignant change can occur
and should be suspected if there is a sudden increase in
pain and swelling. There is limited evidence that intra-
venous pamidronate may help bone pain and promote
healing of lytic lesions.
Osteogenesis imperfecta
Osteogenesis imperfecta (OI) is the name given to a
group of disorders characterised by severe osteoporosis
and multiple fractures in infancy and childhood. Most
cases are caused by mutations in the COL1A1 and
COL1A2 genes, which encode the proteins that make up
type I collagen. This results either in reduced collagen
production (in mild OI) or in formation of abnormal
collagen chains that are rapidly degraded (in severe OI).
Most patients have dominant inheritance but recessive
forms have been described, caused by mutations in the
CRTAP and LEPRE genes, which are involved in post-
translational modification of collagen. Many patients
have no family history and are presumed to have new
mutations. Severity varies from neonatal lethal (type II),
through very severe with multiple fractures in infancy
and childhood (types III and IV), to mild (type I), in
which affected patients typically have blue sclerae. The
diagnosis of OI is usually obvious clinically. In child-
hood, the disease can be mistaken for non-accidental
injury and in adulthood for osteoporosis. In such cases,
genetic testing can be of diagnostic value. Treatment is
multidisciplinary, involving surgical reduction and fixa-
tion of fractures and correction of limb deformities, and
physiotherapy and occupational therapy for rehabilita-
tion of patients with bone deformity. Bisphosphonates
are widely used in the treatment of OI, especially intra-
venous pamidronate in children, but there is limited
evidence that this prevents fractures or deformity.
Osteopetrosis
Osteopetrosis is a rare group of inherited diseases
caused by failure of osteoclast function. Presentation is
highly variable, ranging from a lethal disorder that
presents with bone marrow failure in infancy to a milder
and sometimes asymptomatic form that presents in
adulthood. Severe osteopetrosis is inherited in an auto-
somal recessive manner and presents with failure to
Bone and joint tumours
thrive, delayed dentition, cranial nerve palsies (due to
absent cranial foramina), blindness, anaemia and recur-
rent infections due to bone marrow failure. The adult-
onset type (Albers–Schönberg disease) shows autosomal
dominant inheritance and presents with bone pain,
cranial nerve palsies, osteomyelitis, OA or fracture, or
is sometimes detected as an incidental radiographic
finding. The responsible mutations either affect the
genes that regulate osteoclast differentiation (RANK,
RANKL), causing ‘osteoclast-poor’ osteopetrosis, or
affect the genes involved in bone resorption, causing
‘osteoclast-rich’ osteopetrosis. These include mutations
in the TCIRG1 gene, which encodes a component of the
osteoclast proton pump, and mutations in the CLCN7
gene, which encodes the osteoclast chloride pump.
Management is difficult. IFN-γ treatment can improve
blood counts and reduce frequency of infections, but in
severe cases haematopoietic stem cell transplantation is
required to provide a source of osteoclasts that resorb
bone normally.
Sclerosing bone dysplasias
These are rare diseases characterised by osteosclerosis
and increased bone formation. Van Buchem’s disease
and sclerosteosis are recessive disorders caused by loss-
of-function mutations in the SOST gene (see Fig. 25.2,
p. 1061). The resulting lack of sclerostin causes increased
bone formation and bone overgrowth, leading to
25
enlargement of the cranium and jaw, tall stature and
cranial nerve palsies. There is no effective treatment.
High bone mass syndrome is a benign disorder charac-
terised by unusually high bone density. Most patients
are asymptomatic but bone overgrowth in the palate can
occur. Treatment is not usually required. Camurati–
Engelmann disease is an autosomal dominant condition
caused by gain of function in the TGFB1 gene. It presents
with bone pain, muscle weakness and osteosclerosis
mainly affecting the diaphysis of long bones. Cortico-
steroids can help the bone pain, although analgesics are
also usually required.
BONE AND JOINT TUMOURS
Primary tumours of bones and joints are rare, have a
peak incidence in childhood and adolescence, and can
be benign or malignant (Box 25.83). Paget’s disease of
25.83 Primary tumours of the
musculoskeletal system
Cell type Benign Malignant
Osteoblast Osteoid osteoma Osteosarcoma
Chondrocyte Chondroma Chondrosarcoma
Osteochondroma
Fibroblast Fibroma Fibrosarcoma
Bone marrow cell Eosinophilic Ewing’s sarcoma
granuloma
Endothelial cell Haemangioma Angiosarcoma
Osteoclast precursor Giant cell tumour Malignant giant
cell tumour
1131
 RHEUMATOLOGY AND BONE DISEASE

25 bone (p. 1128) accounts for most cases of osteosarcoma

occurring above the age of 40.
page 710, haemophilia on page 1051 and sickle cell
anaemia on page 1032.

Osteosarcoma Malignant disease

Osteosarcoma presents with local pain, swelling and
tenderness. X-rays may show expansion of the bone
with a surrounding soft tissue mass, often containing
islands of calcification, but further evaluation by MRI or
CT is necessary to determine the extent of tumour. The
diagnosis can be confirmed by biopsy but this should
be done after referral to a specialist team. Treatment
depends on histological type but generally involves sur-
gical removal of the tumour, followed by chemotherapy
and radiotherapy. The prognosis is excellent with benign
tumours and also generally good in cases that present in
childhood and adolescence. The prognosis is poor in
elderly patients with osteosarcoma related to Paget’s
disease of bone.
Malignant disease can cause a variety of non-metastatic
musculoskeletal problems (Box 25.85). One of the most
striking is hypertrophic pulmonary osteoarthropathy,
characterised by clubbing and painful swelling of the
limbs, periosteal new bone formation and arthralgia/
arthritis. The most common causes are bronchial carci-
noma and mesothelioma (pp. 699 and 719), but the con-
dition can be inherited when it is caused by inactivating
mutations in the HPGD gene, which is responsible for
degradation of PGE2, suggesting that over-production of
prostaglandins may generally play a causal role in club-
bing. Bone scans show increased periosteal uptake
before new bone is apparent on X-ray. The course
follows that of the underlying malignancy and resolves
if this is cured.

Metastatic bone disease

Metastatic bone disease may present in a variety of
ways: with localised or generalised progressive bone
pain, generalised regional pain, symptoms of spinal cord
compression, or acute pain due to pathological fracture.
Systemic features, such as weight loss and anorexia, and
symptoms referable to the primary tumour are often
present. The tumours that most commonly metastasise
to bone are myeloma and those of bronchus, breast,
prostate, kidney and thyroid. Management is discussed
in Chapter 11.
RHEUMATOLOGICAL INVOLVEMENT IN
OTHER DISEASES
Many systemic diseases can affect the locomotor system,
and many drugs may cause adverse locomotor effects
(Box 25.84). The most common examples are described
here. Bone disease in sarcoidosis is described on
25.85 Rheumatological manifestations
of malignancy
• Polyarthritis
• Dermatomyositis and polymyositis
• Hypophosphataemic osteomalacia
• Hypertrophic osteoarthropathy
• Vasculitis, connective tissue disease
• Raynaud’s syndrome
• Polymyalgia rheumatica-like syndrome
Endocrine disease
Hypothyroidism (p. 743) may present with carpal tunnel
syndrome, or rarely with very painful, symmetrical
proximal myopathy with muscle hypertrophy. Both
resolve with thyroxine replacement. Hyperpara-
thyroidism (p. 769) predisposes to calcium pyrophos-
phate dihydrate deposition disease and to calcific
periarthritis, especially in patients with renal disease.

25.84 Drug-induced effects on the musculoskeletal system

Musculoskeletal problem Principal drug
Secondary gout Thiazides, furosemide, alcohol
Osteoporosis Corticosteroids, heparin, glitazones, aromatase inhibitors, GnRH agonists
Osteomalacia Anticonvulsants, etidronate and pamidronate (high-dose)
Osteonecrosis Corticosteroids, alcohol
Drug-induced lupus syndrome Procainamide, hydralazine, isoniazid, chlorpromazine
Arthralgias or arthritis Corticosteroid withdrawal, glibenclamide, methyldopa, ciclosporin, isoniazid, barbiturates
Myalgia Corticosteroid withdrawal, L-tryptophan, fibrates, statins
Myopathy Corticosteroids, chloroquine
Myositis, myasthenia Penicillamine, statins
Cramps Corticosteroids, ACTH, diuretics, carbenoxolone
Vasculitis Amphetamines, thiazides
(ACTH = adrenocorticotrophic hormone; GnRH = gonadotrophin-releasing hormone)
1132
 Miscellaneous conditions

Diabetes mellitus (Ch. 21) commonly causes diabetic

cheiroarthropathy characterised by tightening of skin
and periarticular structures, causing flexion deformities
of the fingers that may be painful. Diabetic osteopathy
presents as forefoot pain with radiographic progression
from osteopenia to complete osteolysis of the phalanges
and metatarsals. Diabetes also predisposes to adhesive
capsulitis, Dupuytren’s contracture, septic arthritis and
Charcot’s joints.
Acromegaly (p. 792) can be associated with mechani-
cal back pain, with normal or excessive (not restricted)
movement; carpal tunnel syndrome; Raynaud’s syn-
drome; and an arthropathy (50%). The arthropathy
mainly affects the large joints and has clinical similarities
to OA but with normal or an increased range of move-
ment. X-rays may show widening of joint spaces, squar-
ing of bone ends, generalised osteopenia and tufting of
terminal phalanges. It does not improve with treatment
of the acromegaly. Fig. 25.59 Wrist X-ray showing a neuropathic (Charcot) joint in a
patient with syringomyelia. Note the disorganised architecture with
complete loss of the proximal carpal row, bony fragments and soft tissue
Haematological disease swelling.

Haemochromatosis (p. 972) is complicated by an

arthropathy in about 50% of cases. It typically presents
between the ages of 40 and 50, and may predate other
features of the disease. The small joints of the hands and
wrists are typically affected but the hips, shoulders and
knees may also be involved. The X-ray changes resemble
OA but cysts are often multiple and prominent, with
little osteophyte formation. Involvement of the radiocar-
pal and MCP joints may occur, which is unusual in
primary OA, and about 30% have calcium pyrophos-
phate dihydrate deposition disease and/or pseudogout.
Treatment of the haemochromatosis does not influence
the arthropathy, and management of the arthropathy is
as described for OA. Haemophilia (p. 1051) can be com-
plicated by haemarthrosis, which, if recurrent, can result
in the development of secondary osteoarthritis. Sickle-
cell disease (p. 1032) may be complicated by bone pain,
osteonecrosis and osteomyelitis. Thalassaemia (p. 1033)
may be complicated by bone deformity, especially
affecting the craniofacial bones, and by osteoporosis.
Neurological disease
Neurological disease may result in rapidly destructive
arthritis of joints, first described by Charcot in associa-
tion with syphilis. The cause is incompletely understood
but may involve repetitive trauma as the result of
sensory loss and altered blood flow secondary to
impaired sympathetic nervous system control. The main
predisposing diseases and sites of involvement are:
• diabetic neuropathy (hindfoot)
• syringomyelia (shoulder, elbow, wrist)
• leprosy (hands, feet)
• tabes dorsalis (knees, spine).
The presentation is with subacute or chronic mono-
arthritis. Pain can occur, especially at the onset, but
once the joint is severely deranged, pain is often mini-
mal and signs become disproportionately greater than
symptoms. The joint is often grossly swollen, with
effusion, crepitus, marked instability and deformity,
but usually no increased warmth. X-rays show disor-
ganisation of normal joint architecture and often multi-
ple loose bodies (Fig. 25.59), and either no (atrophic)
or gross (hypertrophic) new bone formation. Manage-
25
ment principally involves orthoses and occasionally
arthrodesis.
MISCELLANEOUS CONDITIONS
Spondylolysis and spondylolisthesis
Spondylolysis describes a break in the integrity of the
neural arch. The principal cause is an acquired defect in
pars interarticularis due to a fracture, mainly seen in
gymnasts, dancers and runners, in whom it is an impor-
tant cause of back pain. Spondylolisthesis describes the
condition where a defect causes slippage of a vertebra
on the one below. This may be congenital, post-traumatic
or degenerative. Rarely, it can result from metastatic
destruction of the posterior elements. Uncomplicated
spondylolysis does not cause symptoms but spondy-
lolisthesis can cause low back pain aggravated by stand-
ing and walking. Occasionally, symptoms of nerve root
or spinal compression may occur. The diagnosis can be
made on lateral X-rays of the lumbar spine but MRI may
be required if there is neurological involvement. Advice
on posture and muscle-strengthening exercises is
required in mild cases. Surgical fusion is indicated for
severe and recurrent low back pain. Surgical decompres-
sion is mandatory prior to fusion in patients with sig-
nificant lumbar stenosis or symptoms of cauda equina
compression.
Diffuse idiopathic skeletal hyperostosis
Diffuse idiopathic skeletal hyperostosis (DISH) is a
common disorder, affecting 10% of men and 8% of
women over the age of 65, and associated with obesity, 1133
 RHEUMATOLOGY AND BONE DISEASE
25
Fig. 25.60 Diffuse idiopathic skeletal hyperostosis (DISH).
Antero-posterior X-ray of thoracic spine showing right-sided, flowing new
bone joining more than four contiguous vertebrae. The disc spaces are
preserved.
hypertension and type 2 diabetes mellitus. It is charac-
terised by florid new bone formation along the antero-
lateral aspect of at least four contiguous vertebral bodies
(Fig. 25.60). DISH is distinguished from lumbar spondy-
losis by the absence of disc space narrowing and mar-
ginal vertebral body sclerosis, and from ankylosing
spondylitis by the absence of sacroiliitis or apophyseal
joint fusion. It is usually an asymptomatic radiographic
finding but can cause back pain or pain at peripheral
sites, such as the heel in association with calcaneal spur
formation.
Pigmented villonodular synovitis
Pigmented villonodular synovitis is an uncommon
proliferative disorder of synovium, which typically
affects young adults. It is caused by a somatic chromo-
somal translocation in synovial cells that places the
CSF1 gene downstream of the COL6A3 gene promoter.
The result is local over-production of macrophage
colony-stimulating factor (M-CSF), which causes accu-
mulation of macrophages in the joint. The presentation
is with joint swelling, limitation of movement and local
discomfort. The diagnosis can be confirmed by MRI or
synovial biopsy. Treatment is by surgical or radiation
synovectomy.
Joint hypermobility
Hypermobility is a relatively uncommon disorder asso-
ciated with joint laxity. It may be primary or secondary
to inherited diseases, such as Marfan’s syndrome
(p. 603), Ehlers–Danlos syndrome (p. 1050) and osteo-
genesis imperfecta (p. 1131). Benign joint hypermobility
syndrome is diagnosed clinically when the modified
1134 Beighton score is 4 or above in the presence of arthralgia
25.86 Modified Beighton score for
joint hypermobility
Clinical test Score
Extend little finger > 90° (1 point each side)
Bring thumb back parallel to/touching (1 point each side)
forearm
Extend elbow > 10° (1 point each side)
Extend knee > 10° (1 point each side)
Touch floor with flat of hands, legs (1 point)
straight
Hypermobile = a score of 6 or more points out of a possible 9
for epidemiological studies, or 4 or more points (with arthralgia
in four or more joints) for a clinical diagnosis of the benign joint
hypermobility syndrome.
in four or more joints (Box 25.86). There is no specific
treatment, apart from the general principles listed on
page 1077.
Dupuytren’s contracture
Dupuytren’s contracture results from fibrosis and con-
tracture of the superficial palmar fascia of the hands. The
patient is unable to extend the fingers fully and there is
puckering of the skin with palpable nodules. The ring
and little fingers are usually the first and worst affected.
It is usually painless, but causes problems due to limita-
tion of hand function and snagging of the curled fingers
in pockets. It is age-related, usually bilateral and more
common in men. There is a strong genetic component
and sometimes may be familial, with dominant inherit-
ance. It can be associated with plantar fibromatosis, Pey-
ronie’s disease, alcohol misuse and chronic vibration
injury. It is very slowly progressive. Often no treatment
is required, but it can be treated medically by local injec-
tions of collagenase or surgically by fasciotomy if symp-
toms are troublesome.
Carpal tunnel syndrome
This is a common nerve entrapment syndrome caused
by compression of the median nerve at the wrist. It
presents with numbness, tingling and pain in a median
nerve distribution (p. 1224). The most common causes
are hypothyroidism, diabetes mellitus, RA, obesity and
pregnancy, especially in the third trimester. In some
patients no underlying cause may be identified. Carpal
tunnel syndrome often responds to treatment of the
underlying condition, but other options include local
steroid injections and surgical decompression.
Trigger finger
This occurs as the result of stenosing tenosynovitis in the
flexor tendon sheath, with intermittent locking of the
finger in flexion. It can arise spontaneously or in associa-
tion with inflammatory diseases like RA. Symptoms
usually respond to local steroid injections but surgical
decompression is occasionally required.

Periodic fever syndromes
These are a group of rare inherited disorders that present
with intermittent attacks of fever, rash, arthralgia and
myalgia. They usually occur in childhood but may
present for the first time in adulthood. They are dis-
cussed in more detail on page 85.
Anterior tibial compartment syndrome
This is characterised by severe pain in the front of
the lower leg, aggravated by exercise and relieved by
rest. Symptoms result from fascial compression of the
muscles in the anterior tibial compartment and may
be associated with foot drop. Treatment is by surgical
decompression.
Synovitis–acne–pustulosis–
hyperostosis–osteitis syndrome
The synovitis–acne–pustulosis–hyperostosis–osteitis
(SAPHO) syndrome is an uncommon disorder charac-
terised by bone pain and swelling due to a sterile osteo-
myelitis and hyperostosis predominantly targeting
the clavicles and bones of the anterior chest wall. Other
features include a pustulotic rash affecting the palms
and soles of the feet, sacroiliitis and synovitis of periph-
eral joints. It most commonly presents in children
and young or middle-aged adults. Various treatments
have been used, including corticosteroids, DMARDs,
Further information
bisphosphonates and TNF blockers, with varying
degrees of success. The cause is unknown but has been
suggested to be an autoimmune process triggered by a
bacterial or viral pathogen.
Further information
Journal articles
Ralston SH. Paget’s disease of bone. N Engl J Med 2013;
368:644–650.
Rudwaleit M. New approaches to diagnosis
and classification of axial and peripheral
spondyloarthropathies. Curr Opin Rheum 2010;
22:275–280.
Sambrook P, Cooper C. Osteoporosis. Lancet 2006;
367:2010–2018.
Scott DL, Woolf F, Huizinga TW. Rheumatoid arthritis.
Lancet 2010; 376:1094–1108.
Zhang W, Doherty M, et al. EULAR recommendations for
gout. Part 2: Management. Ann Rheum Dis 2006;
65:1312–1324.
Websites
www.4s-dawn.com/DAS28
www.basdai.com/BASDAI.php BASDAI calculator.
www.nice.org.uk/CG59 Osteoarthritis. 25
www.nice.org.uk/TA161 and www.nice.org.uk/TA160
Osteoporosis.
www.omim.org Online Mendelian Inheritance in Man
(OMIM): genetic diseases.
www.shef.ac.uk/FRAX/ and www.qfracture.org/ Fracture
risk assessment tools.
1135

Neurological disease
Clinical examination of the nervous
system 1138
Functional anatomy and physiology 1140
Functional anatomy of the nervous
system 1141
Localising lesions in the brainstem 1148
Investigation of neurological disease 1149
Neuroimaging 1149
Neurophysiological testing 1151
Presenting problems in neurological
disease 1155
Headache and facial pain 1156
Dizziness, blackouts and ‘funny turns’ 1157
Status epilepticus 1159
Coma 1159
Delirium 1161
Amnesia 1161
Weakness 1162
Sensory disturbance 1164
Abnormal movements 1165
Abnormal perception 1167
Altered balance and vertigo 1167
Abnormal gait 1168
Abnormal speech and language 1168
Disturbance of smell 1169
Visual disturbance and ocular
abnormalities 1169
Hearing disturbance 1173
Bulbar symptoms – dysphagia and
dysarthria 1173
Bladder, bowel and sexual disturbance 1174
Personality change 1175
Sleep disturbance 1175
Psychiatric disorders 1175
J.P. Leach
R.J. Davenport
Functional symptoms 1175
Headache syndromes 1176
Epilepsy 1178
Vestibular disorders 1186
Disorders of sleep 1187
Excessive daytime sleepiness
(hypersomnolence) 1187
Parasomnias 1187
Neuro-inflammatory diseases 1188
Multiple sclerosis 1188
Acute disseminated encephalomyelitis 1192
Transverse myelitis 1193
Neuromyelitis optica 1193
Paraneoplastic neurological disorders 1193
Neurodegenerative diseases 1194
Movement disorders 1194
Ataxias 1198
Tremor disorders 1199
Dystonia 1200
Hemifacial spasm 1200
Motor neuron disease 1200
Spinal muscular atrophy 1201
Infections of the nervous system 1201
Meningitis 1201
Parenchymal viral infections 1205
Parenchymal bacterial infections 1208
Diseases caused by bacterial toxins 1209
Transmissible spongiform
encephalopathies 1211
26
Intracranial mass lesions and raised
intracranial pressure 1211
Raised intracranial pressure 1212
Brain tumours 1213
Paraneoplastic neurological disease 1216
Hydrocephalus 1216
Idiopathic intracranial hypertension 1217
Head injury 1218
Disorders of cerebellar function 1218
Disorders of the spine and spinal cord 1218
Cervical spondylosis 1218
Lumbar spondylosis 1219
Spinal cord compression 1220
Intrinsic diseases of the spinal cord 1222
Diseases of peripheral nerves 1223
Entrapment neuropathy 1224
Multifocal neuropathy 1224
Polyneuropathy 1224
Guillain–Barré syndrome 1224
Chronic polyneuropathy 1225
Brachial plexopathy 1225
Lumbosacral plexopathy 1226
Spinal root lesions 1226
Diseases of the neuromuscular
junction 1226
Myasthenia gravis 1226
Other myasthenic syndromes 1227
Diseases of muscle 1228
1137
 NEUROLOGICAL DISEASE

CLINICAL EXAMINATION OF THE NERVOUS SYSTEM

Cranial nerves 4
5 Optic fundi
Papilloedema
Optic atrophy
Cupping of disc (glaucoma)
Hypertensive changes
Signs of diabetes

Right 12th nerve palsy:

wasting of right side of tongue

Neck and skull 3 Haemorrhagic papilloedema

Skull size and shape
Neck stiffness and Kernig’s test
Carotid bruit 6 Motor
Wasting, fasciculation
Abnormal posture
Abnormal movements
Tone (including clonus)
Strength
Back 2 Coordination
Scoliosis Tendon reflexes
Operative scars Abdominal reflexes
Evidence of spina bifida occulta Plantar reflexes
Winging of scapula

Wasting of right thenar

Winging of right scapula eminence due to cervical rib
(muscular dystrophy)

7 Sensory
Stance and gait 1
Pin-prick, temperature
Posture
Joint position, vibration
Romberg’s test
Two-point discrimination
Arm swing
Pattern of gait
Tandem (heel-toe) gait

Observation
• General appearance
• Mood (e.g. anxious, depressed) 8 Higher cerebral function
• Facial expression (or lack thereof) Orientation
• Handedness Memory
• Nutritional status Speech and language
• Blood pressure Localised cortical functions

1138
 Clinical examination of the nervous system

1 Examination of gait and posture

Procedure Abnormality Disease
1 Responds to call No response Deafness
Delirium
2 Rising from chair Difficulty rising Proximal muscle weakness
Joint stiffness
3 Examine posture Stooped Parkinsonism
Retropulsion/anteropulsion Postural instability Parkinsonism
4 Examine arms during walking Reduced arm swing Parkinsonism, upper motor neuron lesion
5 Examine routine walking Circumduction (stiff leg moves outwards in Upper motor neuron lesion
‘circular’ manner)
‘Slapping’ due to foot drop Lower motor neuron lesion L5 root or
common peroneal nerve
Narrow-based, short strides Parkinsonism
Wide-based, short strides (marche à petits Frontal lobe lesion
pas, magnetic gait)
Wide-based, irregular strides Cerebellar lesion
High-stepping gait Dorsal column lesion/sensory neuropathy

4 Examination of cranial nerves 6 Root values of tendon

reflexes
Nerve Name Tests
I Olfactory Ask patient about sense of smell (only examine if Reflex Root value
reported change) Upper limb
II Optic Visual acuity Biceps jerk C5/C6
Visual fields Supinator jerk C5/C6
‘Swinging’ torch test for relative afferent pupillary defect Triceps jerk C7
Ophthalmoscopy Finger jerk C8
III Oculomotor Eye movements (nystagmus) Lower limb
Eyelid movement Knee jerk L3/L4
Pupil size, symmetry, reactions Ankle jerk S1
IV Trochlear Eye movements
V Trigeminal Facial sensation
Corneal reflex Neurological examination
Ask patient about taste in old age
VI Abducens Eye movements • Pupils: tend to be smaller,
VII Facial Facial symmetry and movements which makes fundoscopy more
Ask patient about taste difficult.
• Limb tone: difficult to assess
VIII Vestibulocochlear Hearing (rub fingertips next to each ear)
because of poor relaxation and
Tuning fork tests (Rinne and Weber)
concomitant joint disease.
Hallpike test for benign positional vertigo
• Ankle reflexes: may be bilaterally
IX Glossopharyngeal Gag reflex (sensory) absent.
X Vagus Palatal elevation (uvula deviates to side opposite lesion) • Gait assessment: more difficult
Gag reflex (motor) because of concurrent
Cough (bovine) musculoskeletal disease and
pre-existing neurological deficits.
XI Accessory Look for wasting of trapezius/sternocleidomastoid • Sensory testing: especially
Elevation of shoulders difficult when there is cognitive
Turning head to right and left impairment.
XII Hypoglossal Look for wasting/fasciculation • Vibration sense: may be reduced in
Tongue protrusion (deviates to side of lesion) the lower legs.

1139
 NEUROLOGICAL DISEASE

26 Neurology has long been misperceived as a specialty

in which intricate clinical examination and numerous
investigations are required to diagnose obscure and
untreatable conditions. In fact, it requires careful history-
taking with a lesser contribution from targeted examina-
tion and considered investigation. The development of
specific, effective treatments has made accurate diagno-
sis essential.
The brain, spinal cord and peripheral nerves combine
to allow us to perceive and react to the external world,
while maintaining a stable internal environment. The
brain provides a platform for processing information
and forming a response and, in doing so, both forms
and is affected by our personality and mental state.
Nervous system disorders are common, accounting for
around 10% of the UK’s general practice consultations,
20% of acute medical admissions, and most chronic
physical disability. While pathological and anatomical
localisation is important, skill is required to identify
those neurological symptoms not associated with neuro-
logical disease, to differentiate patients requiring investi-
gation and treatment from those who need reassurance.
Initially, it is important to exclude conditions that
constitute neurological emergencies (Box 26.1). If the
presentation is not an emergency, more time can be
taken to reach a diagnosis. The history should provide
a hypothesis for the site and nature of the potential
pathology, which a focused examination may refine and
inform what further investigation would be useful. A
discussion with the patient about possible interventions
and rehabilitation may then take place.
As Stroke has become a specific subspecialty in many
centres, it is described in a separate chapter, although it
is clearly a neurological condition. This chapter should
be read with it, to help clarify how the presentation,
diagnosis and management of stroke differ from other
conditions.

26.1 Neurological emergencies FUNCTIONAL ANATOMY

• Status epilepticus (p. 1159) AND PHYSIOLOGY
• Stroke (if thrombolysis available) (p. 1237)
• Guillain–Barré syndrome (p. 1224) Cells of the nervous system
• Myasthenia gravis (if bulbar and/or respiratory) (p. 1226)
The nervous system comprises billions of connections
• Spinal cord compression (p. 1220)
between billions of specialised cells, supplied by a com-
• Subarachnoid haemorrhage (p. 1246)
plex network of specialised blood vessels. In addition to
• Neuroleptic malignant syndrome (p. 249)
neurons, there are three types of glial cells. Astrocytes

Sensory cell
Spinal cord body in dorsal
Ependymal cell Oligodendrocyte Astrocyte foot processes grey matter root ganglion
surround the brain capillary
Astrocyte Synapse (site of blood–brain barrier) Motor neuron
cell body in
CSF Neuron anterior horn

Schwann cell
Axon Capillary Capillary Tight Sensory Vas
endothelial junction axon nervorum
cell Red blood
cell in capillary Motor axon Node of Ranvier
1140 Fig. 26.1 Cells of the nervous system. (CSF = cerebrospinal fluid)
 Functional anatomy and physiology

form the structural framework for neurons and control
their biochemical environment. Astrocyte foot processes
are intimately associated with blood vessels, forming the
blood–brain barrier (Fig. 26.1). Oligodendrocytes are
responsible for the formation and maintenance of the
myelin sheath, which surrounds axons and is essential
for the rapid transmission of action potentials by salta-
tory conduction. Microglial cells derive from monocytes/
macrophages and play a role in fighting infection and
removing damaged cells. Peripheral neurons have axons
invested in myelin made by Schwann cells. Ependymal
cells line the cerebral ventricles.
Generation and transmission of
the nervous impulse
The role of the central nervous system (CNS) is to gener-
ate outputs in response to external stimuli and changes
Microtubules in
axon down which
neurotransmitters
and/or precursors
are transported
Action
potential
in internal conditions. Each neuron receives input by
synaptic transmission from dendrites (branched projec-
tions of other neurons), which may sum to produce
output in the form of an action potential. This is con-
ducted down axons, with synaptic transmission to other
neurons or, in the motor system, to muscle cells. These
processes require the maintenance of an electrochemical
gradient across neuron cell membranes by specialised
membrane ion channels. Synaptic transmission involves
the release of neurotransmitters that modulate the func-
tion of the target cell by interacting with structures on
the cell surface, including ion channels and other cell
surface receptors (Fig. 26.2). At least 20 different neuro-
transmitters are known to act at different sites in the
nervous system, and all are potentially amenable to
pharmacological manipulation.
The neuronal cell bodies may receive synaptic input
from thousands of other neurons. The synapsing neuron
terminals are also subject to feedback regulation via
receptor sites on the pre-synaptic membrane, modifying
the release of transmitter across the synaptic cleft. In
addition to such acute effects, some neurotransmitters
produce long-term modulation of metabolic function or
gene expression. This effect probably underlies more
complex processes in, for example, long-term memory.

Voltage-gated Functional anatomy of 26

5
calcium
channels
the nervous system
1 Major components of the nervous system and their inter-
relationships are depicted in Figure 26.3.

Ca2+
2 Anterior Posterior
B Ions Cerebral
3
hemispheres
G-protein Sensation
Ions 3 4 Behaviour and
and perception
A motor
Second
messengers New ion channel
e.g. cAMP or modulating
enzyme Cerebellum
Transcription
factor Brainstem
Translation
Heart and
Autonomic

circulation
mRNA Spinal cord
Cell
DNA nucleus GI tract

Fig. 26.2 Neurotransmission and neurotransmitters. (1) An action

potential arriving at the nerve terminal depolarises the membrane and this
opens voltage-gated calcium channels. (2) Entry of calcium causes the Sensory
fusion of synaptic vesicles containing neurotransmitters with the pre-synaptic receptor Muscle
membrane and release of the neurotransmitter across the synaptic cleft.
(3) The neurotransmitter binds to receptors on the post-synaptic membrane
either (A) to open ligand-gated ion channels which, by allowing ion entry,
Autonomic

Bladder
depolarise the membrane and initiate an action potential (4), or (B) to bind to
metabotrophic receptors that activate an effector enzyme (e.g. adenylyl
cyclase) and thus modulate gene transcription via the intracellular second Reproductive
messenger system, leading to changes in synthesis of ion channels or organs Neuromuscular
modulating enzymes. (5) Neurotransmitters are taken up at the pre-synaptic junction
membrane and/or metabolised. (cAMP = cyclic adenosine monophosphate; Fig. 26.3 The major anatomical components of the nervous
DNA = deoxyribonucleic acid; mRNA = messenger ribonucleic acid) system. 1141
 NEUROLOGICAL DISEASE

26 Cerebral hemispheres
The cerebral hemispheres coordinate the highest level
of nervous function, the anterior half dealing with exec-
utive (‘doing’) functions and the posterior half con-
structing a perception of the environment. Each cerebral
hemisphere has four functionally specialised lobes (Fig.
26.4 and Box 26.2), but some functions are lateralised,
and this depends on cerebral dominance (i.e. the hemi-
sphere in which language is represented). Cerebral
dominance aligns limb dominance with language func-
tion: in right-handed individuals the left hemisphere is
almost always dominant, while around half of left-
handers have a dominant right hemisphere.
The frontal lobes are concerned with executive func-
tion, movement, behaviour and planning. In addition to
the primary and supplementary motor cortex, there are
specialised areas for the control of eye movements,
speech (Broca’s area) and micturition.
The parietal lobes integrate sensory perception. The
primary sensory cortex lies in the post-central gyrus
of the parietal lobe. Much of the remainder is devoted
to ‘association’ cortex, which processes and interprets
input from the various sensory modalities. The supra-
marginal and angular gyri of the dominant parietal lobe
form part of the language area (p. 1169). Close to these
are regions dealing with numerical function. The non-
dominant parietal lobe is concerned with spatial aware-
ness and orientation.
The temporal lobes contain the primary auditory
cortex and primary vestibular cortex. On the inner
medial sides lie the olfactory cortex and the para-
hippocampal cortex, which is involved in memory
function. The temporal lobes also contain much of the
limbic system, including the hippocampus and the
amygdala, which are involved in memory and emo-
tional processing. The dominant temporal lobe also
participates in language functions, particularly verbal

26.2 Cortical lobar functions

Effects of damage
Lobe Function Cognitive/behavioural Associated physical signs Positive phenomena
Frontal Personality Disinhibition Impaired smell Seizures – often
Emotional control Lack of initiation Contralateral hemiparesis nocturnal with motor
Social behaviour Antisocial behaviour Frontal release signs1 activity
Contralateral motor Impaired memory Versive head
control Expressive dysphasia movements
Language Incontinence
Micturition
Parietal: Language Dysphasia Contralateral hemisensory loss Focal sensory seizures
dominant Calculation Acalculia Astereognosis2
Dyslexia Agraphaesthesia4
Apraxia3 Contralateral homonymous
Agnosia5 lower quadrantanopia
Asymmetry of optokinetic
nystagmus (OKN)
Parietal: Spatial orientation Neglect of contralateral side Contralateral hemisensory loss Focal sensory seizures
non-dominant Constructional skills Spatial disorientation Astereognosis2
Constructional apraxia Agraphaesthesia4
Dressing apraxia Contralateral homonymous
lower quadrantanopia
Asymmetry of OKN
Temporal: Auditory perception Receptive aphasia Contralateral homonymous Complex hallucinations
dominant Language Dyslexia lower quadrantanopia (smell, sound, vision,
Verbal memory Impaired verbal memory memory)
Smell
Balance
Temporal: Auditory perception Impaired non-verbal Contralateral homonymous Complex hallucinations
non-dominant Melody/pitch perception memory upper quadrantanopia (smell, sound, vision,
Non-verbal memory Impaired musical skills memory)
Smell (tonal perception)
Balance
Occipital Visual processing Visual inattention Homonymous hemianopia Simple visual
Visual loss (macular sparing) hallucinations (e.g.
Visual agnosia phosphenes, zigzag
lines)
1
Grasp reflex, palmomental response, pout response.
2
Inability to determine three-dimensional shape by touch.
3
Inability to perform complex movements in the presence of normal motor, sensory and cerebellar function.
4
Inability to ‘read’ numbers or letters drawn on hand, with the eyes shut.
5
Inability to recognise familiar objects, e.g. faces.
1142
 Functional anatomy and physiology

Central sulcus
Leg Primary sensory cortex
Frontal eye field Supramarginal gyrus
Primary motor cortex Angular gyrus

Parietal lobe
Frontal lobe
Face
Inferior frontal gyrus Wernicke’s area

Broca’s area Primary auditory cortex

Primary vestibular cortex
Superior temporal gyrus
Occipital lobe

Temporal lobe
Supplementary motor area

Foot

Frontal lobe Parietal lobe

Corpus callosum

Primary visual cortex

Temporal lobe
Occipital lobe

Parahippocampal cortex
26
Fig. 26.4 The anatomy of the cerebral cortex.

comprehension (Wernicke’s area). Musical processing

occurs across both temporal lobes, rhythm on the domi-
nant side and melody/pitch on the non-dominant.
The occipital lobes are responsible for visual interpre-
3rd 4th
tation. The contralateral visual hemifield is represented
in each primary visual cortex, with surrounding areas
Reticular
processing specific visual submodalities such as colour, system
movement or depth, and the analysis of more complex
Pyramidal
visual patterns such as faces. motor tract
Deep to the grey matter in the cortices, and the white
matter (composed of neuronal axons), are collections of
cells known as the basal ganglia that are concerned with Cerebellum
5th
motor control; the thalamus, which is responsible for
6th Pontine
the level of attention to sensory perception; the limbic nuclei
7th
system, concerned with emotion and memory; and the
Cranial nerves

hypothalamus, responsible for homeostasis, such as 8th

temperature and appetite control. The cerebral ventri-
cles contain cerebrospinal fluid (CSF), which cushions 9th
the brain during cranial movement. 10th
CSF is formed in the lateral ventricles and protects
and nourishes the CNS. The CSF flows from third to
11th
fourth ventricles and through foramina in the brainstem
to dissipate over the surface of the CNS, eventually 12th
being reabsorbed into the cerebral venous system (see
Fig. 26.41, p. 1217).
Motor Sensory
tracts tracts
The brainstem Fig. 26.5 Anatomy of the brainstem.
In addition to containing all the sensory and motor path-
ways entering and leaving the hemispheres, the brain-
stem houses the nuclei and projections of the cranial the face and eyes) and coordinate sensory input from the
nerves, as well as other important collections of neurons special sense organs and the face, nose, mouth, larynx
in the reticular formation (Fig. 26.5). Cranial nerve nuclei and pharynx. They also relay autonomic messages,
provide motor control to muscles of the head (including including pupillary, salivary and lacrimal functions. The 1143
 NEUROLOGICAL DISEASE
26 reticular formation is predominantly involved in the
control of conjugate eye movements, the maintenance of
balance, cardiorespiratory control and the maintenance
of arousal.
The spinal cord
The spinal cord is the route for virtually all communica-
tion between the extracranial structures and the CNS.
Afferent and efferent fibres are grouped in discrete
bundles but collections of cells in the grey matter
are responsible for lower-order motor reflexes and
the primary processing of sensory information, includ-
ing pain.
Sensory peripheral nervous system
The sensory cell bodies of peripheral nerves are situated
just outside the spinal cord, in the dorsal root ganglia
in the spinal exit foramina, whilst the distal ends of
their neurons utilise various specialised endings for the
conversion of external stimuli into action potentials.
Sensory nerves consist of a combination of large, fast,
myelinated axons (which carry information about joint
position sense and commands to muscles) and smaller,
slower, unmyelinated axons (which carry information
about pain and temperature, as well as autonomic
function).
Motor peripheral nervous system
The anterior horns of the spinal cord comprise lower
motor cell bodies. To increase conduction speed, periph-
eral motor nerve axons are wrapped in myelin produced
by Schwann cells. Motor neurons release acetylcholine
across the neuromuscular junction, which changes
the muscle end-plate potential and initiates muscle
contraction.
The autonomic system
The autonomic system regulates the cardiovascular and
respiratory systems, the smooth muscle of the gastro-
intestinal tract, and many exocrine and endocrine
glands throughout the body. The autonomic system is
controlled centrally by diffuse modulatory systems in
the brainstem, limbic system, hypothalamus and frontal
lobes, which are concerned with arousal and back-
ground behavioural responses to threat. Autonomic
output divides functionally and pharmacologically into
two divisions: the parasympathetic and sympathetic
systems.
The motor system
A programme of movement formulated by the pre-
motor cortex is converted into a series of signals in the
motor cortex that are transmitted to the spinal cord in
the pyramidal tract (Fig. 26.6). This passes through the
internal capsule and the ventral brainstem before decus-
sating in the medulla to enter the lateral columns of the
spinal cord. The pyramidal tract ‘upper motor neurons’
synapse with the anterior horn cells of the spinal cord
grey matter, which form the lower motor neurons.
Any movement necessitates changes in posture and
muscle tone, sometimes in quite separate muscle groups
to those involved in the actual movement. The motor
system consists of a hierarchy of controls that maintain
1144 body posture and muscle tone, on which any movement
Cortical
pyramidal cells
Foot
Motor
cortex
Hand
Mouth
Neuromuscular
junction Basal
ganglia
Cerebellum
Pyramidal Descending
tract A B control of
posture and
balance
Skeletal
muscle
Spinal cord
Lateral
corticospinal
tract
Anterior
horn cells
Fig. 26.6 The motor system. Neurons from the motor cortex descend
as the pyramidal tract in the internal capsule and cerebral peduncle to the
ventral brainstem, where most cross low in the medulla (A). In the spinal
cord the upper motor neurons form the corticospinal tract in the lateral
column before synapsing with the lower motor neurons in the anterior
horns. The activity in the motor cortex is modulated by influences from the
basal ganglia and cerebellum. Pathways descending from these structures
control posture and balance (B).
is superimposed. In the grey matter of the spinal cord,
the lowest order of the motor hierarchy controls reflex
responses to stretch. Muscle spindles sense lengthening
of the muscle; they provide the afferent side of the
stretch reflex and initiate a monosynaptic reflex leading
to protective or reactive muscle contraction. Inputs from
the brainstem are largely inhibitory. Polysynaptic con-
nections in the spinal cord grey matter control more
complex reflex actions of flexion and extension of the
limbs that form the basic building blocks of coordinated
actions, but complete control requires input from the
extrapyramidal system and the cerebellum.
Lower motor neurons
Lower motor neurons in the anterior horn of the
spinal cord innervate a group of muscle fibres termed
a ‘motor unit’. Loss of lower motor neurons causes loss
of contraction within this unit, resulting in weakness
and reduced muscle tone. Subsequently, denervated
muscle fibres atrophy, causing muscle wasting, and
depolarise spontaneously, causing ‘fibrillations’. Except
in the tongue, these are usually only perceptible on
electromyelography (EMG; p. 1152). With the passage
of time, neighbouring intact neurons sprout to provide
re-innervation, but the neuromuscular junctions of the
enlarged motor units are unstable and depolarise spon-
taneously, causing fasciculations (which are large
enough to be visible to the naked eye). Fasciculations

therefore imply chronic partial denervation with
re-innervation.
Upper motor neurons
Upper motor neurons have both inhibitory and excita-
tory influence on the function of anterior horn motor
neurons. Lesions affecting the upper motor neuron
result in increased tone, most evident in the strongest
muscle groups (i.e. the extensors of the lower limbs and
the flexors of the upper limbs). The weakness of upper
motor neuron lesions is conversely more pronounced in
the opposing muscle groups. Loss of inhibition will also
lead to brisk reflexes and enhanced reflex patterns of
movement, such as flexion withdrawal to noxious
stimuli and spasms of extension. The increased tone is
more apparent during rapid stretching (‘spastic catch’),
but may suddenly give way with sustained tension (the
‘clasp-knife’ phenomenon). More primitive reflexes are
also released, manifest as extensor plantar responses.
Spasticity may not be present until some weeks after the
onset of an upper motor neuron lesion. Chronic spas-
ticity in a patient with a spinal cord lesion may also be
exacerbated by increased sensory input – for example,
from a pressure sore or urinary tract infection.
The extrapyramidal system
Circuits between the basal ganglia and the motor cortex
constitute the extrapyramidal system, which controls
muscle tone, body posture and the initiation of move-
ment (see Fig. 26.6). Lesions of the extrapyramidal
system produce an increase in tone that, unlike spas-
ticity, is continuous throughout the range of movement
at any speed of stretch (‘lead pipe’ rigidity). Involuntary
movements are also a feature of extrapyramidal lesions
(p. 1165), and tremor in combination with rigidity
produces typical ‘cogwheel’ rigidity. Extrapyramidal
lesions also cause slowed and clumsy movements
Visual field defects
L R L R
1
2
1
3
4 3
4 Lateral geniculate body
5
5 Lower fibres in
6 parietal lobe
Fig. 26.7 Visual pathways and visual field defects. Schematic representation of eyes and brain in transverse section.
Functional anatomy and physiology
(bradykinesia), which characteristically reduce in size
with repetition, as well as postural instability, which can
precipitate falls.
The cerebellum
The cerebellum fine-tunes and coordinates movements
initiated by the motor cortex. It also participates in the
planning and learning of skilled movements through
reciprocal connections with the thalamus and cortex,
and in articulation of speech. A lesion in a cerebellar
hemisphere causes lack of coordination on the same side
of the body. Cerebellar dysfunction impairs the smooth-
ness of eye movements, causing nystagmus and renders
speech dysarthric. In the limbs, the initial movement is
normal, but as the target is approached, the accuracy of
the movement deteriorates, producing an ‘intention
tremor’. The distances of targets are misjudged (dys-
metria), resulting in ‘past-pointing’. The ability to
produce rapid, accurate, regularly alternating move-
ments is also impaired (dysdiadochokinesis). The central
vermis of the cerebellum is concerned with the coordina-
tion of gait and posture. Disorders of this therefore
produce a characteristic ataxic gait (see below).
Vision
The neurological organisation of visual pathways is
26
shown in Figure 26.7. Fibres from ganglion cells in the
retina pass to the optic disc and then backwards through
the lamina cribrosa to the optic nerve. Nasal optic nerve
fibres (subserving the temporal visual field) cross at
the chiasm, but temporal fibres do not. Hence, fibres in
each optic tract and further posteriorly carry representa-
tion of contralateral visual space. From the lateral geni-
culate nucleus, lower fibres pass through the temporal
lobes on their way to the primary visual area in the
occipital cortex, while the upper fibres pass through the
parietal lobe.
Visual fields
Retina
Optic nerve
2
Optic chiasm
Optic tract
temporal lobe
Upper fibres in anterior Optic
radiation
6
Occipital cortex
1145
 NEUROLOGICAL DISEASE
26 Medial rectus Lateral rectus
Left Right
3rd
4th A
MLF
6th
B Auditory
C tract
8th Pontine
lateral gaze
centre
Fig. 26.8 Control of conjugate eye movements. Downward
projections pass from the cortex to the pontine lateral gaze centre
(A). The pontine gaze centre projects to the 6th cranial nerve nucleus
(B), which innervates the ipsilateral lateral rectus and projects to the
contralateral 3rd nerve nucleus (and hence medial rectus) via the medial
longitudinal fasciculus (MLF). Tonic inputs from the vestibular apparatus
(C) project to the contralateral 6th nerve nucleus via the vestibular nuclei.
Normally, the eyes move conjugately (in unison),
though horizontal convergence allows visual fusion of
objects at different distances. The control of eye move-
ments begins in the cerebral hemispheres, particularly
within the frontal eye fields, and the pathway then
descends to the brainstem with input from the visual
cortex, superior colliculus and cerebellum. Horizontal
and vertical gaze centres in the pons and mid-brain,
respectively, coordinate output to the ocular motor
nerve nuclei (3, 4 and 6), which are connected to each
other by the medial longitudinal fasciculus (MLF) (Fig.
26.8). The MLF is particularly important in coordinating
horizontal movements of the eyes. The extraocular
muscles are then supplied by the oculomotor (3rd),
trochlear (4th) and abducens (6th) cranial nerves.
The pupillary response to light is due to a combina-
tion of parasympathetic and sympathetic activity. Para-
sympathetic fibres originate in the Edinger–Westphal
subnucleus of the 3rd nerve, and pass with the 3rd nerve
to synapse in the ciliary ganglion before supplying the
constrictor pupillae of the iris. Sympathetic fibres origi-
nate in the hypothalamus, pass down the brainstem and
cervical spinal cord to emerge at T1, return up to the
eye in association with the internal carotid artery, and
supply the dilator pupillae.
Speech
Much of the cerebral cortex is involved in the process of
forming and interpreting communicating sounds, espe-
cially in the dominant hemisphere (see Box 26.2, p. 1142).
Decoding of speech sounds (phonemes) is carried out in
the upper part of the posterior temporal lobe. The attri-
bution of meaning, as well as the formulation of the
1146 language required for the expression of ideas and
Broca's
area
Arcuate
fasciculus
Posterior language
comprehension
area (Wernicke's)
Verbal
memory
Corticobulbar
cortex
Bulbar
muscles
Fig. 26.9 Areas of the cerebral cortex involved in the generation
of spoken language.
concepts, occurs predominantly in the lower parts of the
anterior parietal lobe (the angular and supramarginal
gyri). The temporal speech comprehension region is
referred to as Wernicke’s area (Fig. 26.9). Other parts of
the temporal lobe contribute to verbal memory, where
lexicons of meaningful words are ‘stored’. Parts of the
non-dominant parietal lobe appear to contribute to non-
verbal aspects of language in recognising meaningful
intonation patterns (prosody).
The frontal language area is in the posterior end of
the dominant inferior frontal gyrus known as Broca’s
area. This receives input from the temporal and parietal
lobes via the arcuate fasciculus. The motor commands
generated in Broca’s area pass to the cranial nerve nuclei
in the pons and medulla, as well as to the anterior horn
cells in the spinal cord. Nerve impulses to the lips,
tongue, palate, pharynx, larynx and respiratory muscles
result in the series of ordered sounds recognised as
speech. The cerebellum also plays an important role in
coordinating speech, and lesions of the cerebellum lead
to dysarthria, where the problem lies in motor articula-
tion of speech.
The somatosensory system
Sensory information from the limbs ascends the nervous
system in two anatomically discrete systems (Fig. 26.10).
Fibres from proprioceptive organs and those mediating
well-localised touch (including vibration) enter the
spinal cord at the posterior horn and pass without syn-
apsing into the ipsilateral posterior columns. Neural
fibres conveying pain and temperature sensory informa-
tion (nociceptive neurons) synapse with second-order
neurons that cross the midline in the spinal cord before
ascending in the contralateral anterolateral spino-
thalamic tract to the brainstem.
The second-order neurons of the dorsal column
sensory system cross the midline in the upper medulla
to ascend through the brainstem. Here they lie just
medial to the (already crossed) spinothalamic pathway.
 Functional anatomy and physiology

Brainstem lesions can therefore cause sensory loss affect-
ing all modalities of the contralateral side of the body.
Sensory loss on the face due to brainstem lesions is
dependent on the anatomy of the trigeminal fibres
within the brainstem. Fibres from the back of the face
Parietal
cortex
(near the ears) descend within the brainstem to the
upper part of the spinal cord before synapsing, the
second-order neurons crossing the midline and then
ascending with the spinothalamic fibres. Fibres convey-
ing sensation from progressively more forward areas of
the face descend a shorter distance in the brainstem.
Thus, sensory loss in the face from low brainstem lesions
is in a ‘balaclava helmet’ distribution, as the longer
descending trigeminal fibres are affected. Both the dorsal
column and spinothalamic tracts end in the thalamus,
relaying from there to the parietal cortex.

Thalamus Pain
Pain is a complex percept that is only partly related
Gracile and to activity in nociceptor neurons (Fig. 26.11). In the pos-
cuneate nuclei terior horn of the spinal cord, the second-order neuron
of the spinothalamic tract is affected by a number of
influences in addition to its synapse with the fibres
from nociceptors. Branches from the larger mechanocep-
Joint position, tor fibres destined for the posterior column also synapse
vibration
and accurate Dorsal with the second-order spinothalamic neurons and with
touch column interneurons of the grey matter of the posterior horn.
The nociceptor neurons release neurotransmitters (such
as substance P), in addition to excitatory transmitters,
which influence the excitability of the spinothalamic
neurons. Activity in the posterior horn neurons is modu-
lated by fibres descending from the peri-aqueductal
grey matter of the mid-brain and raphe nuclei of the
26
medulla. Neurons of this ‘descending analgesia system’
Pain, are activated by endogenous opiate (endorphin) pep-
temperature tides. The spinal cord’s posterior horn is therefore
and poorly
localised touch much more than a relay station in pain transmission; its
Vestibulospinal complexity allows it to ‘gate’ and modulate painful sen-
tract sation before it ascends in the spinothalamic tract. In the
Lateral
spinothalamic diencephalon, the perception of pain is further influ-
tract enced by the rich interconnections of the thalamus with
Fig. 26.10 The main somatic sensory pathways. the limbic system.

Pain perception Limbic system

Peri-aqueductal
grey matter

Raphe nuclei
of medulla

Descending
pain perception
modulation

Dorsal
column

Posterior
Spinothalamic horn
tract
Crossing Mechanoceptor
spinothalamic (mechanical stimuli)
tract neuron

Spinal cord Nociceptor

grey matter (pain stimuli)

Fig. 26.11 The pain perception system. 1147

 NEUROLOGICAL DISEASE
26 Sphincter control
The sympathetic supply to the bladder leaves from
T11–L2 to synapse in the inferior hypogastric plexus,
while the parasympathetic supply leaves from S2–4. In
addition, a somatic supply to the external (voluntary)
sphincter arises from S2–4, travelling via the pudendal
nerves.
Storage of urine is maintained by inhibiting para-
sympathetic activity and thus relaxing the detrusor
muscle of the bladder wall. Continence is maintained by
simultaneous sympathetic and somatic (via the puden-
dal nerve) mediated tonic contraction of the urethral
sphincters. Voiding is usually under conscious control,
and triggered by relaxation of tonic inhibition on the
pontine micturition centre from higher centres, leading
to relaxation of the pelvic floor muscles and external and
internal urethral sphincters, along with parasympathetic-
mediated detrusor contraction.
Personality and mood
The physiology and pathology of mood disorders are
discussed elsewhere (Ch. 10) but it is important to
remember that any process affecting brain function will
have some effect on mood and affect. Conversely, mood
disorder will have a significant effect on perception and
function. It can be difficult to disentangle whether psy-
chological and psychiatric changes are the cause or the
effect of any neurological symptoms.
Sleep
The function of sleep is unknown but it is required for
good health. Sleep is controlled by the reticular activat-
ing system in the upper brainstem and diencephalon. It
is composed of different stages that can be visualised on
electroencephalography (EEG). As drowsiness occurs,
normal EEG background alpha rhythm disappears and
activity becomes dominated by deepening slow-wave
activity. As sleep deepens and dreaming begins, the
limbs become flaccid, movements are ‘blocked’ and EEG
signs of rapid eye movements (REM) are superimposed
26.3 Major focal brainstem syndromes
Name of syndrome Site of lesions
Weber Anterior cerebral peduncle
(mid-brain)
Claude Cerebral peduncle
Involving red nucleus
Parinaud Dorsal mid-brain (tectum)
Millard–Gubler Ponto-medullary junction
Wallenberg Lateral medulla
1148
on the slow wave. REM sleep persists for a short spell
before another slow-wave spell starts, the cycle repeat-
ing several times throughout the night. REM periods
become longer as the sleep period progresses. REM
sleep seems to be the most important part of the sleep
cycle for refreshing cognitive processes, and REM sleep
deprivation causes tiredness, irritability and impaired
judgement.
Localising lesions in the brainstem
After taking a history and examining the patient, the
clinician should have an idea of the nature and site of
any pathology. Given the density of tracts and nuclei in
the brainstem (see Fig. 26.5), detailed localisation may
be possible on the basis of history and examination
alone, to be confirmed or refuted by investigation.
Brainstem lesions typically present with symptoms
due to cranial nerve, cerebellar and upper motor neuron
dysfunction and are most commonly caused by vascular
disease. Since the anatomy of the brainstem is very pre-
cisely organised, it is usually possible to localise the site
of a lesion on the basis of careful history and examina-
tion in order to determine exactly which tracts/nuclei
are affected, usually invoking the fewest number of
lesions.
For example, in a patient presenting with sudden
onset of upper motor neuron features affecting the right
face, arm and leg in association with a left 3rd nerve
palsy, the lesion will be in the left cerebral peduncle in
the brainstem and the pathology is likely to have been a
small stroke, as the onset was sudden. This combination
of signs is known as Weber’s syndrome, and is one of
several well-described brainstem syndromes, which are
listed in Box 26.3. The effects of individual cranial nerve
deficits are discussed in the sections on eye movements
(p. 1169) and on facial weakness, sensory loss in brain-
stem lesions, dysphonia and dysarthria, and bulbar
symptoms (pp. 1163, 1165, 1168 and 1173).
Clinical features
Ipsilateral 3rd palsy
Contralateral upper motor neuron 7th palsy
Contralateral hemiplegia
Ipsilateral 3rd palsy
Contralateral cerebellar signs
Vertical gaze palsy
Convergence disorders
Convergence retraction nystagmus
Pupillary and lid disorders
Ipsilateral 6th palsy
Ipsilateral lower motor neuron 7th palsy
Contralateral hemiplegia
Ipsilateral 5th, 9th, 10th, 11th palsy
Ipsilateral Horner’s syndrome
Ipsilateral cerebellar signs
Contralateral spinothalamic sensory loss
Vestibular disturbance
 Investigation of neurological disease

properties of radioactive tracers to mark cerebral blood

INVESTIGATION OF NEUROLOGICAL
DISEASE
Experienced clinicians will make around 90% of neuro-
logical diagnoses on history alone, with a lesser
contribution from examination and investigation. As
investigations become more complex and more easily
available, it is tempting to adopt a ‘scan first, think later’
approach to neurology. The frequency of ‘false-positive’
results, the wide range of normality and the unnecessary
expense, inconvenience and worry caused to patients
should encourage a more thoughtful approach. Investi-
gation may include assessment of structure (imaging)
and function (neurophysiology). Neurophysiological
testing has become so complex that in many countries
it constitutes a separate specialty focusing on electro-
encephalography, evoked potentials, nerve conduction
studies and electromyography.
Neuroimaging
Neurological imaging has traditionally allowed assess-
ment of structure only. Various techniques are available,
including X-rays (plain X-rays, computed tomography
(CT), CT angiography, myelography and angiography),
magnetic resonance (MR imaging (MRI), MR angiogra-
phy (MRA)) and ultrasound (Doppler imaging of blood
vessels). The uses and limitations of each of these are
shown in Box 26.4.
It is now possible to use imaging techniques to assess
CNS function. Single photon emission clinical tomog-
raphy (SPECT) scanning can use the lipid-soluble
flow at the time of injection. This can be useful in
investigating dementia or epilepsy. SPECT can also
be used in the diagnosis of movement disorders: for
example, by examining dopamine activity to assess the
function of the basal ganglia in patients with possible
parkinsonism.
Functional MRI (fMRI) can be used to assess blood
flow during specific tasks (e.g. speaking, remembering,
calculation), which can provide ‘maps’ of cortical func-
tion that are accurate enough to help plan lesionectomy
and epilepsy surgery. Similarly, MR spectroscopy is
being developed to identify the chemical composition of
specific regions, providing clues as to whether lesions
are ischaemic, neoplastic or inflammatory.
Head and orbit
Plain skull X-rays are now largely restricted to the
diagnosis of fractures and sinus disease. CT or MRI is
needed for intracranial imaging. CT will show bone and
calcification well, and will easily image collections of
blood. It will also detect abnormalities of the brain and
ventricles, such as atrophy, tumours, cysts, abscesses,
vascular lesions and hydrocephalus. Diagnostic yield is
often improved by the use of intravenous contrast and
thinner slicing using spiral CT. Surrounding bone struc-
tures render posterior fossa CT images less useful, and
CT is less sensitive to white matter changes than MRI.
26
MRI resolution is unaffected by bone and so is more
useful in the investigation of posterior fossa disease. Its
sensitivity to cortical and white matter changes makes
it effective in picking up inflammatory conditions such
as multiple sclerosis, and in investigating epilepsy.

26.4 Imaging techniques for the nervous system

Technique Applications Advantages Disadvantages Comments
X-ray/CT Plain X-rays, CT, CTA Widely available Ionising radiation X-rays: used for fractures
Radiculography Relatively cheap Contrast reactions or foreign bodies
Myelography Relatively quick Invasive (myelography and CT: first line for stroke
Intra-arterial angiography) Intra-arterial angiography:
angiography gold standard for vascular
lesions
MRI Structural imaging High-quality soft Expensive Functional MR and
MRA tissue images, useful Less widely available spectroscopy: mainly
Functional MRI for posterior fossa MRA images blood flow, not research tools
MR spectroscopy and temporal lobes vessel anatomy
No ionising radiation Claustrophobic
Non-invasive Pacemakers contraindicate MRI
Contrast (gadolinium) reactions
Ultrasound Doppler Cheap Operator-dependent Screening tool to assess
Duplex scans Quick Poor anatomical definition need for carotid
Non-invasive endarterectomy
Radio-isotope Isotope brain scan In vivo imaging of Poor spatial resolution Isotope scans obsolete.
SPECT functional anatomy Ionising radiation SPECT: useful in movement
PET (ligand binding, Expensive disorders, epilepsy and
blood flow) Not widely available dementias
PET: mainly research tool

(CT = computed tomography; CTA = computed tomographic angiography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging;
PET = positron emission tomography; SPECT = single photon emission clinical tomography)
1149
 NEUROLOGICAL DISEASE

26 A B

C D

Fig. 26.12 Different techniques of imaging the head and brain. A Skull X-ray showing lytic skull lesion (eosinophilic granuloma – arrow). B CT
showing complete middle cerebral artery infarct (arrows). C MRI showing widespread areas of high signal in multiple sclerosis (arrows). D SPECT after
caudate infarct showing relative hypoperfusion of overlying right cerebral cortex (arrows).

Different MRI techniques will increase sensitivity to
acute ischaemic stroke and may allow detection of
abnormalities by filtering signals from other tissues (e.g.
adipose tissues in the orbits).
Examples of brain imaged by the various techniques
are shown in Figure 26.12.
Cervical, thoracic and
lumbar spine
Plain X-rays are useful in the investigation of trauma to
vertebrae, but their value in providing information
about non-bony tissues is limited, which makes them
far less helpful in the assessment of inflammatory and
degenerative conditions of the spine. MRI has trans-
formed the investigation of these areas, since it can
give information not only about the vertebrae and
1150
intervertebral discs, but also about their effects on the
spinal cord and nerve roots. Myelography is an invasive
technique involving injection of contrast into the lumbar
theca. While the outline of the nerve roots and spinal
cord provides information about abnormal structure,
the accuracy and wide availability of MRI have reduced
the need for this. Myelography may still be used for
technical reasons or where MRI is unavailable, contra-
indicated, or precluded by the patient’s claustrophobia.
Examples of the cervical spine imaged by plain X-rays,
myelography and MRI are shown in Figure 26.13.
Blood vessels
Imaging of the extra- and intracranial blood vessels and
disturbance of arterial or venous blood flow is described
in Chapter 27.

A B
C6
C7
Fig. 26.13 Different techniques of imaging the cervical spine. A Lateral X-ray showing bilateral C6/7 facet dislocation. B Myelogram showing
widening of cervical cord due to astrocytoma (arrows). C MRI showing posterior epidural compression from adenocarcinomatous metastasis to the
posterior arch of T1 (arrows).
Neurophysiological testing
Electroencephalography
The electroencephalogram (EEG) is used to detect elec-
trical activity arising in the cerebral cortex. The EEG
involves placing electrodes on the scalp to record the
amplitude and frequency of the resulting waveforms.
With closed eyes, the normal background activity is
8–13 Hz (known as alpha rhythm), most prominent
occipitally and suppressed on eye opening. Other fre-
quency bands seen over different parts of the brain
in different circumstances are beta (faster than 13/s),
theta (4–8/s) and delta (slower than 4/s). Normal
EEG changes evolve with age and with alertness;
lower frequencies predominate in the very young and
during sleep.
In recent years, digital technology has allowed longer,
cleaner EEG recordings that can be analysed in a number
of ways and recorded alongside contemporaneous video
of any clinical ‘event’. Meanwhile, the development of
intracranial recording allows more sensitive monitoring
via surgically placed electrodes in and around lesions to
help increase the efficacy and improve the safety of epi-
lepsy surgery.
Abnormalities in the EEG result from a number of
conditions. Examples include an increase in fast fre-
quencies (beta) seen with sedating drugs such as ben-
zodiazepines, or marked focal slowing noted over a
structural lesion such as a tumour or an infarct. Improved
quality and accessibility of imaging have made EEG
redundant in lesion localisation, except in the specialist
investigation of epilepsy (p. 1182). EEG remains useful
in progressive and continuous disorders such as reduced
consciousness (p. 1159), in encephalitis (p. 1205), and in
Investigation of neurological disease
C
26
certain dementias such as Creutzfeldt–Jakob disease
(p. 1211).
Since sleep induces marked changes in cerebral activ-
ity, EEG can be useful in characterising those conditions
where sleep patterns are disturbed. In paroxysmal dis-
orders such as epilepsy, EEG is at its most useful when
it captures activity during one of the events in question.
Up to 5% of some normal populations may demonstrate
epileptiform discharges on EEG which prevent its use as
a screening test for epilepsy. Over 50% of patients with
proven epilepsy will have a normal ‘routine’ EEG, and,
conversely, the presence of epileptiform features does
not of itself make a diagnosis (most notably in younger
patients with a family history of epilepsy). In view of
this, the EEG should not be used where epilepsy is
merely ‘suspected’.
The EEG in epilepsy is predominantly used in its
classification and prognosis, and in some patients to
localise the seat of epileptiform discharges when surgery
is being considered. During an epileptic seizure, high-
voltage disturbances of background activity (‘dis-
charges’) will often be noted. These may be generalised,
as in the 3-Hz ‘spike and wave’ of childhood absence
epilepsy, or more focal, as in localisation-related epilep-
sies (Fig. 26.14). Techniques such as hyperventilation or
photic stimulation can be used to increase the yield of
epileptiform changes, particularly in the generalised epi-
lepsy syndromes. While some argue that it is possible to
detect ‘spikes’ and ‘sharp waves’ to lend support to a
clinical diagnosis, these are non-specific and therefore
not diagnostic.
Nerve conduction studies
Electrical stimulation of a nerve causes an impulse
to travel both efferently and afferently along the
1151
 NEUROLOGICAL DISEASE

26 A B

2
5 4 3 2

11 10 9 8 7 6
3

15 14 13 12 4
16
5

7
8

10

11

Secondary generalised
seizure
Fig. 26.14 EEGs in epilepsy. A Generalised epileptic discharge, as seen in epilepsy syndromes such as childhood absence or juvenile myoclonic
epilepsy. B Focal sharp waves over the right parietal region (circled), with spread of discharge to cause a generalised tonic–clonic seizure.

underlying axons. Nerve conduction studies (NCS) increasing CMAP with high-frequency RNS is seen in
make use of this, recording action potentials as they pass Lambert–Eaton myasthenic syndrome (p. 1227).
along peripheral nerves and (with motor nerves) as they
pass into the muscle belly. Digital recording has Electromyography
enhanced sensitivity and reproducibility of these tiny
Electromyography (EMG) is usually performed with
potentials. By measuring the time taken to traverse a
NCS, and involves needle recording of muscle electrical
known distance, it is possible to calculate nerve conduc-
potential during rest and contraction. At rest, muscle is
tion velocities (NCVs). Healthy nerves at room tempera-
electrically silent but loss of nerve supply causes muscle
ture will conduct at a speed of 40–50 m/s. If the recorded
membrane to become unstable, manifest as fibrillations,
potential is smaller than expected, this provides evi-
positive sharp waves (‘spontaneous activity’) or fascicu-
dence of a reduction in the overall number of function-
lations. During muscle contraction, motor unit action
ing axons. Significant slowing of conduction velocity,
potentials are recorded. Axonal loss or destruction will
in contrast, suggests impaired saltatory conduction
result in fewer motor units. Resultant sprouting of
due to peripheral nerve demyelination. Such changes in
remaining units will lead to increasing size of each indi-
NCS may be diffuse (as in a hereditary demyelinating
vidual unit on EMG. Myopathy, in contrast, will cause
peripheral neuropathy, p. 1223), focal (as in pressure
muscle fibre splitting, which will result in a large number
palsies, p. 1224) or multifocal (e.g. Guillain–Barré syn-
of smaller units on EMG. Other abnormal activity, such
drome, p. 1224; mononeuritis multiplex, p. 1224). The
as myotonic discharges, may signify abnormal ion
information gained can allow the disease responsible for
channel conduction, as in myotonic dystrophy or myo-
peripheral nerve dysfunction to be better deduced (see
tonia congenita.
Box 26.99, p. 1223).
Specialised single fibre EMG (SFEMG) can be used to
Stimulation of motor nerves allows for the recording
investigate neuromuscular junction transmission. Meas-
of compound muscle action potentials (CMAPs) over
uring ‘jitter’ and ‘blocking’ can identify the effect of anti-
muscles (Fig. 26.15). These are around 500 times
bodies in reducing the action of acetylcholine on the
larger than sensory nerve potentials, typically around
receptor.
1–20 millivolts. Since a proportion of stimulated impulses
in motor nerves will ‘reflect’ back to the anterior horn
cell body (forming the ‘F’ wave), it is also possible to Evoked potentials
obtain some information about the condition of nerve The cortical response to visual, auditory or electrical
roots. stimulation can be measured on an EEG as an evoked
Repetitive nerve stimulation (RNS) at 3–15/s pro- potential (EP). If a stimulus is provided – for example,
vides consistent CMAPs in healthy muscle. In myasthe- to the eye – the tiny EEG response can be discerned
nia gravis (p. 1226), where there is partial blockage of when averaging 100–1000 repeated stimuli. Assessing
acetylcholine receptors, however, there is a diagnostic the latency (the time delay) and amplitude can give
1152 fall (decrement) in CMAP amplitude. In contrast, an information about the integrity of the relevant pathway.
 Investigation of neurological disease

CMAP
Amplitude

L2 F wave

L1 Fig. 26.15 Motor nerve conduction tests.

Anterior Electrodes (R) on the muscle (abductor pollicis
horn cells
here) record the compound muscle action potential
S2 S1 R (CMAP) after stimulation at the median nerve at
the wrist (S1) and from the elbow (S2). The velocity
from elbow to wrist can be determined if the
Abductor distance between the two stimulating electrodes (d)
d pollicis
brevis is known. A prolonged L1 (L = latency) would be
Antidromic caused by dysfunction distally in the median nerve
conduction (e.g. in carpal tunnel syndrome). A prolonged
Generates L2 is caused by slow nerve conduction (as in
F wave demyelinating neuropathy). The F wave is a small
delayed response that appears when the electrical
signal travels backwards to the anterior horn cell,
d Median nerve sparking a second action potential in a minority of
NCV =
L2 – L1 fibres (see text). (NCV = nerve conduction velocity)

Routine blood tests

5uV 5uV
Many systemic conditions that can affect the nervous 26
system can be identified by simple blood tests. Nutri-
tional deficiencies, metabolic disturbances, inflamma-
5uV 5uV tory conditions, or infections may all present or be
associated with neurological symptoms, and basic blood
tests (full blood count, erythrocyte sedimentation rate,
C-reactive protein, biochemical screening) may provide
5uV 5uV clues. Specific blood tests will be highlighted in the rel-
evant subsections of this chapter.

P100
Immunological tests
5uV 5uV Recent developments have seen a host of new immune-
P100
mediated conditions emerge in clinical neurology, with
effects ranging from muscle and neuromuscular junction
disturbance (causing weakness and muscle pain) to spe-
5uV 5uV cific neuronal ion channels (causing cognitive decline,
epilepsy and psychiatric changes). The last decade has
seen the identification of many causative antibodies (see
100 200 300 100 200 300 Boxes 26.62 and 26.63, p. 1194), and it is likely that further
conditions will turn out to have an immune basis.
L ms R ms

Fig. 26.16 Visual evoked responses (VER) recording. The
abnormality is in the left hemisphere, with delay in latency and a reduction
in signal of the P100.
MRI now provides more information about CNS path-
ways, thus reducing reliance on EPs. In practice, visual
evoked potentials (VEPs) are most commonly used to
help differentiate CNS demyelination from small-vessel
white-matter changes (Fig. 26.16).
Genetic testing
An increasing number of inherited neurological condi-
tions can now be diagnosed by DNA analysis (p. 60).
These include diseases caused by increased numbers
of trinucleotide repeats, such as Huntington’s disease
(p. 1198), myotonic dystrophy (p. 1228) and some types
of spinocerebellar ataxia (p. 1199). Mitochondrial DNA
can also be sequenced to diagnose relevant disorders
(p. 60).

Magnetic stimulation
Central conduction times can also be measured using
electromagnetic induction of action potentials in the
cortex or spinal cord by the local application of special-
ised coils. Again, MRI has made this largely redundant,
other than for research.
Lumbar puncture
Lumbar puncture (LP) is the technique used to obtain
a CSF sample and provides an indirect measure of
intracranial pressure. After local anaesthetic injection, a
needle is inserted between lumbar spinous processes 1153
 NEUROLOGICAL DISEASE

26 26.5 How to interpret CSF results

Subarachnoid Acute bacterial Multiple
Normal haemorrhage meningitis Viral meningitis Tuberculous meningitis sclerosis
Pressure 50–250 mm Increased Normal/ Normal Normal/increased Normal
of water increased
Colour Clear Blood-stained Cloudy Clear Clear/cloudy Clear
Xanthochromic
Red cell count 0–4 Raised Normal Normal Normal Normal
(× 106/L)
White cell 0–4 Normal/slightly 1000–5000 10–2000 50–5000 lymphocytes 0–50
count raised polymorphs lymphocytes lymphocytes
(× 106/L)
Glucose > 50–60% of Normal Decreased Normal Decreased Normal
blood level
Protein < 0.45 g/L Increased Increased Normal/ Increased Normal/
increased increased
Microbiology Sterile Sterile Organisms on Sterile/virus Ziehl–Nielson/auramine Sterile
Gram stain detected stain or tuberculosis
and/or culture culture positive
Oligoclonal Negative Negative Can be positive Can be positive Can be positive Often positive
bands

(usually between L3 and L4) through the dura and into
the spinal canal. Intracranial pressure can be deduced (if
patients are lying on their side) and CSF removed for
analysis. CSF pressure measurement is important in the
diagnosis and monitoring of idiopathic intracranial
hypertension (p. 1217). In this condition, the LP itself is
therapeutic.
CSF is normally clear and colourless, and the tests
that are usually performed include a naked eye exami-
nation of the CSF and centrifugation to determine the
colour of the supernatant (yellow, or xanthochromic,
some hours after subarachnoid haemorrhage (p. 1246).
Routine analysis will involve a cell count, as well as
assay of glucose and protein.
CSF assessment is important in investigating infec-
tions (meningitis or encephalitis), subarachnoid haemor-
rhage and inflammatory conditions (multiple sclerosis,
sarcoidosis and cerebral lupus). Normal values and
abnormalities found in specific conditions are shown in
Box 26.5.
More sophisticated analysis allows measurement of
antibody formation solely within the CNS (oligoclonal
bands), genetic analysis (e.g. polymerase chain reaction
(PCR) for herpes simplex or tuberculosis), immunologi-
cal tests (paraneoplastic antibodies) and cytology (to
detect malignant cells).
If there is a cranial space-occupying lesion causing
raised intracranial pressure, LP presents a theoretical
risk of downward shift of intracerebral contents, a
potentially fatal process known as coning (p. 1212).
Consequently, LP is contraindicated if there is any
clinical suggestion of raised intracranial pressure
(papilloedema), depressed level of consciousness, or
focal neurological signs suggesting a cerebral lesion,
until imaging (by CT or MRI) has excluded a space-
occupying lesion or hydrocephalus. When there is a risk
1154 of local haemorrhage (thrombocytopenia, disseminated
intravascular coagulation or anticoagulant treatment),
then caution should be exercised or specific measures
should be taken. LP can be safely performed in patients
on antiplatelet drugs or low-dose heparin, but may be
unsafe in patients who are fully anticoagulated due to
the increased risk of epidural haematoma.
About 30% of LPs are followed by a postural head-
ache, due to reduced CSF pressure. The frequency of
headache can be reduced by using smaller or atraumatic
needles. Other rarer complications involve transient
radicular pain, and pain over the lumbar region during
the procedure. Aseptic technique renders secondary
infections such as meningitis extremely rare.
Biopsy
Biopsies of nervous tissue (peripheral nerve, muscle,
meninges or brain) are occasionally required for
diagnosis.
Nerve biopsy can help in the investigation of periph-
eral neuropathy. Usually, a distal sensory nerve (sural
or radial) is targeted. Histological examination can help
identify underlying causes, such as vasculitides or infil-
trative disorders like amyloid. Nerve biopsy should not
be undertaken lightly since there is an appreciable mor-
bidity; it should be reserved for cases where the diagno-
sis is in doubt after routine investigations and where it
will influence management.
Muscle biopsy is performed more frequently and is
indicated for the differentiation of myositis and myo-
pathies. These conditions can usually be distinguished
by histological examination, and enzyme histochemistry
can be useful when mitochondrial diseases and storage
diseases are suspected. The quadriceps muscle is most
commonly biopsied but other muscles may also be
sampled if they are involved clinically. Although pain
and infection can follow the procedure, these are less of
a problem than after nerve biopsy.

Brain biopsy is required when imaging fails to clarify
the nature of intracerebral lesions: for example, in unex-
plained degenerative diseases such as unusual cases of
dementia and in patients with brain tumour. Most biop-
sies are performed stereotactically through a burr-hole
in the skull, which lowers complication rates. Neverthe-
less, haemorrhage, infection and death still occur and
brain biopsy should only be considered if a diagnosis is
otherwise elusive.
PRESENTING PROBLEMS IN
NEUROLOGICAL DISEASE
While history is important in all medical specialties, it is
especially key in neurology, where many neurological
diagnoses have no confirmatory test. History-taking
allows doctor and patient to get to know one another –
many neurological diseases follow chronic paths, and
this may be the first of many such consultations. It also
allows the clinician to obtain information about the
patient’s affect, cognition and psychiatric state.
History-taking is a highly active process and, whilst
there are generic templates (Box 26.6), each indi-
vidual story will follow its own course, and diagnostic
considerations during the history will guide further
questioning.
It is important to be clear about what patients mean
by certain words. Patients may find it difficult to
describe symptoms – for instance, weakness may be
26.6 How to take a neurological history
Introduction
• Age and sex
• Handedness
Presenting complaint
• Symptoms (clarify: see text)
• Overall pattern: intermittent or persistent?
If intermittent, how often do symptoms occur and how
long do they last?
• Speed of onset: seconds, minutes, hours, days, weeks,
months, years, decades?
• Better, worse or the same over time?
• Associated symptoms (including non-neurological)
• Disability caused by symptoms
Change in walking
Difficulty with fine hand movements, e.g. writing, fastening
buttons, using cutlery
• Effect on work, family life and leisure
Background
• Previous neurological symptoms and whether similar to
current symptoms
• Previous medical history
• Domestic situation
• Driving licence status
• Medications (current and at time of symptom onset)
• Alcohol/smoking habits
• Recreational drug and other toxin exposure
• Family history and developmental history
• What are patient’s thoughts/fears/concerns?
Presenting problems in neurological disease
called ‘numbness’, while there are many possible inter-
pretations of ‘dizziness’. These must be clarified; even in
emergency situations, a clear, accurate history is the
foundation of any management plan. While the story
should come primarily from the patient, input from
eye-witnesses and family members is crucial if the
patient is unable to provide details or if there has been
loss of consciousness. This need for corroboration and
clarification means the telephone is as important as any
investigation.
The aim of the history is to answer two key issues:
where is the lesion and what is the lesion (Box 26.7)?
These should remain uppermost in the doctor’s mind
whilst eliciting the history. Some common combina-
tions of symptoms may suggest particular locations
for a lesion (Box 26.8). Enquiry about handedness is
important; lateralisation of the dominant hand helps
designate the dominant hemisphere, which in turn may
help to localise any pathologies, or to plan rehabilitation
or treatment strategies in asymmetrical disorders such
as stroke or Parkinson’s disease.
Epidemiology must be borne in mind; how likely is
it that this particular patient has any specific condition
under consideration? For example, a 20-year-old with
right-sided headache and tenderness will not have tem-
poral arteritis, but this is an important possibility if such
symptoms present in a 78-year-old female.
Determining the evolution and speed of onset and
progression of a disease is important (Box 26.9). For
26
example, if right-hand weakness occurred overnight, it
would suggest a stroke in an older person or an acute
entrapment neuropathy in a younger one. Evolution
over several days, however, might make demyelination
(multiple sclerosis) a possible diagnosis, or perhaps a
subdural haematoma if the weakness was preceded by
a head injury in an older person taking warfarin. Pro-
gression over weeks might bring an intracranial mass
lesion or motor neuron disease into the differential. Slow
progression over a year or so, with difficulty in using the
hand, could suggest a degenerative process such as
Parkinson’s disease. The impact on day-to-day activities,
such as walking, climbing stairs and carrying out fine
hand movements, should also be established in order to
gauge the level of associated disability.
26.7 The key diagnostic questions
Where is the lesion?
• Is it neurological?
• If so, to which part of the nervous system does it localise?
Central versus peripheral
Sensory versus motor versus both
What is the lesion?
• Hereditary or congenital
• Acquired
Traumatic
Infective
Neoplastic
Degenerative
Inflammatory or immune-mediated
Vascular
Functional
1155
 NEUROLOGICAL DISEASE

26 26.8 How to ‘localise’ neurological disease

Combination of symptoms/signs Probable site Possible pathology Other important information
Painless loss of hemilateral Cerebral cortex Usually vascular, inflammatory Associated systemic symptoms
function or neoplastic Tempo of evolution
Pyramidal weakness of all four Spinal cord Usually vascular, inflammatory Associated systemic symptoms
limbs or both legs, bladder or neoplastic Tempo of evolution
signs, sensory loss
Cranial nerve lesions, with limb Brainstem Usually vascular or Associated systemic symptoms
pyramidal signs or sensory loss Mid-brain inflammatory Tempo of evolution
± sphincter disturbance Pons Rarely neoplastic
Medulla
Visual loss + pyramidal signs Widespread cerebral lesions Usually inflammatory Tempo of evolution
and/or cerebellar signs Less commonly vasculitic
Weakness and/or sensory loss in Several peripheral nerves Usually inflammatory or diabetic Associated systemic symptoms
a combination of individual (‘mononeuritis multiplex’)
peripheral nerves
Widespread LMN and UMN signs Upper and lower motor Motor neuron disease Associated localised cervical
neurons Cervical myeloradiculopathy symptoms
Distal loss of sensation and/or Generalised peripheral See causes of neuropathy Associated systemic symptoms
weakness nerves (p. 1223)

(LMN/UMN = lower/upper motor neuron)

patients, whether presenting in clinic or as emergencies,

26.9 The evolution of symptoms have primary syndromes (Box 26.10). The tempo of
evolution of headache is critical; sudden-onset head-
Onset Evolution Possible causes
ache, maximal immediately, is always a ‘red flag’ (Box
Sudden Stable/improvement Vascular (stroke/transient 26.11) and should prompt rapid assessment in hospital
(minutes ischaemic attack (TIA)) for possible subarachnoid hemorrhage or other sinister
to hours) Nerve entrapment causes, even though only 10–25% of patients harbour
syndromes serious pathology. Clues to other possible causes (e.g.
Functional rash in meningitis) should be sought (p. 1201). Headache
Gradual Progressive over Demyelination that evolves over hours to days is much less likely to be
days Infection sinister.
Gradual Progressive over Neoplastic/paraneoplastic
weeks to months
Gradual Progressive over Genetic 26.10 Primary and secondary
months to years Degenerative headache syndromes
Primary headache syndromes
• Migraine (with or without aura)
Estimates of the frequency and duration of specific • Tension-type headache
events are essential when taking details of a paroxysmal • Trigeminal autonomic cephalalgia (including cluster
disorder such as migraine and epilepsy. Vague terms headache)
such as ‘a lot’ or ‘sometimes’ are unhelpful, and it can • Primary stabbing/coughing/exertional/sex-related headache
assist the patient if choices are given to estimate numbers, • Thunderclap headache
such as once a day, week or month. • New daily persistent headache syndrome
Many neurological symptoms are not explained by Secondary causes of headache
disease. Describing these as ‘functional’ is less pejorative • Medication overuse headache (chronic daily headache)
and more acceptable to patients than ‘psychogenic’ • Intracerebral bleeding (subdural haematoma, subarachnoid or
or ‘hysterical’. Functional symptoms require considera- intracerebral haemorrhage)
ble experience in diagnosis, and are frequently missed • Raised intracranial pressure (brain tumour, idiopathic
(p. 1175). intracranial hypertension)
• Infection (meningitis, encephalitis, brain abscess)
• Inflammatory disease (temporal arteritis, other vasculitis,
Headache and facial pain arthritis)
• Referred pain from other structures (orbit,
Headache is common and causes considerable worry, temporomandibular joint, neck)
but rarely represents sinister disease. The causes may be For full diagnostic listings see www.ihs-classification.org/en/
1156 divided into primary (benign) or secondary, and most

26.11 ‘Red flag’ symptoms in headache
Symptom Possible explanation
Sudden onset (maximal Subarachnoid haemorrhage
immediately or within minutes) Cerebral venous sinus
thrombosis
Pituitary apoplexy
Meningitis
Focal neurological symptoms Intracranial mass lesion
(other than for typically Vascular
migrainous) Neoplastic
Infection
Constitutional symptoms Meningoencephalitis
Weight loss Neoplastic (lymphoma or
General malaise metastases)
Pyrexia Inflammatory (vasculitic)
Meningism
Rash
Raised intracranial pressure Intracranial mass lesion
(worse on wakening/lying
down, associated vomiting)
New onset aged > 60 yrs Temporal arteritis
It is important to establish whether the headache
comes and goes, with periods of no headache in between
(usually migraine), or whether it is present all or almost
all the time. Associated symptoms, such as preceding
visual symptoms, nausea/vomiting or photophobia/
phonophobia, may support a diagnosis of migraine,
but others, such as progressive focal symptoms or con-
stitutional upset like weight loss or fever, may suggest
a more sinister cause (e.g. cancer or meningitis). The
behaviour of the patient during headache is often
instructive; migraine patients typically retire to bed to
sleep in a dark room, whereas cluster headache often
induces agitated and restless behaviour.
Headache duration may indicate a diagnosis; head-
aches that have been present for months or years are
almost never sinister (although paradoxically worry
patients), whereas new-onset headache, especially in the
elderly, is more of a concern. In a patient over 60 years
with head pain localised to one or both temples, tempo-
ral arteritis (p. 1117) should be considered, especially if
temporal pulses are absent and/or the arteries are
enlarged and tender. Most outpatients with headache
will have migraine (intermittent, lasting a few hours,
associated with migrainous symptoms) or chronic daily
headache syndrome (often present for months to years,
without associated symptoms and refractory to analge-
sia). These are easy to recognise but patients are often
very worried about their symptoms, so it is important to
elicit such concerns and to explain why sinister disease
is unlikely and investigation is rarely required. Sinusitis,
‘eye strain’, food allergies and uncomplicated hyperten-
sion are almost never the explanation for persistent
headache.
Ocular pain
Assuming ocular disease (such as acute glaucoma) has
been excluded, ocular pain may be due to trigeminal
autonomic cephalalgias (TACs) or, rarely, inflammatory
or infiltrative lesions at the apex of the orbit or the
Presenting problems in neurological disease
cavernous sinus, when 3rd, 4th, 5th or 6th cranial nerve
involvement is usually evident.
Facial pain
Pain in the face can be due to dental or temporoman-
dibular joint problems. Acute sinusitis is usually appar-
ent from other features of sinus congestion/infection
and may cause localised pain over the affected sinus, but
is almost never the explanation for persistent facial pain
or headache.
Facial pain is not uncommon in migraine but some
syndromes can present solely with facial pain. The most
common neurological causes of facial pain are trigemi-
nal neuralgia, herpes zoster (shingles) and post-herpetic
neuralgia, all characterised by their extreme severity. In
trigeminal neuralgia, the patient describes bouts of brief
(seconds), lancinating pain (‘electric shocks’), most fre-
quently felt in the second and third divisions of the
nerve and often triggered by talking or chewing. Facial
shingles most commonly affects the first (ophthalmic)
division of the trigeminal nerve, and pain usually pre-
cedes the rash. Post-herpetic neuralgia may follow, typi-
cally a continuous burning pain throughout the affected
territory, with marked sensitivity to light touch (allo-
dynia) and resistance to treatment. Destructive lesions
of the trigeminal nerve usually cause numbness rather
than pain.
26
Persistent idiopathic facial pain is most frequently
seen in middle-aged women, who report persistent pain,
with no abnormal signs or investigations, and is similar
to other forms of idiopathic chronic pain.
Dizziness, blackouts and ‘funny turns’
Episodic lost or altered consciousness is a frequent
symptom in primary care and hospital practice. The
terms used for such spells vary so much among
patients that they should not be taken for granted. Some
patients use ‘blackout’ to describe a purely visual
symptom, rather than loss of consciousness. Some
individuals may understand ‘dizziness’ to mean an
abnormal perception of movement (vertigo), but others
will mean a feeling of faintness, and yet others unsteadi-
ness (Box 26.12). The clinician thus needs to elucidate
the exact nature of the symptoms that the patient experi-
ences (Fig. 26.17).
The history should always be supplemented by a
direct eye-witness account if available. Often a history
of ‘shaking’ as described to the first aider will become
‘fitting’ when described to the ambulance crew, which
then is reported as ‘definite seizure’ in the emergency
room. Careful history with corroboration will usually
establish whether there has been full consciousness,
altered consciousness, vertigo, transient amnesia or
something else. Vertigo is caused by an alteration in
function of the peripheral vestibular organs or the
central control mechanisms of balance and posture, and
will be discussed elsewhere (p. 1167).
Loss of consciousness
Consciousness may be defined as an awareness of the
environment and ability to respond to it. Loss of con-
sciousness (LOC), other than in sleep, suggests a global
dysfunction of the brain. This most commonly occurs 1157
 NEUROLOGICAL DISEASE

26 Dizzy turn or blackout

Sensation of movement? Other

Loss of balance? Lightheaded?
(vertigo) description

Presyncope
(reduced cerebral
perfusion)

Labyrinthine Central vestibular • Ataxia • Hypoglycaemia • Anxiety* • Epileptic

dysfunction dysfunction • Weakness (Ch. 21) • Hyperventilation seizure
• Infection • ‘Physiological’ • Loss of joint • Post-concussive
• ‘Vestibular (visual–vestibular position sense syndrome
neuronitis’ mismatch) • Gait dyspraxia • Panic attack
• Benign • Demyelination • Joint disease • Non-epileptic
positional • Migraine • Visual attack
vertigo • Posterior fossa disturbance
• Ménière’s mass lesion • Fear of falling
disease • Vertebro-basilar (Ch. 7)
• Ischaemia/ ischaemia
infarction • Other
• Trauma (e.g. disorders of
• Perilymph cranio-vertebral Impaired cerebral
fistula junction) perfusion
• Other (Ch. 18)
(e.g. drugs,
otosclerosis
etc.) Syncope
(loss of cerebral
perfusion)

* Anxiety is the most common cause

of dizziness in those under 65 years Loss of consciousness (‘blackout’)

Fig. 26.17 A diagnostic approach to the patient with dizziness, funny turns or blackouts. (Neurological causes are shown in green.)

26.12 Dizziness in old age 26.13 How to differentiate seizures from syncope
• Prevalence: common, affecting up to 30% of people aged Seizure Syncope
> 65 yrs. Aura (e.g. olfactory) + –
• Symptoms: most frequently described as a combination of
unsteadiness and lightheadedness. Cyanosis + –
• Most common causes: postural hypotension, cardiovascular Tongue-biting + –/+
disease, cervical spondylosis. Many patients have more than Post-ictal confusion + –
one underlying cause.
• Arrhythmia: can present with lightheadedness either at rest Post-ictal amnesia + –
or on activity. Post-ictal headache + –
• Anxiety: frequently associated with dizziness but rarely the
Rapid recovery – +
only cause.
• Falls: multidisciplinary workup is required if dizziness is
associated with falls.

pseudoseizure) need to be considered in the differential

because of temporary loss of blood supply to the whole
brain (syncope or faint). Alternatively, LOC can occur
due to a sudden electrical dysfunction of the brain, as
occurs during a seizure. Whilst most episodes of tran-
sient LOC are due to syncope or seizure, psychogenic
1158 blackouts (also known as non-epileptic seizure or
diagnosis.
No amount of investigation can replace a clear history
in these circumstances. The subjective experience is
important, but objective description from an eye-witness
(even if only by telephone) is equally helpful. Features
in the history useful in distinguishing a seizure from
syncope are shown in Box 26.13.

Syncope
Typically, syncope is preceded by a brief feeling of light-
headedness. Neurocardiogenic syncope (p. 555) is more
likely on standing, and may be provoked by pain or
emotion. There may be darkening of vision, ringing in
the ears, symptoms of hyperventilation, distal tingling,
feelings of nausea, clamminess or sweating. The LOC is
gradual and brief, and the patient recovers quickly
without confusion as long as he or she has assumed a
horizontal position. There is often some brief stiffening
and limb twitching, which requires differentiation from
seizure-like movements. It is rare for syncope to cause
injury or to cause amnesia after regaining awareness.
During a syncopal attack, incontinence of urine can
occur. Tongue-biting is less common in syncope and, if
present, usually involves little trauma.
Cardiac syncope (p. 555), caused by a sudden drop in
cardiac output, may be provoked by exertion in those
with severe aortic stenosis, ischaemia or hypertrophic
obstructive cardiomyopathy, or without warning in
patients with cardiac arrhythmia.
Seizures
The diagnosis of generalised tonic–clonic seizures, in
which there is loss of consciousness, falling to the ground
and clonic movements (p. 1180), is easy but lack of eye-
witness accounts can leave uncertainty. Less dramatic
seizures, such as absences (p. 1181) or some focal sei-
zures (p. 1180), which cause alteration of consciousness
without the patient falling to the ground, may merely be
experienced as ‘lost time’. Since epileptic seizures are the
result of specific processes that vary from patient to
patient, their manifestation tends to be intermittent and
stereotyped and often clusters in time, for reasons
incompletely understood.
Non-epileptic attack disorder, psychogenic
seizures, pseudoseizures, psychogenic
non-epileptic seizures
This disorder is recognised in all cultures but nomencla-
ture has yet to be standardised. Around 10% of patients
referred to a first seizure clinic will have LOC resulting
from psychological reactions to circumstances or trau-
matic life events. Clinical pointers to the diagnosis
include specific emotional triggers, partially retained
awareness, dramatic movements or vocalisation, very
prolonged duration (up to hours), rapid recovery or
subsequent emotional distress. Diagnosis is important,
as such patients are at significant risk of being harmed
by inappropriate treatment if they are assumed to have
epilepsy. Conversely, a hasty diagnosis may lead to
treatment being withheld in atypical or prolonged sei-
zures. Specialist help is necessary to plan management.
Status epilepticus
Status epilepticus is seizure activity not resolving spon-
taneously, or recurrent seizure with no recovery of con-
sciousness in between. Persisting seizure activity has a
recognised mortality and is a medical emergency.
Diagnosis is usually clinical and can be made on the
basis of the description of prolonged rigidity and/or
clonic movements with loss of awareness. As seizure
activity becomes prolonged, movements may become
Presenting problems in neurological disease
26.14 Management of status epilepticus
Initial
• Ensure airway is patent; give oxygen to prevent cerebral
hypoxia
• Check pulse, blood pressure, BM stix® and respiratory rate
• Secure intravenous access
• Send blood for:
Glucose, urea and electrolytes, calcium and magnesium,
liver function, anti-epileptic drug levels
Full blood count and clotting screen
Storing a sample for future analysis (e.g. drug misuse)
• If seizures continue for > 5 mins: give diazepam 10 mg IV
(or rectally) or lorazepam 4 mg IV; repeat once only after
15 mins
• Correct any metabolic trigger, e.g. hypoglycaemia
Ongoing
If seizures continue after 30 mins
• IV infusion (with cardiac monitoring) with one of:
Phenytoin: 15 mg/kg at 50 mg/min
Fosphenytoin: 15 mg/kg at 100 mg/min
Phenobarbital: 10 mg/kg at 100 mg/min
• Cardiac monitor and pulse oximetry
Monitor neurological condition, blood pressure, respiration;
check blood gases
If seizures still continue after 30–60 mins
• Transfer to intensive care
Start treatment for refractory status with intubation,
26
ventilation and general anaesthesia using propofol or
thiopental
EEG monitor
Once status controlled
• Commence longer-term anticonvulsant medication with
one of:
Sodium valproate 10 mg/kg IV over 3–5 mins, then
800–2000 mg/day
Phenytoin: give loading dose (if not already used as above)
of 15 mg/kg, infuse at < 50 mg/min, then 300 mg/day
Carbamazepine 400 mg by nasogastric tube, then
400–1200 mg/day
• Investigate cause
more subtle. Cyanosis, pyrexia, acidosis and sweating
may occur, and complications include aspiration, hypo-
tension, cardiac arrhythmias and renal or hepatic failure.
In patients with pre-existing epilepsy, the most likely
cause is a fall in anti-epileptic drug levels. In de novo
status epilepticus, it is essential to exclude precipitants
such as infection (meningitis, encephalitis), neoplasia
and metabolic derangement (hypoglycaemia, hypo-
natraemia, hypocalcaemia). Treatment and investigation
are outlined in Box 26.14.
Coma
Conscious level should be measured using the Glasgow
Coma Scale (GCS, Box 26.15). Although developed
for use in head injury, GCS is widely used in medical
coma, but disorders that affect language or limb func-
tion (e.g. left hemisphere stroke, locked-in syndrome)
may reduce its usefulness. Nevertheless, it provides
useful prognostic information, and serial recordings 1159
 NEUROLOGICAL DISEASE

26 can plot improvement or deterioration. It is important

to record the three components of the scale, rather
than just the sum score. Thus, a description of eye-
opening (E2) and withdrawing (M4) to pain and making
sounds only (V2) provides a much more useful picture
than GCS 8.
Persisting loss of consciousness or coma (defined
as GCS ≤ 8) occurs if the arousal mechanisms in the
brainstem and diencephalon are disturbed, and localises
to either the brainstem or both cerebral hemispheres.
There are many causes of coma (Box 26.16), including
neurological (structural or non-structural brain disease)
or non-neurological (e.g. type II respiratory failure). The
mode of onset of coma and any precipitating event is
crucial to establishing the cause, and should be obtained
from family or other witnesses (by telephone if

26.15 Glasgow Coma Scale

Eye-opening (E) 26.16 Causes of coma
• Spontaneous 4 Metabolic disturbance
• To speech 3
• Drug overdose • Uraemia
• To pain 2
• Nil 1 • Diabetes mellitus • Hepatic failure
Hypoglycaemia • Respiratory failure
Best motor response (M) Ketoacidosis • Hypothermia
• Obeys commands 6 Hyperosmolar coma • Hypothyroidism
• Localises 5 • Hyponatraemia • Thiamin deficiency
• Withdraws 4 Trauma
• Abnormal flexion 3
• Extensor response 2 • Cerebral contusion • Global axonal injury
• Nil 1 • Extradural haematoma (deceleration)
• Subdural haematoma
Verbal response (V)
Vascular disease
• Orientated 5
• Confused conversation 4 • Subarachnoid haemorrhage • Intracerebral haemorrhage
• Inappropriate words 3 • Brainstem infarction/ • Cerebral venous sinus
• Incomprehensible sounds 2 haemorrhage thrombosis
• Nil 1 Infections
Coma score = E + M + V • Meningitis • Cerebral abscess
Always present GCS as breakdown, not a sum score • Encephalitis • Systemic sepsis
(unless 3 or 15) Others
• Minimum sum 3 • Epilepsy • Functional (‘pseudo-coma’)
• Maximum sum 15 • Brain tumour

26.17 UK criteria for the diagnosis of brain death

Preconditions for considering a diagnosis of brain death
• The patient is deeply comatose
(a) There must be no suspicion that coma is due to depressant drugs, such as narcotics, hypnotics, tranquillisers
(b) Hypothermia has been excluded – rectal temperature must exceed 35°C
(c) There is no profound abnormality of serum electrolytes, acid–base balance or blood glucose concentrations, and any metabolic or
endocrine cause of coma has been excluded
• The patient is maintained on a ventilator because spontaneous respiration has been inadequate or has ceased. Drugs, including
neuromuscular blocking agents, must have been excluded as a cause of the respiratory failure
• The diagnosis of the disorder leading to brain death has been firmly established. There must be no doubt that the patient is suffering
from irremediable structural brain damage
Tests for confirming brain death
• All brainstem reflexes are absent
(a) The pupils are fixed and unreactive to light
(b) The corneal reflexes are absent
(c) The vestibulo-ocular reflexes are absent – there is no eye movement following the injection of 20 mL of ice-cold water into each
external auditory meatus in turn
(d) There are no motor responses to adequate stimulation within the cranial nerve distribution
(e) There is no gag reflex and no reflex response to a suction catheter in the trachea
• No respiratory movement occurs when the patient is disconnected from the ventilator long enough to allow the carbon dioxide
tension to rise above the threshold for stimulating respiration (PaCO2 must reach 6.7 kPa (50 mmHg))
The diagnosis of brain death should be made by two experienced doctors, one of whom should be a consultant and the other a consultant
or specialist registrar. The tests are usually repeated after an interval of 24 hours, depending on the clinical circumstances, before brain
death is finally confirmed.
1160

necessary). Failure to obtain an adequate history for
patients in coma is a common cause of diagnostic delay.
Once the patient is stable from a cardiorespiratory per-
spective, examination should include accurate assess-
ment of conscious level (see below) and thorough
general medical examination, looking for clues such as
needle tracks indicating drug abuse, rashes, fever and
focal signs of infection, including neck stiffness or evi-
dence of head injury. Focal neurological signs may
suggest a structural explanation (stroke or tumour) or
may be falsely localising (p. 1212).
Brain death and minimally
conscious states
Coma is loss of consciousness related to loss of brain
function. Brain death is a state in which cortical and
brainstem function is irreversibly lost. Diagnostic crite-
ria for brain death vary between countries (Box 26.17);
if satisfied, these criteria allow support to be withdrawn
and natural death to occur. Diagnosing brain death is
complex and should only be done by a clinician with
appropriate expertise, as clinical differentiation from
reduced consciousness can be challenging (Box 26.18).
The ‘locked-in’ syndrome, in which the patient is para-
lysed except for eye movements, requires preserved
hemisphere function (and thus consciousness), but a
strategically placed lesion in the ventral pons (usually
infarction) causes complete paralysis. The vegetative
state implies some retention of brainstem function and
minimal cortical function, with loss of awareness of the
environment. Minimally conscious states imply reten-
tion of awareness and intact brainstem function. Confi-
dent distinction between these states is important and
requires careful assessment, often over a period of time.
Brain death is, by definition, irreversible, but other states
may offer hope for improvement. Difficult ethical issues
regarding management often arise.
26.18 Classification of brain death and reduced conscious states
Diagnosis Features
Brain death See Box 26.17
Vegetative No reaction to verbal stimuli
state (VS) Some reaction to noxious stimuli
‘Persistent Sleep–wake cycles (periods of eye
VS’ > 1 mth opening)
‘Permanent Maintained respiratory drive
VS’ > 1 yr Intact brainstem reflexes
Occasional automatic movements
(yawning, swallowing)
Minimally Some reaction to verbal stimuli
conscious Some reaction to noxious stimuli
state Spontaneous movements
Intact brainstem reflexes
Locked-in Some retained cranial nerve reflexes
syndrome Some response to verbal stimuli (e.g.
eye movements to communicate)
No limb movement to noxious stimuli
Presenting problems in neurological disease
Delirium
Delirium is a common result of cortical impairment and
is more common in old age. It manifests as a disturbance
of arousal with global impairment of mental function
causing drowsiness with disorientation, perceptual
errors and muddled thinking. Fluctuation is typical and
confusion is often worse at night. Emotional disturbance
(anxiety, irritability or depression) and psychomotor
changes (agitation, restlessness or retardation) are
common. The assessment and management of this con-
dition are covered in more detail on page 173.
Amnesia
Memory disturbance is a common symptom. In the
absence of significant functional impairment (e.g. inabil-
ity to work, dyspraxias, loss of daily function), many
patients will prove to have benign memory dysfunction
related to age, mood or psychiatric disorders. Investiga-
tion and treatment of the dementias are discussed else-
where (p. 250).
Temporary loss of memory may be due to a transient
toxic confusional state, the post-ictal period after seizure,
or transient global amnesia. These are usually distin-
guished on the basis of the history.
26
Transient global amnesia
This predominantly affects middle-aged patients with
an abrupt, discrete loss of anterograde memory function
lasting up to a few hours. During the episode, patients
are unable to record new memories, and this results in
repetitive questioning, the hallmark of this condition.
Consciousness is preserved and patients may perform
even complex motor acts normally. During the attack
there is retrograde amnesia for the events of the past
Investigation Prognosis
Cranial imaging for primary cause Invariably fatal
EEG – no electrical activity
Cranial Doppler – no cortical blood
flow
Cranial imaging for primary cause Prognosis better post trauma
Maintained cortical blood flow
EEG demonstrates reactivity
Imaging for primary cause Depends on cause – recovery
unlikely to progress beyond
6 mths
1161
 NEUROLOGICAL DISEASE

26 few days, weeks or years. After 4–6 hours, memory func-

tion and behaviour return to normal but the patient has
persistent, complete amnesia for the duration of the
attack itself. There are no seizure markers and, unlike
epileptic amnesia, transient global amnesia recurs in
around 10–20% only. A vascular aetiology is unlikely
and amnesia may be due to a benign process similar to
migraine, occurring in the hippocampus. The patient has
no physical signs and, if imaging is normal and no
seizure markers are present, then the patient can be
reassured.
Persistent amnesia
Patients with persistent memory disturbance must have
serious neurological disease excluded. Symptoms cor-
roborated by relatives or colleagues are likely to be more
significant than those noted by the patient only. Where
poor concentration is at the heart of cognitive deteriora-
tion, it is more likely to be due to an underlying mood
disorder.
It is important to assess the timing of onset and to
establish which aspects of memory are affected. Com-
plaints of getting lost or of losing complex abilities
are more pathological than word-finding difficulties.
Disturbance of episodic or working memory (previously
called ‘short-term memory’) must be distinguished from
semantic memory (memory for concept-based knowl-
edge unrelated to specific experiences). Episodic memory
is selectively impaired in Korsakoff’s syndrome (often
secondary to alcohol) or bilateral temporal lobe damage.
It can also be seen in conjunction with other types of
dementia. Progressive deterioration over months sug-
gests an underlying dementia, but it is important to
perform a full medical assessment to detect any under-
lying medical problem.
It is important to identify and treat depression
(p. 243) in patients with memory loss. Depression
may present as a ‘pseudo-dementia’, with concentration
and memory impairment as dominant features, and
this is often reversible with antidepressant medication.
However, any patient with dementia (particularly of the
Alzheimer’s type) may develop depression in the early
stages of their illness. Specific causes of progressive
dementia, with their treatment and investigation, are
listed elsewhere (p. 250).
Weakness
The assessment of weakness requires the application of
basic anatomy, physiology and some pathology to the
interpretation of the history and clinical findings. Points
to consider are shown in Boxes 26.19 and 26.20, and in
Figure 26.18. The pattern and evolution of weakness and
the clinical signs provide clues to the site and nature of
the lesion.

26.19 Distinguishing signs in upper versus lower motor neuron syndromes

Upper motor neuron lesion Lower motor neuron lesion
Inspection Normal (may be wasting in chronic lesions) Wasting, fasciculation
Tone Increased with clonus Normal or decreased, no clonus
Pattern of weakness Preferentially affects extensors in arms, flexors in leg Typically focal, in distribution of nerve root or
Hemiparesis, paraparesis or tetraparesis peripheral nerve, with associated sensory changes
Deep tendon reflexes Increased Decreased/absent
Plantar response Extensor (Babinski sign) Flexor

26.20 How to assess weakness

Clinical finding Likely level of lesion/diagnosis
Pattern and distribution
Isolated muscles Radiculopathy or mononeuropathy
Both limbs on one side (hemiparesis) Cerebral hemisphere, less likely cord or brainstem
One limb Neuronopathy, plexopathy, cord/brain
Both lower limbs (paraparesis) Spinal cord; look for a sensory level
Fatigability Mysasthenia gravis
Bizarre, fluctuating, not following anatomical rules Functional
Signs
Upper motor neuron Brain/spinal cord
Lower motor neuron Peripheral nervous system
Evolution of the weakness
Sudden and improving Stroke/mononeuropathy
Evolving over months or years Meningioma, cervical spondylotic myelopathy
Gradually worsening over days or weeks Cerebral mass, demyelination
Associated symptoms
Absence of sensory involvement Motor neuron disease, myopathy, myasthenia
1162

Contralateral
hemiplegia
Upper
motor
neuron Tetraplegia
lesion
Upper limbs
Paraplegia
Lower limbs
Fig. 26.18 Patterns of motor loss according to the anatomical site of the lesion.
It is important to establish whether the patient
has loss of power rather than reduced sensation or
generalised fatigue. Pain may restrict movement and
thus mimic weakness. Paradoxically, sensory neglect
(p. 1164) may leave patients unaware of even severe
weakness.
Patients with parkinsonism may complain of weak-
ness; extrapyramidal signs of rigidity (cogwheel or lead
pipe) and bradykinesia should be evident, and a resting
tremor, usually asymmetrical, may provide a further
clue (p. 1194). Observation is as important as formal
strength testing. Movement restricted by pain should be
apparent, and other features (contractures, wasting, fas-
ciculations, abnormal movements/postures) all provide
diagnostic clues. Simple observation of the patient
walking into the consulting room may be diagnostic.
Weakness is a common functional symptom. Func-
tional weakness does not conform to typical organic
patterns, and the signs in Box 26.19 are absent. On
examination, the signs are often variable (e.g. the
patient can walk but appears to have no leg movement
when assessed on the couch), and strength may appear
to ‘give way’, with the patient able to achieve full
power for brief bursts. This does not occur in disease.
Hoover’s sign is useful to confirm functional weakness,
and relies on the normal phenomenon of simultaneous
hip extension when the contralateral hip flexes. In func-
tional weakness, one may see hip extension weakness
(rare in organic disease), which then returns to full
strength on testing contralateral hip flexion. This sign
may be demonstrated to the patient in a non-
confrontational manner, to show that the potential limb
power is intact.
Presenting problems in neurological disease
Cerebral
hemispheres
Spinal cord
Anterior horn, Lower
motor root, motor
plexus and neuron
peripheral nerve lesion
26
Facial weakness
Facial nerve palsy (Bell’s palsy)
One of the most common causes of facial weakness is
Bell’s palsy, a lower motor neuron lesion of the 7th
(facial) nerve, affecting all ages and both sexes.
The lesion is within the facial canal. Symptoms
usually develop subacutely over a few hours, with pain
around the ear preceding the unilateral facial weakness.
Patients often describe the face as ‘numb’, but there is
no objective sensory loss (except to taste if the chorda
tympani is involved). Hyperacusis may occur if the
nerve to stapedius is involved, and there may be dimin-
ished salivation and tear secretion. Examination reveals
an ipsilateral lower motor neuron facial nerve palsy.
Vesicles in the ear or on the palate may indicate primary
herpes zoster infection (p. 318).
Steroids improve recovery rates if started within
72 hours of onset but antiviral drugs are not effective.
Taping the eye shut overnight helps prevent exposure
keratitis and corneal abrasion. About 80% of patients
recover spontaneously within 12 weeks. Plastic surgery
may be considered for the minority left with facial
disfigurement after 12 months. Recurrence is unusual
and should prompt further investigation. Aberrant
re-innervation may occur during recovery, producing
unwanted facial movements, such as eye closure when
the mouth is moved (synkinesis), or ‘crocodile tears’
(tearing during salivation).
Unlike Bell’s palsy, lesions with an upper motor
neuron origin partly spare the upper face. Cortical
lesions may cause a facial weakness either in isolation
or with associated hemiparesis and speech difficulties. 1163
 NEUROLOGICAL DISEASE

26 Sensory disturbance
Sensory symptoms are common and are frequently
benign. Patients often find sensory symptoms difficult
to describe, and sensory examination is difficult for
both doctor and patient. While neurological disease
can cause sensory symptoms, systemic disorders can
also be responsible. Tingling in both hands and around
the mouth can occur as the result of hyperventilation
(p. 657) or hypocalcaemia (p. 768). When there is dys-
function of the relevant cerebral cortex, the patient’s
perception of the wholeness or actual presence of the
relevant part of the body may be distorted.
Numbness and paraesthesia
The history may give the best clues to localisation and
pathology. Certain common patterns are recognised:
in migraine, the aura may consist of spreading tingling
or paraesthesia, followed by numbness evolving over
20–30 minutes over one half of the body, often splitting
the tongue. Sensory loss caused by a stroke or transient
ischaemic attack (TIA) occurs much more rapidly and
is typically negative (numbness) rather than positive
(tingling). Rarely, unpleasant paraesthesia of sensory
epilepsy spreads within seconds. The sensory alteration
of inflammatory spinal cord lesions often ascends from
one or both lower limbs to a distinct level on the trunk
over hours to days. Psychogenic sensory change can
occur as a manifestation of anxiety or as part of a conver-
sion disorder (p. 246). In such cases, the distribution
usually does not conform to a known anatomical pattern
nor fit with any organic disease. Care must be taken in
diagnosing non-organic sensory problems; a careful
history and examination will ensure there is no other
objective neurological deficit.
Sensory neurological examination needs to be under-
taken and interpreted with care since the findings
depend, by definition, on subjective reports. However,
the reported distribution of sensory loss can be useful
when combined with the coexisting deficits of motor
and/or cranial nerve function (Fig. 26.19).
Sensory loss in peripheral nerve lesions
Here the symptoms are usually of sensory loss and par-
aesthesia. Single nerve lesions cause disturbance in the
sensory distribution of the nerve, whereas in diffuse
neuropathies the longest neurons are affected first,
giving a characteristic ‘glove and stocking’ distribution.
If smaller nerve fibres are preferentially affected (e.g. in
diabetic neuropathy), temperature and pin-prick (pain)
are reduced, whilst vibration sense and proprioception
(modalities served by the larger, well-myelinated,
sensory nerves) may be spared. In contrast, vibration
and proprioception are particularly affected if the neu-
ropathy is demyelinating in character (p. 1224), produc-
ing symptoms of tightness and swelling with impairment
of proprioception and vibration sensation.
Sensory loss in nerve root lesions
These typically present with pain as a prominent feature,
either within the spine or in the limb plexuses. It is often
felt in the myotome rather than the dermatome. The

C5

C7

L5

A Generalised peripheral B Sensory roots C Single dorsal column D Transverse thoracic

neuropathy lesion spinal cord lesion

E Unilateral cord lesion F Central cord lesion G Mid-brainstem lesion H Hemisphere (thalamic)
(Brown–Séquard) lesion
Fig. 26.19 Patterns of sensory loss. A Generalised peripheral neuropathy. B Sensory roots: some common examples. C Single dorsal column
lesion (proprioception and some touch loss). D Transverse thoracic spinal cord lesion. E Unilateral cord lesion (Brown–Séquard): ipsilateral dorsal
column (and motor) deficit and contralateral spinothalamic deficit. F Central cord lesion: ‘cape’ distribution of spinothalamic loss. G Mid-brainstem
lesion: ipsilateral facial sensory loss and contralateral loss on body below the vertex. H Hemisphere (thalamic) lesion: contralateral loss on one side of
1164 face and body.

nerve root involved may be deduced from the der-
matomal pattern of sensory loss, although overlap may
lead to this being smaller than expected.
Sensory loss in spinal cord lesions
Transverse lesions of the spinal cord produce loss of all
sensory modalities below that segmental level, although
the clinical level may only be manifest 2–3 segments
lower than the anatomical site of the lesion. Very often,
there is a band of paraesthesia or hyperaesthesia at the
top of the area of sensory loss. Clinical examination may
reveal dissociated sensory loss, i.e. different patterns in
the spinothalamic and dorsal columnar pathways. If the
transverse lesion is vascular due to anterior spinal artery
thrombosis, the spinothalamic pathways may be affected
while the posterior one-third of the spinal cord (the
dorsal column modalities) may be spared.
Lesions damaging one side of the spinal cord will
produce loss of spinothalamic modalities (pain and tem-
perature) on the opposite side, and of dorsal column
modalities (joint position and vibration sense) on the
same side of the body – the Brown–Séquard syndrome
(p. 1221).
Lesions in the centre of the spinal cord (such as
syringomyelia: see Box 26.98 and Fig. 26.46, p. 1222)
spare the dorsal columns but involve the spino-
thalamic fibres crossing the cord from both sides over
the length of the lesion. There is no sensory loss in seg-
ments above and below the lesion; this is described as
‘suspended’ sensory loss. There is sometimes reflex loss
at the level of the lesion if afferent fibres of the reflex arc
are affected.
An isolated lesion of the dorsal columns is not uncom-
mon in multiple sclerosis. This produces a characteristic
unpleasant, tight feeling over the limb(s) involved and,
while there is no loss of pin-prick or temperature sensa-
tion, the associated loss of proprioception may severely
limit function of the affected limb(s).
Sensory loss in brainstem lesions
Lesions in the brainstem can be associated with sensory
loss, but the distribution depends on the site of the
lesion. A lesion limited to the trigeminal nucleus or its
sensory projections will cause ipsilateral facial sensory
disturbance. For example, pain resembling trigeminal
neuralgia can be seen in patients with multiple sclerosis.
The anatomy of the trigeminal connections means that
lesions in the medulla or spinal cord can give rise to
‘balaclava’ patterns of sensory loss (p. 1147). Sensory
pathways running up from the spinal cord can also be
damaged in the brainstem, resulting in simultaneous
sensory loss in arm(s) and/or leg(s).
Sensory loss in hemispheric lesions
The temporal, parietal and occipital lobes receive sensory
information regarding the various modalities of touch,
vision, hearing and balance (see Box 26.2, p. 1142). The
initial points of entry into the cortex are the respective
primary cortical areas (see Fig. 26.4, p. 1143). Damage
to any of these primary areas will result in reduction or
loss of the ability to perceive that particular modality:
‘negative’ symptomatology. Abnormal excitation of
these areas can result in a false perception (‘positive’
symptoms), the most common of which is migrainous
visual aura (flashing lights or teichopsiae).
Presenting problems in neurological disease
Cortical lesions are more likely to cause a mixed
motor and sensory loss. Substantial lesions of the pari-
etal cortex (as in large strokes) can cause severe loss of
proprioception and may even abolish conscious aware-
ness of the existence of the affected limb(s). The resulting
loss of function in the limb may be impossible to distin-
guish from paralysis. Pathways are so tightly packed in
the thalamus that even small lacunar strokes can cause
isolated contralateral hemisensory loss.
Neuropathic pain
Neuropathic pain is a positive neurological symptom
caused by dysfunction of the pain perception apparatus,
in contrast to nociceptive pain, which is secondary to
pathological processes such as inflammation. Neuro-
pathic pain has distinctive features and typically pro-
vokes a very unpleasant, persistent, burning sensation.
There is often increased sensitivity to touch, so that light
brushing of the affected area causes exquisite pain (allo-
dynia). Painful stimuli are felt as though they arise from
a larger area than that touched, and spontaneous bursts
of pain may also occur. Pain may be elicited by other
modalities (allodynia) and is considerably affected by
emotional influences. The most common causes of neu-
ropathic pain are diabetic neuropathies, trigeminal and
post-herpetic neuralgias, and trauma to a peripheral
26
nerve. Treatment of these syndromes can be difficult.
Drugs that modulate various parts of the nociceptive
system, such as gabapentin, carbamazepine or tricyclic
antidepressants, may help. Localised treatment (topical
treatment or nerve blocks) sometimes succeeds but may
increase the sensory deficit and worsen the situation.
Electrical stimulation has occasionally proved success-
ful. For further information, see Chapter 12.
Abnormal movements
Disorders of movement lead to either extra, unwanted
movement (hyperkinetic disorders) or too little move-
ment (hypokinetic disorders) (Box 26.21). In either case,
the lesion often localises to the basal ganglia, although
some tremors are related to cerebellar or brainstem dis-
turbance. Functional movement disorders are common,
and may mimic all of the organic syndromes below. The
most important hypokinetic disorder is Parkinson’s
disease (p. 1194). Parkinsonism is a clinical description
of a collection of symptoms, including tremor, brady-
kinesia and rigidity. Whilst the history is always impor-
tant, observation is clearly vital; much of the skill in
diagnosing movement disorders lies in pattern recogni-
tion. Once it is established whether the problem is
hypo- or hyperkinetic, the next task is to categorise the
movements further, accepting that there is often overlap.
Videoing the movements (with the patient’s permis-
sion), so that they can be shown to a movement disorder
expert, may provide a quick diagnosis in cases of
uncertainty.
Tremor
Tremor is caused by alternating agonist/antagonist
muscle contractions and produces a rhythmical oscilla-
tion of the body part affected. In the assessment of
tremor, the position, body part affected, frequency and 1165
 NEUROLOGICAL DISEASE

26 26.21 Movement disorders

Description Features Examples
Hypokinetic disorders
Parkinsonism Akinesia Idiopathic Parkinson’s disease
Rigidity Other degenerative syndromes
Tremor Drug-induced
Loss of postural reflexes (See Box 26.64)
Other features depending on cause
Catatonia Mutism Usually psychiatric; if neurological, is most
Sustained posturing and waxy flexibility commonly of vascular origin
Hyperkinetic disorders
Tremor Rhythmical oscillation of body part (see Essential tremor
Box 26.22) Parkinson’s disease
Drug-induced
Chorea Jerky, brief, involuntary movements Huntington’s disease
Drug-induced
Tics Stereotyped, repetitive movements, Tourette’s syndrome
briefly suppressible
Myoclonus Shock-like muscle jerks Epilepsy
Hypnic jerks (p. 1187)
Focal cortical disease
Dystonia Sustained muscle contraction causing Genetic
abnormal postures ± tremor Generalised dystonic syndromes
Focal dystonias in adults (e.g. torticollis)
Others Various Paroxysmal hyperkinetic dyskinesias
Hemifacial spasm
Tardive syndromes

26.22 Causes and characteristics of tremors

Body part affected Position Frequency Amplitude Character
Physiological Both arms > legs Posture, movement High Small (fine) Enhanced by anxiety,
emotion, drugs, toxins
Parkinsonism Unilateral or Rest Low (3–4 Hz) Moderate Typically pill-rolling, thumb
asymmetrical Postural and and index finger, other
Arm > leg, chin, re-emergent may features of parkinsonism
never head occur
Essential Bilateral arms, head Movement High (8–10 Hz) Low to moderate Family history; 50% respond
tremor to alcohol
Dystonic Head, arms, legs Posture Variable Variable Other features of dystonia,
often jerky tremors
Functional Any Any Variable Variable Distractible

amplitude should be considered, as these provide diag-
nostic clues (Box 26.22).
Other hyperkinetic syndromes
Non-rhythmic involuntary movements include chorea,
athetosis, ballism, dystonia, myoclonus and tics. They
are categorised by clinical appearance, and coexistence
and overlap are common, such as in choreoathetosis.
• Chorea: jerky, brief, purposeless involuntary
movements, appearing as fidgety movements
affecting different areas; they suggest disease in
the caudate nucleus (as in Huntington’s disease,
1166 p. 1198) and are a common complication of
prolonged levodopa treatment for Parkinson’s
disease. Other causes are shown in Box 26.23.
• Athetosis: slower, writhing movement of the limbs,
often combined with chorea and having similar
causes.
• Ballism: a more dramatic form of chorea, causing
often-violent flinging movements of one limb
(monoballism) or one side of the body
(hemiballism). The lesion localises to the
contralateral subthalamic nucleus and the most
common cause is stroke.
• Dystonia: sustained involuntary muscle contraction
that causes abnormal postures or movement. It may
 Presenting problems in neurological disease

damage to which gives rise to sensory (including visual)

26.23 Causes of chorea inattention, disorders of spatial perception, and disrup-
tion of spatially orientated behaviour, leading to apraxia.
Hereditary
Apraxia is the inability to perform complex, organised
• Huntington’s disease (HD) • Dentato-rubro-pallidoluysian
activity in the presence of normal basic motor, sensory
and HD-like syndromes atrophy
• Wilson’s disease • Benign hereditary chorea and cerebellar function (after weakness, numbness and
• Neuroacanthocytosis • Paroxysmal dyskinesias ataxia have been excluded as causes). Examples of
complex motor activities include dressing, using cutlery
Cerebral birth injury (including kernicterus) and geographical orientation. Other abnormalities that
Cerebral trauma can result from damage to the association cortex involve
Drugs difficulty reading (dyslexia) or writing (dysgraphia), or
• Levodopa • Anticonvulsants the inability to recognise familiar objects (agnosia). The
• Antipsychotics • Oral contraceptive results of damage to particular lobes of the brain are
Metabolic given in Box 26.2 (p. 1142).
• Disorders affecting thyroid, • Pregnancy
parathyroid, glucose,
sodium, calcium and Altered balance and vertigo
magnesium balance
Autoimmune
Balance is a complicated dynamic process that requires
• Post-streptococcal • Systemic lupus ongoing modification of both axial and limb muscles to
(Sydenham’s chorea) erythematosus (SLE) compensate for the effects of gravity and alterations in
• Antiphospholipid antibody body position and load (and hence centre of gravity) in
syndrome order to prevent a person from falling. This requires
input from a variety of sensory modalities (visual, ves-
Structural lesions of basal ganglia (usually caudate)
tibular and proprioceptive), processing by the cere-
• Vascular • Brain tumour
• Demyelination bellum and brainstem, and output via a number of
descending pathways (e.g. vestibulospinal, rubrospinal
and reticulospinal tracts).
Disorders of balance can therefore arise from any
26
be generalised (usually in childhood-onset genetic part of this process. Disordered input (loss of vision,
syndromes) or, more commonly, focal/segmental vestibular disorders or lack of joint position sense),
(such as in torticollis, when the head is twisted processing (damage to vestibular nuclei or cerebellum)
repeatedly to one side). Some dystonias only occur or motor function (spinal cord lesions, leg weakness
with specific tasks, such as writer’s cramp or other of any cause) can all impair balance. The patient may
occupational ‘cramps’. Dystonic tremor is associated, complain of different symptoms, depending on the
and is asymmetrical and of large amplitude. location of the lesion. For example, loss of joint position
• Myoclonus: brief, isolated, random jerks of muscle sense or cerebellar function may result in a sensation of
groups. This is physiological at the onset of sleep unsteadiness, while damage to the vestibular nuclei
(hypnic jerks). Similarly, a myoclonic jerk is a or labyrinth may result in an illusion of movement such
component of the normal startle response, which as vertigo (see below). A careful history is vital. Since
may be exaggerated in some rare (mostly genetic) vision can often compensate for lack of joint position
disorders. Myoclonus may occur in disorders of the sense, patients with peripheral neuropathies or dorsal
cerebral cortex, such as some forms of epilepsy. column loss will often find their problem more notice-
Alternatively, myoclonus can arise from subcortical able in the dark.
structures or, more rarely, from segments of the Examination of such patients may yield physical
spinal cord. signs that again depend on the site of the lesion. Sensory
• Tics: stereotyped repetitive movements, such as abnormalities may be manifest as altered visual acuities
blinking, winking, head shaking or shoulder or visual fields, possibly with abnormalities on fundo-
shrugging. Unlike dyskinesias, the patient may be scopy, altered eye movements (including nystagmus,
able to suppress them, although only for a short p. 1171), impaired vestibular function (p. 1186) or lack
time. Isolated tics are common in childhood and of joint position sense. Disturbance of cerebellar function
usually disappear. Tourette’s syndrome is defined may be manifest as nystagmus, dysarthria or ataxia, or
by the presence of multiple motor and vocal tics difficulty with gait (unsteadiness or inability to perform
that may evolve over time; it is frequently tandem gait, p. 1168). Leg weakness, if present, will be
associated with psychiatric disease, including detectable on examination of the limbs.
obsessive compulsions, depression, self-harm or
attention deficit disorder. Tics may also occur in
Huntington’s and Wilson’s diseases, or after Vertigo
streptococcal infection. Vertigo is defined as an abnormal perception of move-
ment of the environment or self, and occurs because of
conflicting visual, proprioceptive and vestibular infor-
Abnormal perception mation about a person’s position in space. Vertigo com-
monly arises from imbalance of vestibular input and
The parietal lobes are involved in the higher processing is within the experience of most people, since this is
and integration of the primary sensory information. This the ‘dizziness’ that occurs after someone has spun
takes place in areas referred to as ‘association’ cortex, round vigorously and then stops. Bilateral labyrinthine 1167
 NEUROLOGICAL DISEASE
26 dysfunction often causes some unsteadiness. Labyrin-
thine vertigo usually lasts days at a time, though it may
recur, whilst vertigo arising from central (brainstem)
disorders is often persistent and accompanied by other
brainstem signs. Benign paroxysmal positional vertigo
(p. 1186) lasts a few seconds on head movement. A care-
ful history will reveal the likely cause in most patients.
Abnormal gait
Many neurological disorders can affect gait. Observing
patients as they walk into the consulting room can be
very informative, although formal examination is also
important. Neurogenic gait disorders need to be distin-
guished from those due to skeletal abnormalities, usually
characterised by pain producing an antalgic gait, or
limp. Gait alteration incompatible with any anatomical
or physiological deficit may be due to functional
disorders.
Pyramidal gait
Upper motor neuron lesions cause characteristic exten-
sion of the affected leg. The resultant tendency for the
toes to strike the ground on walking requires the leg
to swing outwards at the hip (circumduction). Never-
theless, a shoe on the affected side worn down at the
toes may provide evidence of this type of gait. In hemi-
plegia, the asymmetry between affected and normal
sides is obvious on walking, but in paraparesis both
lower limbs swing slowly from the hips in extension and
are dragged stiffly over the ground – described as
‘walking in mud’.
Foot drop
In normal walking, the heel is the first part of the foot to
hit the ground. A lower motor neuron lesion affecting
the leg will cause weakness of ankle dorsiflexion, result-
ing in a less controlled descent of the foot, which makes
a slapping noise as it hits the ground. In severe cases,
the foot will have to be lifted higher at the knee to allow
room for the inadequately dorsiflexed foot to swing
through, resulting in a high-stepping gait.
Myopathic gait
During walking, alternating transfer of the body’s
weight through each leg requires adequate hip abduc-
tion. In proximal muscle weakness, usually caused by
muscle disease, the hips are not properly fixed by these
muscles and trunk movements are exaggerated, produc-
ing a rolling or waddling gait.
Ataxic gait
An ataxic gait can result from lesions in the cerebellum,
vestibular apparatus or peripheral nerves. Patients with
lesions of the central portion of the cerebellum (the
vermis) walk with a characteristic broad-based gait ‘as
if drunk’ (cerebellar function is particularly sensitive to
alcohol). Patients with acute vestibular disturbances
walk similarly but the accompanying vertigo is charac-
teristic. Inability to walk heel to toe may be the only sign
of less severe cerebellar dysfunction.
Proprioceptive defects can also cause an ataxic
gait. The impairment of joint position sense makes
walking unreliable, especially in poor light. The feet
1168 tend to be placed on the ground with greater emphasis,
presumably to enhance proprioceptive input, resulting
in a ‘stamping’ gait.
Apraxic gait
In an apraxic gait, power, cerebellar function and prop-
rioception are normal on examination of the legs. The
patient may be able to carry out complex motor tasks
(e.g. bicycling motion) while recumbent and yet cannot
formulate the motor act of walking. In this higher cere-
bral dysfunction, the feet appear stuck to the floor and
the patient cannot walk. Gait apraxia is a sign of diffuse
bilateral hemisphere disease (such as normal pressure
hydrocephalus) or diffuse frontal lobe disease.
Marche à petits pas
This gait is characterised by small, slow steps and
marked instability. It differs from the festination found
in Parkinson’s disease (see below) in that it lacks increas-
ing pace and freezing. The usual cause is small-vessel
cerebrovascular disease, and there are accompanying
bilateral upper motor neuron signs.
Extrapyramidal gait
The rigidity and bradykinesia of basal ganglia dysfunc-
tion (p. 1194) lead to a stooped posture and characteristic
gait difficulties, with problems initiating walking and
controlling the pace of the gait. Patients may become
stuck whilst trying to start walking or when walking
through doorways (‘freezing’). The centre of gravity will
be moved forwards to aid propulsion, which, with poor
axial control, can lead to an accelerating pace of shuf-
fling and difficulty stopping. This produces the festinant
gait: initial stuttering steps that quickly increase in fre-
quency while decreasing in length.
Abnormal speech and language
Speech disturbance may be isolated to disruption of
sound output (dysarthria) or may involve language
disturbance (dysphasia). Dysphonia (reduction in the
sound/volume) is usually due to mechanical laryngeal
disruption, whereas dysarthria is more typically neuro-
logical in origin. Dysphasia is always neurological
and localises to the dominant cerebral hemisphere
(usually left, regardless of handedness). Combinations
of speech and swallowing problems are explained
below (p. 1173).
Dysphonia
Dysphonia describes hoarse or whispered speech. The
most common cause is laryngitis, but dysphonia can also
result from a lesion of the 10th cranial nerve or disease
of the vocal cords, including laryngeal dystonia. Parkin-
sonism may cause hypophonia with marked reduction
in speech volume, often in association with dysarthria,
making speech difficult to understand.
Dysarthria
Dysarthria is characterised by poorly articulated or
slurred speech and can occur in association with lesions
of the cerebellum, brainstem and lower cranial nerves,
as well as in myasthenia or myopathic disease. Lan-
guage function is not affected. The quality of the speech
tends to differ depending on the cause, but it can be very
 Presenting problems in neurological disease

26.24 Causes of dysarthria

Type Site Characteristics Associated features
Myopathic Muscles of speech Indistinct, poor articulation Weakness of face, tongue and neck
Myasthenic Motor end plate Indistinct with fatigue and dysphonia Ptosis, diplopia, facial and neck weakness
Fluctuating severity
Bulbar Brainstem Indistinct, slurred, often nasal Dysphagia, diplopia, ataxia
‘Scanning’ Cerebellum Slurred, impaired timing and Ataxia of limbs and gait, tremor of
cadence, ‘sing-song’ head/limbs
Nystagmus
Spastic Pyramidal tracts Indistinct, breathy, mumbling Poor rapid tongue movements, increased
(‘pseudo-bulbar’) reflexes and jaw jerk
Parkinsonian Basal ganglia Indistinct, rapid, stammering, quiet Tremor, rigidity, slow shuffling gait
Dystonic Basal ganglia Strained, slow, high-pitched Dystonia, athetosis

difficult to distinguish the different types clinically (Box
26.24). Dysarthria is discussed further in the section on
bulbar symptoms (p. 1173).
Dysphasia
Dysphasia (or aphasia) is a disorder of the language
content of speech. It can occur with lesions over a
wide area of the dominant hemisphere (Fig. 26.20). Dys-
phasia may be categorised according to whether the
speech output is fluent or non-fluent. Fluent aphasias,
also called receptive aphasias, are impairments related
mostly to the input or reception of language, with dif-
ficulties either in auditory verbal comprehension or in
the repetition of words, phrases or sentences spoken by
others. Speech is easy and fluent, but there are difficul-
ties related to the output of language as well, such as
paraphasia (either substitution of similar-sounding
non-words, or incorrect words) and neologisms
Central
sulcus
3 5 2 1 4
(non-existent words). Examples include Wernicke’s
aphasia (which localises to the superior posterior tem-
poral lobe), transcortical sensory aphasia, conduction
aphasia and anomic aphasia.
Non-fluent aphasias, also called expressive apha-
sias, are difficulties in articulating, but in most cases
there is relatively good auditory verbal comprehension.
26
Examples include Broca’s aphasia (associated with
pathologies in the inferior frontal region), transcortical
motor aphasia and global aphasia.
‘Pure’ aphasias are selective impairments in reading,
writing or the recognition of words. These disorders
may be quite selective. For example, a person is able
to read but not write, or is able to write but not read.
Examples include pure alexia, agraphia and pure
word deafness.
Dysphasia (a focal symptom) is frequently misinter-
preted as confusion (which is non-focal). Dysphasia can
be misheard/misspelt as dysphagia, and for this reason
some prefer to use ‘aphasia’ to avoid confusion.
Disturbance of smell
Symptomatic olfactory loss almost always is due to local
causes (nasal obstruction), follows head injury or is idio-
pathic. Hyposmia may occur early in Parkinson’s
disease. Frontal lobe lesions are a rare cause. Positive
olfactory symptoms may arise from Alzheimer’s disease
or epilepsy.

Visual disturbance and

Sylvian
fissure
Fig. 26.20 Classification of cortical speech problems.
(1) Wernicke’s aphasia: fluent dysphasia with poor comprehension and
poor repetition. (2) Conduction aphasia: fluent aphasia with good
comprehension and poor repetition. (3) Broca’s aphasia: non-fluent aphasia
with good comprehension and poor repetition. (4) Transcortical sensory
aphasia: fluent aphasia with poor comprehension and good repetition.
(5) Transcortical motor aphasia: non-fluent aphasia with good
comprehension and good repetition. Large lesions affecting all of regions
1–5 cause global aphasia.
ocular abnormalities
Disturbances of vision may be due to primary ocular
disease or to disorders of the central connections and
visual cortex. Visual symptoms are usually negative
(loss of vision) but sometimes are positive, most
commonly in migraine. Eye movements may be dis-
turbed, giving rise to double vision (diplopia) or blurred
vision.
Visual loss
Visual loss can occur as the result of lesions in any areas
between the retina and the visual cortex. Patterns of 1169
 NEUROLOGICAL DISEASE

26 26.25 Clinical manifestations of visual field loss

Site of lesion Common causes Complaint Visual field loss Associated physical signs
Retina/optic disc Vascular disease Partial/complete visual Altitudinal field defect Reduced acuity
(including vasculitis) loss depending on site, Arcuate scotoma Visual distortion (macula)
Glaucoma involving one or both eyes Abnormal retinal
Inflammation appearance
Optic nerve Optic neuritis Partial/complete loss of Central or paracentral Reduced acuity
Sarcoidosis vision in one eye scotoma Reduced colour vision
Tumour Often painful Monocular blindness Relative afferent pupillary
Leber’s hereditary Central vision particularly defect
optic neuropathy affected Optic atrophy (late)
Optic chiasm Pituitary tumour May be none Bitemporal hemianopia Pituitary function
Craniopharyngioma Rarely diplopia (‘hemifield abnormalities
Sarcoidosis slide’)
Optic tract Tumour Disturbed vision to one Incongruous contralateral
Inflammatory disease side of midline homonymous hemianopia
Temporal lobe Stroke Disturbed vision to one Contralateral Memory/language
Tumour side of midline homonymous upper disorders
Inflammatory disease quadrantanopia
Parietal lobe Stroke Disturbed vision to one Contralateral Contralateral sensory
Tumour side of midline homonymous lower disturbance
Inflammatory disease Bumping into things quadrantanopia Asymmetry of optokinetic
nystagmus
Occipital lobe Stroke Disturbed vision to one Homonymous hemianopia Damage to other structures
Tumour side of midline (may be macula-sparing) supplied by posterior
Inflammatory disease Difficulty reading cerebral circulation
Bumping into things

visual field loss are explained by the anatomy of the
visual pathways (see Fig. 26.7, p. 1145). Associated clini-
cal manifestations are described in Box 26.25. Visual
symptoms affecting one eye only are liable to be due to
lesions anterior to the optic chiasm.
Transient visual loss is quite common and sudden-
onset visual loss lasting less than 15 minutes is likely to
have a vascular origin. It may be difficult to know
whether the visual loss was monocular (carotid circula-
tion) or binocular (vertebrobasilar circulation), and it can
help to ask if the patient tried closing each eye in turn
to see whether the symptom affected one eye or both.
Visual field testing is an important part of the examina-
tion, either at the bedside or formally with perimetry.
Field defects become more symmetrical (congruous), the
closer the lesion comes to the visual cortex.
Migrainous visual symptoms are very common and,
when associated with typical headache and other
migraine features, rarely pose a diagnostic challenge.
However, they may occur in isolation, making distinc-
tion from TIA difficult, but TIAs typically cause negative
(transient blindness) symptoms, whereas migraine
causes positive phenomena (see below). TIAs often last
for a shorter time (a few minutes), compared to the 10–
60-minute duration of migraine aura, and will have an
abrupt onset and end, unlike the gradual evolution of a
migraine aura.
Positive visual phenomena
The most common cause is migraine; patients may
describe silvery zigzag lines (fortification spectra) or
1170 flashing coloured lights (teichopsia), usually preceding
the headache. Simple flashes of light (phosphenes) may
indicate damage to the retina (e.g. detachment) or to
the primary visual cortex. Formed visual hallucinations
may be caused by drugs, or may be due to epilepsy or
‘release phenomena’ in a blind visual field (Charles
Bonnet’s syndrome).
Double vision
Subtle double vision (diplopia) may be reported as
blurred rather than double vision and most commonly
arises from misalignment of the eyes. Monocular diplo-
pia is rare and indicates ocular disease, while binocular
diplopia suggests a probable neurological cause. Closing
either eye in turn will abort binocular diplopia. Once
the presence of binocular diplopia is confirmed, it should
be established whether the diplopia is maximal in any
particular direction of gaze, whether the images are
separated horizontally or vertically, and whether there
are any associated symptoms or signs, such as ptosis or
pupillary disturbance.
Binocular diplopia occurs when eye movement is
impaired, so that the image is not projected to the same
points on the two retinae. It may result from central
disorders or from disturbance of the ocular motor
nerves, muscles or the neuromuscular junction (see Fig.
26.8, p. 1146). The pattern of double vision, along with
any associated features, usually allows inference of
which nerves/muscles are affected, whilst the mode of
onset and other features (e.g. fatigability in myasthenia)
provide further clues about the cause.
The causes of ocular motor nerve palsies are listed in
Box 26.26.
 Presenting problems in neurological disease

26.26 Common causes of damage to cranial nerves 3, 4 and 6

Site Common pathology Nerve(s) involved Associated features
Brainstem Infarction 3 (mid-brain) Contralateral pyramidal signs
Haemorrhage 6 (ponto-medullary junction) Ipsilateral lower motor neuron facial
Demyelination palsy
Intrinsic tumour Other brainstem/cerebellar signs
Intrameningeal Meningitis (infective/malignant) 3, 4 and/or 6 Meningism, features of primary
disease course
Raised intracranial pressure 6 Papilloedema
3 (uncal herniation) Features of space-occupying lesion
Aneurysms 3 (posterior communicating artery) Pain
6 (basilar artery) Features of subarachnoid
haemorrhage
Cerebello-pontine angle tumour 6 8, 7, 5 nerve lesions (order of
likelihood)
Ipsilateral cerebellar signs
Trauma 3, 4 and/or 6 Other features of trauma
Cavernous Infection/thrombosis 3, 4 and/or 6 May be 5 nerve involvement also
sinus Carotid artery aneurysm Pupil may be fixed, mid-position
Caroticocavernous fistula (sympathetic plexus on carotid may
also be affected)
Superior orbital Tumour (e.g. sphenoid wing 3, 4 and/or 6 May be proptosis, chemosis
fissure meningioma)
Granuloma

26
Orbit Vascular (e.g. diabetes, vasculitis) 3, 4 and/or 6 Pain
Infections Pupil often spared in vascular 3rd
Tumour nerve palsy
Granuloma
Trauma

Nystagmus The brainstem and the cerebellum are involved in

maintaining eccentric positions of gaze. Lesions will
Nystagmus describes a repetitive to-and-fro move-
therefore allow the eyes to drift back in towards primary
ment of the eyes. Usually slow drifts are the primary
position, producing nystagmus with fast component
abnormal movement, each followed by fast (corrective)
beats in the direction of gaze (gaze-evoked nystagmus).
phases. Nystagmus occurs because the control systems
This is the most common type of ‘central’ nystagmus; it
of the eyes are defective, causing them to drift off target;
is most commonly bidirectional and not usually accom-
corrections then become necessary to return fixation to
panied by vertigo. Other signs of brainstem dysfunction
the object of interest, causing nystagmus. The direction
may be evident. Brainstem disease may also cause verti-
of the fast phase is usually designated as the direction
cal nystagmus.
of the nystagmus because it is easier to see. Nystagmus
Unilateral cerebellar lesions may result in gaze-
may be horizontal, vertical or torsional, and usually
evoked nystagmus when looking in the direction of
involves both eyes synchronously. It may be a physio-
the lesion, where the fast phases are directed towards
logical phenomenon in response to sustained vestibular
the side of the lesion. Cerebellar hemisphere lesions
stimulation or movement of the visual world (opto-
also cause ‘ocular dysmetria’, an overshoot of target-
kinetic nystagmus). There are many causes of pathologi-
directed, fast eye movements (saccades) resembling
cal nystagmus, the most common sites of lesions being
‘past-pointing’ in limbs.
the vestibular system, brainstem and cerebellum.
Nystagmus also occurs as a consequence of drug
In vestibular lesions, damage to one of the horizontal
toxicity and nutritional deficiency (e.g. thiamin). The
canals or its connections will allow the tonic output from
severity is variable, and it may or may not result in
the healthy, contralateral side to cause the eyes to drift
visual degradation, though it may be associated with
towards the side of the lesion. This elicits recurrent com-
a sensation of movement of the visual world (oscil-
pensatory fast movements away from the side of the
lopsia). Nystagmus may occur as a congenital phe-
lesion, manifest as unidirectional horizontal nystagmus.
nomenon, in which case both phases are equal and
Vertical and torsional components can be seen with
‘pendular’ rather than having alternating fast and slow
damage to other parts of the vestibular apparatus. The
components.
nystagmus of peripheral labyrinthine lesions is accom-
panied by vertigo and usually by nausea, vomiting and
unsteadiness, but as the CNS habituates, the nystagmus Ptosis
disappears (fatigues) quite quickly. Central vestibular Various disorders may cause drooping of the eyelids
nystagmus is more persistent. (ptosis) and these are listed in Box 26.27. 1171
 NEUROLOGICAL DISEASE

26 26.27 Common causes of ptosis

Mechanism Causes Associated clinical features
3rd nerve palsy Isolated palsy (see Box 26.26) Ptosis is usually complete
Central/supranuclear lesion Extraocular muscle palsy (eye ‘down and out’)
Depending on site of lesion, other cranial nerve palsies (e.g. 4,
5 and 6) or contralateral upper motor neuron signs
Sympathetic lesion Central (hypothalamus/brainstem) Ptosis is partial
(Horner’s syndrome: Peripheral (lung apex, carotid artery Lack of sweating on affected side
see Fig. 26.21) pathology) Depending on site of lesion, brainstem signs, signs of apical
Idiopathic lung/brachial plexus disease, or ipsilateral carotid artery stroke
Myopathic Myasthenia gravis Extraocular muscle palsies
Dystrophia myotonica More widespread muscle weakness, with fatigability in
myasthenia
Progressive external ophthalmoplegia
Other characteristic features of individual causes
Other Pseudo-ptosis (e.g. blepharospasm) Eyebrows depressed rather than raised
Local orbital/lid disease May be local orbital abnormality
Age-related levator dehiscence

26.28 Pupillary disorders

Disorder Cause Ophthalmological features Associated features
3rd nerve palsy See Box 26.27 Dilated pupil Other features of 3rd nerve palsy
Extraocular muscle palsy (eye is typically (see Box 26.27)
‘down and out’)
Complete ptosis
Horner’s syndrome Lesion to sympathetic Small pupil Ipsilateral failure of sweating
(see Fig. 26.21) supply Partial ptosis (anhidrosis)
Iris heterochromia (if congenital)
Holmes–Adie Lesion of ciliary Dilated pupil Generalised areflexia
syndrome (tonic pupil) ganglion (usually Light-near dissociation (accommodate
idiopathic) but do not react to light)
Vermiform movement of iris during
contraction
Disturbance of accommodation
Argyll Robertson pupil Dorsal mid-brain lesion Small, irregular pupils Other features of tabes dorsalis
(syphilis or diabetes) Light-near dissociation (p. 1209)
Local pupillary Trauma/inflammatory Irregular pupils, often with adhesions to Other features of trauma/underlying
damage disease lens (synechiae) inflammatory disease (e.g. cataract,
Variable degree of reactivity blindness etc.)
Relative afferent Damage to optic nerve Pupils symmetrical but degree of Decreased visual acuity/colour
pupillary defect dilatation depends on which eye vision
(Marcus Gunn pupil) stimulated Central scotoma
Papilloedema/optic disc pallor

Abnormal pupillary responses

Abnormal pupillary responses may arise from lesions at
several points between the retina and brainstem. Lesions
of the oculomotor nerve, ciliary ganglion and sympa-
thetic supply produce characteristic ipsilateral disorders
of pupillary function. ‘Afferent’ defects result from
damage to an optic nerve, impairing the direct response
of a pupil to light, although leaving the consensual
response from stimulation of the normal eye intact.
Structural damage to the iris itself can also result in Fig. 26.21 Right-sided Horner’s syndrome due to paravertebral
pupillary abnormalities. Causes are given in Box 26.28. metastasis at T1. There is ipsilateral partial ptosis and a small
1172 An example is shown in Figure 26.21. pupil.
 Presenting problems in neurological disease

A Choroid B Choroid Increased C

CSF
Optic disc Venous CSF pressure
dilatation

Optic Optic
nerve Swollen nerve
optic disc
Retinal
veins Central retinal vein Axonal transport
block
Meningeal sheath
Swollen axons

Fig. 26.22 Mechanism of optic disc oedema (papilloedema). A Normal. B Disc oedema (e.g. due to cerebral tumour). C Fundus photograph
of the left eye showing optic disc oedema with a small haemorrhage on the nasal side of the disc.

26.29 Common causes of optic disc swelling

Raised intracranial pressure (papilloedema)
• Cerebral mass lesion (tumour, abscess)
• Obstructive hydrocephalus
• Idiopathic intracranial hypertension
Obstruction of ocular venous drainage
• Central retinal vein occlusion
• Cavernous sinus thrombosis
Systemic disorders affecting retinal vessels
• Hypertension
• Vasculitis
26
• Hypercapnia
Optic nerve damage
• Demyelination (optic neuritis/papillitis)
• Leber’s hereditary optic neuropathy Fig. 26.23 Fundus photograph of the left eye of a patient with
• Anterior ischaemic optic neuropathy familial optic atrophy. Note marked pallor of optic disc.
• Toxins (e.g. methanol)
• Infiltration of optic disc
• Sarcoidosis
• Glioma
• Lymphoma trauma and degenerative conditions (e.g. Friedreich’s
ataxia, p. 1199).

Papilloedema
There are several causes of swelling of the optic disc, but
the term ‘papilloedema’ is reserved for swelling second-
ary to raised intracranial pressure, when obstructed axo-
plasmic flow from retinal ganglion cells results in
swollen nerve fibres, which in turn cause capillary and
venous congestion, producing papilloedema. The earli-
est sign is the cessation of venous pulsation seen at the
disc, progression causing the disc margins to become
red (hyperaemic). Disc margins become indistinct and
haemorrhages may occur in the retina (Fig. 26.22). Lack
of papilloedema never excludes raised intracranial pres-
sure. Other causes of optic disc swelling are listed in Box
26.29. Some normal variations of disc appearance (e.g.
optic nerve drusen) can mimic disc swelling.
Optic atrophy
Loss of nerve fibres causes the optic disc to appear pale,
as the choroid becomes visible (Fig. 26.23). A pale disc
(optic atrophy) follows optic nerve damage, and causes
include previous optic neuritis or ischaemic damage,
long-standing papilloedema, optic nerve compression,
Hearing disturbance
Each cochlear organ has bilateral cortical representation,
so unilateral hearing loss is a result of peripheral organ
damage. Bilateral hearing dysfunction is usual, and is
most commonly due to age-related degeneration or
noise damage, although infection and drugs (particu-
larly diuretics and aminoglycoside antibiotics) can be a
primary cause. Prominent deafness may suggest a mito-
chondrial disorder (see Box 26.109, p. 1229).
Bulbar symptoms – dysphagia
and dysarthria
Swallowing is a complex activity involving the coordi-
nated action of lips, tongue, soft palate, pharynx and
larynx, which are innervated by cranial nerves 7, 9, 10,
11 and 12. Structural causes of dysphagia are considered
on page 851. Neurological mechanisms are vulnerable to
damage at different points, resulting in dysphagia that
is usually accompanied by dysarthria. Tempo is again
crucial: acute onset of dysphagia may occur as a result
of brainstem stroke or a rapidly developing neuropathy, 1173
 NEUROLOGICAL DISEASE
26 26.30 Causes of pseudobulbar and bulbar palsy
Pseudobulbar
Genetic – Kennedy’s disease (X-linked bulbospinal neuronopathy)
Vascular Bilateral hemisphere (lacunar) infarction
Degenerative Motor neuron disease (p. 1200)
Inflammatory/infective Multiple sclerosis (p. 1188)
Cerebral vasculitis
Neoplastic High brainstem tumours
such as Guillain–Barré syndrome or diphtheria. Inter-
mittent fatigable muscle weakness (including dys-
phagia) would suggest myasthenia gravis. Dysphagia
developing over weeks or months may be seen in motor
neuron disease, polymyositis, basal meningitis and
inflammatory brainstem disease. More slowly develop-
ing dysphagia suggests a myopathy or possibly a brain-
stem or skull-base tumour.
Pathologies affecting lower cranial nerves (9, 10, 11
and 12) frequently manifest bilaterally, producing
dysphagia and dysarthria. The term ‘bulbar palsy’ is
used to describe lower motor neuron lesions, either
within the medulla or outside the brainstem. The tongue
is wasted and fasciculating, and palatal movement is
reduced.
Upper motor neuron innervation of swallowing is
bilateral, so persistent dysphagia is unusual with a uni-
lateral upper motor lesion (the exception being in the
acute stages of, for example, a hemispheric stroke).
Widespread lesions above the medulla will cause upper
motor neuron bulbar paralysis, known as ‘pseudobulbar
palsy’. Here the tongue is small and contracted, and
moves slowly; the jaw jerk is brisk. Causes of bulbar and
pseudobulbar palsies are shown in Box 26.30.
Bladder, bowel and sexual disturbance
Whilst isolated disturbances of bladder, bowel and
sexual function are rarely the sole presenting features
of neurological disease, they are common complica-
tions of many chronic disorders such as multiple sclero-
sis, stroke and dementia, and are frequently found post
head injury. Abnormalities in these functions con-
siderably reduce quality of life for patients. Incontinence
and its management are discussed elsewhere (pp. 472,
918 and 175).
Bladder dysfunction
The anatomy and physiology involved in controlling
bladder functions are discussed on page 466 but it
is worth emphasising the role of the pontine micturi-
tion centre, which is itself under higher control via
inputs from the pre-frontal cortex, mid-brain and
hypothalamus.
In the absence of conscious control (e.g. in coma or
1174 dementia), distension of the bladder to near-capacity
Bulbar
Medullary infarction (see Box 26.3, p. 1148)
Motor neuron disease
Syringobulbia
Myasthenia (p. 1226)
Guillain–Barré syndrome (p. 1224)
Poliomyelitis (p. 1207)
Lyme disease (p. 334)
Vasculitis
Brainstem glioma
Malignant meningitis
evokes reflex detrusor contraction (analogous to the
muscle stretch reflex), and reciprocal changes in sympa-
thetic activation and relaxation of the distal sphincter
result in coordinated bladder emptying.
Damage to the lower motor neuron pathways (the
pelvic and pudendal nerves) produces a flaccid bladder
and sphincter with overflow incontinence, often accom-
panied by loss of pudendal sensation. Such damage may
be due to disease of the conus medullaris or sacral nerve
roots, either within the dura (as in inflammatory or car-
cinomatous meningitis) or as they pass through the
sacrum (trauma or malignancy), or due to damage to the
nerves themselves in the pelvis (infection, haematoma,
trauma or malignancy).
Damage to the pons or spinal cord results in an
‘upper motor neuron’ pattern of bladder dysfunction
due to uncontrolled over-activity of the parasympathetic
supply. The bladder is small and highly sensitive to
being stretched. This results in frequency, urgency and
urge incontinence. Loss of the coordinating control of
the pontine micturition centre will also result in the phe-
nomenon of detrusor–sphincter dyssynergia, in which
detrusor contraction and sphincter relaxation are not
coordinated; the spastic bladder will often try to empty
against a closed sphincter. This manifests as both
urgency and an inability to pass urine, which is distress-
ing and painful. The resultant incomplete bladder
emptying predisposes to urinary infection, and the
prolonged high bladder pressure may result in renal
failure; post-micturition bladder ultrasound may
confirm incomplete bladder emptying. More severe
lesions of the spinal cord, as in spinal cord compression
or trauma, can result in painless urinary retention, as
bladder sensation, normally carried in the lateral spino-
thalamic tracts, will be cut off.
Damage to the frontal lobes gives rise to loss of aware-
ness of bladder fullness and consequent incontinence.
Coexisting cognitive impairment may result in inappro-
priate micturition. These features are seen typically in
hydrocephalus, frontal tumours, dementia and bifrontal
subdural haematomas.
When a patient presents with bladder symptoms, it
is important to try to localise the lesion on the basis
of history and examination, remembering that most
bladder problems are not neurological unless there are
overt neurological signs. Clinical features and manage-
ment are summarised in Box 26.31.

26.31 Neurogenic bladder: clinical features and treatment
Site of lesion
Atonic (lower Lesions of sacral segments of
motor neuron) cord (conus medullaris)
Lesions of sacral roots and nerves
Hypertonic (upper Pyramidal tract lesion in spinal
motor neuron) cord or brainstem
Cortical Post-central
Pre-central
Frontal
Rectal dysfunction
The rectum has an excitatory cholinergic input from the
parasympathetic sacral outflow, and inhibitory sympa-
thetic supply similar to the bladder. Continence depends
largely on skeletal muscle contraction in the puborectalis
and pelvic floor muscles supplied by the pudendal
nerves, as well as the internal and external anal sphinc-
ters. Damage to the autonomic components usually
causes constipation (a common early symptom in
Parkinson’s disease) but diabetic neuropathy can be
associated with diarrhoea. Lesions affecting the conus
medullaris, the somatic S2–4 roots and the pudendal
nerves may cause faecal incontinence.
Erectile failure and
ejaculatory failure
These related functions are under autonomic control via
the pelvic nerves (parasympathetic, S2–4) and hypogas-
tric nerves (sympathetic, L1–2). Descending influences
from the cerebrum are important for erection, but it can
occur as a reflex phenomenon in response to genital
stimulation. Erection is largely parasympathetic, and
may be impaired by a number of drugs, including
anticholinergic, antihypertensive and antidepressant
agents. Sympathetic activity is important for ejaculation,
and may be inhibited by α-adrenoceptor antagonists
(α-blockers). For further information on erectile failure,
see page 474.
Personality change
While this is often due to psychiatric illness, neuro-
logical conditions that alter the function of the frontal
lobes can cause personality change and mood disorder
(see Box 26.2, p. 1142). Personality change due to a
frontal lobe disorder may occur as the result of structural
damage due to stroke, trauma, tumour or hydrocepha-
lus. The nature of any change may help localise the
lesion.
Patients with mesial frontal lesions become increas-
ingly withdrawn, unresponsive and mute (abulic), often
in association with urinary incontinence, gait apraxia
and an increase in tone known as gegenhalten, in which
Functional symptoms
Result Treatment
Loss of detrusor contraction Intermittent self-catheterisation
Difficulty initiating micturition In-dwelling catheterisation
Bladder distension with overflow
Urgency with urge incontinence Anticholinergics:
Bladder sphincter incoordination Solifenacin
(dyssynergia) Tolterodine
Incomplete bladder emptying Imipramine
Intermittent self-catheterisation
Loss of awareness of bladder Intermittent or in-dwelling
fullness catheterisation
Difficulty initiating micturition
Inappropriate micturition
Loss of social control
the patient varies the resistance to movement in propor-
tion to the force exerted by the examiner.
Patients with lesions of the dorsolateral pre-frontal
cortex develop a dysexecutive syndrome, which involves
difficulties with speech, motor planning and organisa-
tion. Those with orbitofrontal lesions of the frontal lobes,
in contrast, become disinhibited, displaying grandiosity
or irresponsible behaviour. Memory is substantially 26
intact but frontal release signs may emerge, such as a
grasp reflex, palmomental response or pout. Proximity
to the olfactory bulb and tracts means that inferior
frontal lobe tumours may be associated with anosmia.
Disturbance to the cortical areas responsible for
speech or memory can result in changes that may be
interpreted as changes in personality.
Sleep disturbance
Disturbances of sleep are common and are not usually
due to neurological disease. Patients may complain of
insomnia (difficulty sleeping), excessive daytime sleepi-
ness, disturbed behaviour during night-time sleep, para-
somnia (sleep walking and talking, or night terrors) or
disturbing subjective experiences during sleep and/or
its onset (nightmares, hypnagogic hallucinations, sleep
paralysis). A careful history (from the bed-partner as
well as the patient) usually allows specific causes of
sleep disturbance to be identified and these are dis-
cussed in more detail on page 1187.
Psychiatric disorders
Psychiatric disorders are described in Chapter 10 but
may cause or result from neurological problems. Care is
needed in their identification, as effective management
will help the underlying neurological illness.
FUNCTIONAL SYMPTOMS
Many patients presenting with neurological symptoms
do not have a defined neurological disease and are best
described as having functional symptoms (p. 236). Some 1175
 NEUROLOGICAL DISEASE
26 26.32 Clinical features suggestive of
functional disorder
• Situational provocation
• Associated psychological disorders
Anxiety
Depression
• Lack of anatomical coherence to neurological symptoms
• Florid or bizarre descriptions of individual symptoms
• History of other medically unexplained symptoms
• Hoover’s sign (p. 1163)
• Predisposing history of childhood neglect or abuse
of these are psychogenic (or conversion) disorders. Such
patients often have unexplained symptoms affecting
multiple systems and a long list of consultations and
negative tests from other medical specialties when they
present. Considering the possibility of a functional
origin may save the patient further unnecessary, inva-
sive and inconvenient investigation and anxiety.
Weakness and sensory symptoms predominate
among functional symptoms, but pain or loss of con-
sciousness can occur. Associated symptoms, such as
tiredness, lethargy, poor concentration, bowel upset
(irritable bowel syndrome) and gynaecological com-
plaints, are common. A functional origin of neurological
problems should always be considered, as it can allow
for more rapid diagnosis and avoid unnecessarily
painful or hazardous investigation. Some clinical fea-
tures may hint at a functional origin for symptoms (Box
26.32). It is the clinician’s job to elicit the context of the
patient’s symptoms in a sensitive and non-judgemental
way. Whatever the illness, it is important to acknowl-
edge that mood and sleep disturbance will exacerbate
neurological symptoms, thus increasing disability
resulting from neurological disorders. The best practi-
tioners have the skill to carry the patient with them
when describing the patterns of behaviour contributing
to symptoms.
Assessment to detect an underlying or exacerbating
mood disorder is vital in all patients, ensuring that
depression and anxiety are managed to minimise their
secondary effects on neurological symptoms.
HEADACHE SYNDROMES
Headaches may be classified as primary or secondary,
depending on the underlying cause (see Box 26.10,
p. 1156). Secondary headache may be due to structural,
infective, inflammatory or vascular conditions, which
are discussed later in this chapter. The primary head-
ache syndromes are described here.
Tension-type headache
This is the most common type of headache and is
experienced to some degree by the majority of the
population.
Pathophysiology
Tension headache is incompletely understood. Emotions
and anxiety are common precipitants and there is some-
times an associated depressive illness. Anxiety about the
1176 headache itself may lead to continuation of symptoms,
and patients often become convinced of a serious under-
lying condition. Muscular spasms may worsen this in
some patients.
Clinical features
The pain of tension headache is usually characterised
as ‘dull’, ‘tight’ or like a ‘pressure’, and there may be
a sensation of a band round the head or pressure at
the vertex. It is of constant character and generalised,
but often radiates forwards from the occipital region.
In contrast to migraine, the pain can remain unabated
for weeks or months without interruption, although
the severity may vary, and there is no associated vomit-
ing or photophobia. Activities are usually continued
throughout, and the pain may be less noticeable when
the patient is occupied. The pain is usually less severe
in the early part of the day, becoming more troublesome
as the day goes on. Tenderness may be present over the
skull vault or in the occiput but is easily distinguished
from the triggered pains of trigeminal neuralgia and the
exquisite tenderness of temporal arteritis. Analgesics
may be taken with chronic regularity despite little effect,
and may serve to perpetuate the symptoms (see ‘Medi-
cation overuse headache’ below).
Management
Most benefit is given by providing a careful assessment,
followed by discussion of likely precipitants and reas-
surance that the prognosis is good. Excessive use of
analgesia, particularly those containing codeine, may
maintain and exacerbate the headache (analgesic head-
ache). Physiotherapy (with muscle relaxation and stress
management) may help and low-dose amitriptyline
can provide benefit. There is evidence that patients
benefit from a perception that their problem has been
taken seriously and rigorously assessed. Investigation
may contribute to such reassurance, especially if con-
cerns about an underlying lesion are strong, but patients
should understand the purpose and likely outcome of
such imaging.
Migraine
Migraine usually appears before middle age; it affects
about 20% of females and 6% of males at some point in
life. Some patients assume that migraine is a term
encompassing any severe headache but it has a charac-
teristic presentation, discussed below.
Pathophysiology
The cause of migraine is unknown but there is increas-
ing evidence that the aura (see below) is due to dys-
function of ion channels causing a spreading front of
cortical depolarisation (excitation) followed by hyper-
polarisation (depression of activity). This process (the
‘spreading depression of Leão’) spreads over the cortex
at a rate of about 3 mm/minute, corresponding to
the aura’s symptomatic spread. The headache phase is
associated with vasodilatation of extracranial vessels
and may be relayed by hypothalamic activity. Acti-
vation of the trigeminovascular system is probably
important. A genetic contribution is implied by fre-
quently positive family history, and similar phenomena
occurring in disorders such as CADASIL (p. 1242). The
female preponderance and the frequency of migraine
attacks at certain points in the menstrual cycle also

suggest hormonal influences. Oestrogen-containing oral
contraception sometimes exacerbates migraine, and
increases the small risk of stroke in patients who suffer
from migraine with aura. Doctors and patients often
over-estimate the role of dietary precipitants such as
cheese, chocolate or red wine. When psychological
factors contribute, the migraine attack often occurs after
a period of stress, being more likely on Friday evening
at the end of the working week or at the beginning of a
holiday.
Clinical features
Some patients report a prodrome of malaise, irritability
or behavioural change for some hours or days. Around
20% of patients experience an aura, and are said to have
migraine with aura (previously known as classical
migraine). The aura is most often visual, consisting of
fortification spectra, which are shimmering, silvery
zigzag lines that march across the visual fields for up to
40 minutes, sometimes leaving a trail of temporary
visual field loss (scotoma). In some there is a sensory
aura of tingling followed by numbness, spreading
over 20–30 minutes, from one part of the body to
another. Dominant hemisphere involvement may also
cause transient speech disturbance. The 80% of patients
with characteristic headache but no ‘aura’ are said
to have migraine without aura (previously called
‘common’ migraine).
Migraine headache is usually severe and throbbing,
with photophobia, phonophobia and vomiting lasting
from 4 to 72 hours. Movement makes the pain worse,
and patients prefer to lie in a quiet, dark room.
Caution should be taken in ascribing the cause of an
individual’s limb weakness or isolated aura without
headache to migraine. In such cases, other structural
disorders of the brain, or even focal epilepsy, need to be
considered.
In a smaller number of patients, the symptoms of the
aura do not resolve, leaving more permanent neuro-
logical disturbance. This persistent migrainous aura may
occur with or without evidence of brain infarction.
Management
Avoidance of identified triggers or exacerbating factors
(such as the combined contraceptive pill) may prevent
attacks. Treatment of an acute attack consists of simple
analgesia with aspirin, paracetamol or non-steroidal
anti-inflammatory agents. Nausea may require an
antiemetic such as metoclopramide or domperidone.
Severe attacks can be aborted by one of the increasing
number of ‘triptans’ (e.g. sumatriptan), which are potent
5-hydroxytryptamine (5-HT) agonists. These can be
administered orally, by subcutaneous injection or by
nasal spray. Care should be taken to avoid accelerating
use. Caution is needed with ergotamine preparations
since they may lead to dependence. Overuse of any
analgesia, including triptans, may contribute to associ-
ated medication overuse headache.
If attacks are frequent (more than 3–4 per month),
prophylaxis should be considered. Many drugs can be
used, but the most frequently used are vasoactive drugs
(calcium channel blockers and β-adrenoceptor ant-
agonists (β-blockers)), antidepressants (amitriptyline,
dosulepin) and anti-epileptic drugs (valproate, topiram-
ate). Women with aura should avoid oestrogen
Headache syndromes
treatment for either oral contraception or hormone
replacement, although the increased risk of ischaemic
stroke is minimal.
Medication overuse headache
With increasing availability of over-the-counter medica-
tion, headache syndromes perpetuated by analgesia
intake are becoming much more common. Medication
overuse headache (MOH) can complicate any other
headache syndrome, but is especially associated with
migraine and tension headache. The medications that
are the most common culprits are compound analgesia
(particularly codeine and other opiate-containing prepa-
rations) and triptans, and MOH is usually associated
with use on more than 10–15 days per month.
Management is by withdrawal of the responsible
analgesics; patients should be warned that the initial
effect will be to exacerbate the headache. Migraine
prophylactics may be helpful in reducing the rebound
headaches. In severe cases, hospital admission with or
without a course of corticosteroids may be helpful.
Cluster headache
Cluster headaches (also known as migrainous neuralgia)
are much less common than migraine. There is a 5 : 1
male predominance and onset is usually in the third
26
decade.
Pathophysiology
The cause is unknown, but this type of headache differs
from migraine in its character, lack of genetic predis-
position, lack of provoking dietary factors, opposing
gender imbalance and different drug effect. Functional
imaging studies have suggested abnormal hypothalamic
activity. Patients are more often smokers with a higher
than average alcohol consumption.
Clinical features
Cluster headache is strikingly periodic, featuring runs of
identical headaches beginning at the same hour for
weeks at a time (the eponymous ‘cluster’). Patients may
experience either one or several attacks within a 24-hour
period. Cluster headache causes severe, unilateral peri-
orbital pain with autonomic features, such as unilateral
lacrimation, nasal congestion and conjunctival injection
(occasionally with the other features of Horner’s syn-
drome). The pain, though severe, is characteristically
brief (30–90 minutes). In contrast to the behaviour of
those with migraine, patients are often highly agitated
during the headache phase. The cluster period is typi-
cally a few weeks, followed by remission for months
to years, but a small proportion do not experience
remission.
Management
Acute attacks can usually be halted by subcutaneous
injections of sumatriptan or by inhalation of 100%
oxygen. The brevity of the attack probably prevents
other migraine therapies from being effective. Migraine
prophylaxis is often ineffective too but attacks can be
prevented in some patients by sodium valproate, vera-
pamil, methysergide or short courses of oral cortico-
steroids. Patients with severe debilitating clusters can be
helped with lithium therapy, although this requires
monitoring (p. 245). 1177
 NEUROLOGICAL DISEASE

26 26.33 Benign paroxysmal headaches

Character of pain Duration Location Comment
Ice pick Stabbing Very brief (split-second) Variable, usually Benign, more common in
temporoparietal migraine
Ice cream Sharp, severe 30–120 secs Bitemporal/occipital Obvious trigger by cold
stimuli
Exertional/ Bursting, thunderclap Severe for mins then less Generalised Subarachnoid haemorrhage
coital severe for hrs needs to be excluded
Cough Bursting Secs to mins Occipital or generalised Intracranial pathology
needs to be excluded
(especially craniocervical
junction)
Cluster Severe unilateral, with 30–90 mins 1–3 times per Periorbital Usually in men, occurring
headache ptosis, tearing, conjunctival day in clusters over weeks/
(migrainous injection, unilateral nasal months
neuralgia) congestion
Chronic Severe unilateral with 5–20 mins, frequently Periorbital/temporal Usually in women,
paroxysmal cluster headache-like through day responds to indometacin
hemicrania autonomic features (see
above)
SUNCT* Severe, sharp, triggered by 15–120 secs, repetitive Periorbital May respond to
touch or neck movements through day carbamazepine

*Short-lasting, Unilateral, Neuralgiform headache with Conjunctival injection, Tearing, rhinorrhoea and forehead sweating.

Trigeminal neuralgia
This is characterised by unilateral lancinating facial
pain, most commonly involving the second and/or third
divisions of the trigeminal nerve territory, usually in
patients over the age of 50 years.
Pathophysiology
Trigeminal neuralgia is thought to be caused by an
irritative lesion involving the trigeminal root zone, in
some cases an aberrant loop of artery. Other compres-
sive lesions, usually benign, are occasionally found.
Trigeminal neuralgia associated with multiple sclerosis
may result from a plaque of demyelination in the
brainstem.
Clinical features
The pain is repetitive, severe and very brief. It may be
triggered by touch, a cold wind or eating. Physical signs
are usually absent, although the spasms may make the
patient wince and sit silently (tic douloureux). Similar
symptoms may occur in multiple sclerosis or with other
brainstem lesions, in which case there may be associated
sensory changes in the trigeminal nerve territory or else-
where. There is a tendency for the condition to remit and
relapse over many years.
Management
The pain usually responds at least partially to car-
bamazepine. It is wise to start with a low dose and
increase gradually, according to effect. In patients who
cannot tolerate carbamazepine, gabapentin, pregabalin,
amitriptyline or steroids may be effective. The possibil-
ity of surgical treatment should be entertained, espe-
cially where response is incomplete in younger patients.
1178 Decompression of the vascular loop encroaching on
the trigeminal root is said to have a 90% success rate.
Otherwise, localised injection of alcohol or phenol into
a peripheral branch of the nerve may be effective.
Headaches associated with
specific activities
These usually affect men in their thirties and forties.
Patients develop a sudden, severe headache with exer-
tion, including sexual activity. There is usually no vom-
iting and no neck stiffness, and the headache lasts less
than 10–15 minutes, though a less severe dullness may
persist for some hours. Subarachnoid haemorrhage
needs to be excluded by CT and/or CSF examination
(see Fig. 27.12, p. 1246) after a first event. The pathogen-
esis of these headaches is unknown. Although frighten-
ing, attacks are usually brief and patients may only need
reassurance and simple analgesia for the residual head-
ache. The syndrome may recur, and prevention may be
necessary with propranolol or indometacin.
Other headache syndromes
A number of rare headache syndromes produce pains
about the eye similar to cluster headaches (Box 26.33).
These include chronic paroxysmal hemicrania and
SUNCT (short-lasting unilateral neuralgiform head-
aches with conjunctival injection and tearing). The rec-
ognition of these syndromes is useful since they often
respond to specific treatments such as indometacin.
EPILEPSY
A seizure can be defined as the occurrence of signs and/
or symptoms due to abnormal, excessive or synchronous

26.34 Classification of seizures
(2010 ILAE Classification)
Generalised seizures
• Tonic–clonic (in any • Myoclonic
combination) Myoclonic
• Absence Myoclonic atonic
Typical Myoclonic tonic
Atypical • Clonic
Absence with special • Tonic
features • Atonic
• Myoclonic absence
• Eyelid myoclonia
Focal seizures
• Without impairment of consciousness or awareness (was
‘simple partial’)
Focal motor
Focal sensory
• With impairment of consciousness or awareness (was
‘complex partial’)
• Evolving to a bilateral, convulsive seizure (was ‘secondarily
generalised seizure’)
Tonic
Clonic
Tonic–clonic
Unknown
• Epileptic spasms
neuronal activity in the brain. ‘Epilepsy’ is the tendency
to have unprovoked seizures. The lifetime risk of seizure
is about 5%, although incidence is highest at the extremes
of age. Whilst the prevalence of active epilepsy in Euro-
pean countries is about 0.5%, the figure in developing
countries may be higher because of parasitic illnesses
such as cysticercosis (p. 380).
Historical terms such as ‘grand mal’ (implying tonic–
clonic seizures) and ‘petit mal’ (intended by its origina-
tors to mean ‘absence seizures’ but commonly used to
describe ‘anything other than grand mal’) have been
superseded. Subsequent revisions, including terms such
as ‘complex partial’ and ‘simple partial’, have been
imprecise and confusing, carrying little information
about underlying pathology, treatment or prognosis.
The modern equivalents for these terms will be given
below, but it is preferable to adhere to the 2010 iteration
of the International League Against Epilepsy’s classifica-
tion (Box 26.34).
Pathophysiology
To function normally, the brain must achieve an ongo-
ing balance between excitation and inhibition, in order
to remain responsive to the environment without con-
tinued unrestrained spontaneous activity. The inhibi-
tory transmitter gamma-aminobutyric acid (GABA) is
particularly important, acting on ion channels to enhance
chloride inflow and reduce the chances of action poten-
tial formation. Excitatory amino acids (glutamate and
aspartate) allow influx of sodium and calcium, produc-
ing the opposite effect. It is likely that many seizures
result from an imbalance between this excitation and
inhibition. Intracellular recordings during seizures dem-
onstrate a paroxysmal depolarisation shift in neuronal
membrane potential, predisposing to recurrent action
Epilepsy
A
Focal seizure
± secondary
generalisation
B
Primary
generalised
seizure
26
Fig. 26.24 The pathophysiological classification of seizures.
A A focal seizure originates from a paroxysmal discharge in a focal
area of the cerebral cortex (often the temporal lobe); the seizure may
subsequently spread to the rest of the brain (secondary generalisation) via
diencephalic activating pathways. B In primary generalised seizures the
abnormal electrical discharges originate from the diencephalic activating
system and spread simultaneously to all areas of the cortex.
potentials. In vivo, epileptic cortex shows repetitive dis-
charges involving large groups of neurons.
Seizures may be related to a localised disturbance in
the cortex, becoming manifest in the first instance as
focal seizures. Any disturbance of cortical architecture
and function can precipitate this, whether focal infec-
tion, tumour, hamartoma or trauma-related scarring. If
focal seizures remain localised, the symptoms experi-
enced depend on which cortical area is affected. If areas
in the temporal lobes become involved, then awareness
of the environment becomes impaired but without asso-
ciated tonic–clonic movements. When both hemispheres
are involved, either at onset or after spread, the seizure
becomes generalised (Fig. 26.24).
In seizures that are generalised at onset, the abnormal
activity probably originates in the central mechanisms
controlling cortical activation (see Fig. 26.24) and spreads
rapidly. Such epilepsies constitute around 30% of all
epilepsy, and are likely to reflect widespread distur-
bance of structure or function. Animal models have
revealed mutations in genes for ion channels and recep-
tors that cause seizures. In humans, many generalised
epilepsies will have a genetic basis, and these almost
always become apparent before the age of 35.
Seizure activity is usually apparent on EEG as
spike and wave discharges (see Fig. 26.14, p. 1152).
Other generalised seizure activity may involve merely
brief loss of awareness (absence seizures), single jerks
(myoclonus) or loss of tone (atonic seizures), as detailed
in Box 26.34. 1179
 NEUROLOGICAL DISEASE

26 Clinical features
Seizure type and epilepsy type
26.36 Causes of focal seizures

To classify seizure type, the clinician should ask first Idiopathic

whether there is a focal onset, and second whether the • Benign Rolandic epilepsy of childhood
seizures conform to one of the recognised patterns (see • Benign occipital epilepsy of childhood
Box 26.34). Epilepsy that starts in patients beyond their Focal structural lesions
mid-thirties will almost invariably reflect a focal cere-
Genetic
bral event. Where activity remains focal, this will be
• Tuberous sclerosis • von Hippel–Lindau disease
obvious. Even when generalised tonic–clonic seizures
(p. 1302) (p. 1216)
occur, seizures beginning in one cortical area will cause
• Autosomal dominant frontal • Neurofibromatosis
positive neurological symptoms and signs correspond- lobe epilepsy (p. 1215)
ing to the normal function of that area. Occipital onset • Autosomal dominant partial • Cerebral migration
will cause visual changes (lights and blobs of colour), epilepsy with auditory abnormalities
temporal lobe onset will cause false recognition (déjà features (ADPEAF)
vu), sensory strip involvement will cause sensory altera-
tion (burning, tingling), and motor strip involvement Infantile hemiplegia
will cause jerking. Dysembryonic
Patients can experience more than one type of seizure • Cortical dysgenesis • Sturge–Weber syndrome
attack, and it is important to document each attack type Mesial temporal sclerosis (associated with febrile convulsions)
and the patient’s age at its onset, along with its fre-
Cerebrovascular disease (Ch. 27)
quency, duration and typical features. Any triggers
• Intracerebral haemorrhage • Arteriovenous malformation
should be identified (Box 26.35). The type of seizure,
• Cerebral infarction • Cavernous haemangioma
other clinical features and investigations can then be
used to determine the epilepsy syndrome, as discussed Tumours (primary and secondary) (p. 1213)
below. Where there is doubt about the type, this is best Trauma (including neurosurgery)
stated and a full classification should be deferred until Infective (p. 1201)
the evolution of the clinical features clarifies the picture. • Cerebral abscess • Subdural empyema
Some patients will give a history of a previous local (pyogenic) • Encephalitis
cortical insult, and it can be reasonably (but not invari- • Toxoplasmosis • Human immunodeficiency
ably) inferred that this is the seat of epileptogenesis. • Cysticercosis virus (HIV)
• Tuberculoma
Focal seizures
Inflammatory
The classification of focal seizures is shown in Box 26.34.
• Sarcoidosis • Vasculitis
They are caused by localised cortical activity with
retained awareness. The localisation of such symptoms
is described above. A spreading pattern of seizure may
occur, the abnormal sensation spreading much faster
(in seconds) than a migrainous focal sensory attack. Seizures arising from the anterior parts of the
Awareness may become impaired if spread occurs frontal lobe may produce bizarre behaviour patterns,
to the temporal lobes (previously ‘complex partial including limb posturing, sleep walking, or even frenetic
seizure’). Patients stop and stare blankly, often blinking ill-directed motor activity with incoherent screaming.
repetitively, making smacking movements of their lips Video EEG may be necessary to differentiate these from
or displaying other automatisms, such as picking at their psychogenic attacks (which are more common), but
clothes. After a few minutes, consciousness returns but abruptness of onset, stereotyped nature, relative brevity
the patient may be muddled and feel drowsy for a and nocturnal preponderance may indicate the frontal
period of up to an hour. The age of onset, preceding onset. Causes of focal seizures are given in Box 26.36.
aura, longer duration and post-ictal symptoms usually
Generalised seizures
make these easy to differentiate from childhood absence
seizures (see below). Tonic–clonic seizures. An initial ‘aura’ may be experi-
enced by the patient, depending on the cortical area
from which the seizure originates (as above). The
patient then becomes rigid (tonic) and unconscious,
falling heavily if standing (‘like a log’) and risking facial
26.35 Trigger factors for seizures injury. During this phase, breathing stops and central
cyanosis may occur. As cortical discharges reduce in
• Sleep deprivation frequency, the limbs produce jerking (clonic) move-
• Missed doses of anti-epileptic drugs in treated ments for a variable time. Afterwards, there is a flaccid
patients state of deep coma, which can persist for some minutes.
• Alcohol (particularly withdrawal) The patient may be confused, disorientated and/or
• Recreational drug misuse amnesic after regaining consciousness. During the
• Physical and mental exhaustion attack, urinary incontinence and tongue-biting may
• Flickering lights, including TV and computer screens
occur. A severely bitten, bleeding tongue after an
(generalised epilepsy syndromes only)
attack of loss of consciousness is pathognomonic of a
• Intercurrent infections and metabolic disturbances
generalised seizure. Subsequently, the patient usually
• Uncommon: loud noises, music, reading, hot baths
1180 feels unwell and sleepy, with headache and myalgia.

26.37 Causes of generalised tonic–clonic
seizures
Generalisation from focal seizures
• See Box 26.36
Genetic
• Inborn errors of metabolism (p. 64)
• Storage diseases (p. 450)
• Phakomatoses (e.g. tuberous sclerosis, p. 1302)
Cerebral birth injury
Hydrocephalus
Cerebral anoxia
Drugs
• Antibiotics: penicillin, isoniazid, metronidazole
• Antimalarials: chloroquine, mefloquine
• Ciclosporin
• Cardiac anti-arrhythmics: lidocaine, disopyramide
• Psychotropic agents: phenothiazines, tricyclic
antidepressants, lithium
• Amphetamines (withdrawal)
Alcohol (especially withdrawal)
Toxins
• Organophosphates (sarin) • Heavy metals (lead, tin)
Metabolic disease
• Hypocalcaemia • Hypoglycaemia
• Hyponatraemia • Renal failure
• Hypomagnesaemia • Liver failure
Infective
• Post-infectious • Meningitis (p. 1201)
encephalopathy
Inflammatory
• Multiple sclerosis (uncommon) (p. 1188)
• SLE (p. 1109)
Diffuse degenerative diseases
• Alzheimer’s disease (uncommonly) (p. 251)
• Creutzfeldt–Jakob disease (rarely) (p. 1211)
Witnesses are usually frightened by the event, often
believe the person to be dying, and may struggle to give
a clear account of the episode. Some may not describe
the tonic or clonic phase, and may not mention cyanosis
or tongue-biting. In less typical episodes, post-ictal con-
fusion, or sequelae such as headache or myalgia, may be
the main pointers to the diagnosis. Causes of generalised
tonic–clonic seizures are listed in Box 26.37.
Absence seizures. Absence seizures (previously ‘petit
mal’) always start in childhood. The attacks are rarely
mistaken for focal seizures because of their brevity. They
can occur so frequently (20–30 times a day) that they are
mistaken for daydreaming or poor concentration in
school.
Myoclonic seizures. These are typically brief, jerking
movements, predominating in the arms. In epilepsy,
they are more marked in the morning or on awakening
from sleep, and tend to be provoked by fatigue, alcohol
or sleep deprivation.
Atonic seizures. These are seizures involving brief loss
of muscle tone, usually resulting in heavy falls with or
without loss of consciousness. They only occur in the
context of epilepsy syndromes that involve other forms
of seizure.
Epilepsy
Tonic seizures. These are associated with a generalised
increase in tone and an associated loss of awareness.
They are usually seen as part of an epilepsy syndrome
and are unlikely to be isolated.
Clonic seizures. Clonic seizures are similar to tonic–
clonic seizures. The clinical manifestations are similar
but without a preceding tonic phase.
Seizures of uncertain generalised or focal nature
Epileptic spasms. While these are highlighted in the
classification system, they are unusual in adult practice
and occur mainly in infancy. They signify widespread
cortical disturbance and take the form of marked con-
tractions of the axial musculature, lasting a fraction
of a second but recurring in clusters of 5–50, often
on awakening.
Epilepsy syndromes
Many patients with epilepsy fall into specific patterns,
depending on seizure type(s), age of onset and treat-
ment responsiveness: the so-called electroclinical syn-
dromes (Box 26.38). It is anticipated that genetic testing
will ultimately demonstrate similarities in molecular
pathophysiology.
Box 26.39 highlights the more common epilepsy syn-
dromes, which are largely of early onset and are sensi-
tive to sleep deprivation, hyperventilation, alcohol and 26
26.38 Electroclinical epilepsy syndromes
Adolescence to adulthood
• Juvenile absence epilepsy (JAE)
• Juvenile myoclonic epilepsy (JME)
• Epilepsy with generalised tonic–clonic seizures alone
• Progressive myoclonus epilepsies (PME)
• Autosomal dominant epilepsy with auditory features (ADEAF)
• Other familial temporal lobe epilepsies
Less specific age relationship
• Familial focal epilepsy with variable foci (childhood to adult)
• Reflex epilepsies
Distinctive constellations
• Mesial temporal lobe epilepsy with hippocampal sclerosis
(MTLE with HS)
• Rasmussen’s syndrome
• Gelastic (from the Greek word for laughter) seizures with
hypothalamic hamartoma
• Hemiconvulsion–hemiplegia–epilepsy
Epilepsies with structural–metabolic causes
• Malformations of cortical development (hemimegalencephaly,
heterotopias etc.)
• Neurocutaneous syndromes (tuberous sclerosis complex,
Sturge–Weber etc.)
• Tumour
• Infection
• Trauma
• Angioma
• Perinatal insults
• Stroke etc.
Epilepsies of unknown cause
Conditions with epileptic seizures traditionally not diagnosed
• Benign neonatal seizures (BNS)
• Febrile seizures (FS)
1181
 NEUROLOGICAL DISEASE

26 26.39 Common epilepsy syndromes

Age of onset Type of seizure EEG features Treatment Prognosis
Childhood absence 4–8 yrs Frequent brief 3/sec spike and wave Ethosuximide 40% develop GTCS,
epilepsy absences Sodium valproate 80% remit in adulthood
Levetiracetam
Juvenile absence 10–15 yrs Less frequent Poly-spike and wave Sodium valproate 80% develop GTCS,
epilepsy absences than Levetiracetam 80% seizure-free in
childhood absence adulthood
Juvenile myoclonic 15–20 yrs GTCS, absences, Poly-spike and wave, Sodium valproate 90% remit with AEDs
epilepsy morning myoclonus photosensitivity Levetiracetam but relapse if AED
withdrawn
GTCS on awakening 10–25 yrs GTCS, sometimes Spike and wave on Sodium valproate 65% controlled with
myoclonus waking and sleep Levetiracetam AEDs but relapse off
onset treatment

(AED = anti-epileptic drug; GTCS = generalised tonic–clonic seizures)

photic stimulation. Epilepsies that do not fit into any of

these diagnostic categories can be delineated first on the 26.40 Investigation of epilepsy
basis of the presence or absence of a known structural
or metabolic condition (presumed cause), and then on From where is the epilepsy arising?
the basis of the primary mode of seizure onset (general- • Standard EEG • EEG with special electrodes
ised versus focal). • Sleep EEG (foramen ovale, subdural)
What is the cause of the epilepsy?
Investigations
Structural lesion?
Single seizure • CT • MRI
All patients with transient loss of consciousness should Metabolic disorder?
have a 12-lead ECG. Where seizure is suspected or defi- • Urea and electrolytes • Blood glucose
nite, patients should have imaging with either CT or • Liver function tests • Serum calcium, magnesium
MRI, although the yield is low unless focal signs are
Inflammatory or infective disorder?
present. EEG may help to assess prognosis once a firm • Full blood count, erythrocyte sedimentation rate, C-reactive
diagnosis has been made. The recurrence rate after a first protein
seizure is approximately 40%, and most recurrent attacks • Chest X-ray
occur within a month or two of the first. Further seizures • Serology for syphilis, HIV, collagen disease
are less likely if an identified trigger can be avoided (see • CSF examination
Box 26.35).
Are the attacks truly epileptic?
Other investigations for infective, toxic and metabolic
• Ambulatory EEG • Videotelemetry
causes (Box 26.40) may be appropriate. An EEG per-
formed immediately after a seizure may be more helpful
in showing focal features than if performed after a delay.
Epilepsy
26.41 Indications for brain imaging in epilepsy
The same investigations are required in a patient with
suspected epilepsy (Box 26.40). Where more than one • Epilepsy starting after the age of 16 yrs
seizure has occurred, an EEG may help to establish the • Seizures having focal features clinically
type of epilepsy and guide therapy. As imaging becomes • EEG showing a focal seizure source
more sensitive, focal changes are picked up more often. • Control of seizures difficult or deteriorating
Investigations should be revisited if the epilepsy is
intractable to treatment.
Inter-ictal EEG is abnormal in only about 50% of
patients with recurrent seizures, so it cannot be used to confident diagnosis of a recognised epilepsy syndrome
exclude epilepsy. The sensitivity can be increased to (e.g. juvenile myoclonic epilepsy) can be made. While
about 85% by prolonging recording time and including CT will exclude a major structural cause of epilepsy,
a period of natural or drug-induced sleep, but this MRI is required to demonstrate subtle changes such as
does not replace a well-taken history. Ambulatory EEG hippocampal sclerosis, which may direct or inform
recording or video EEG monitoring may help with dif- surgical intervention.
ferentiation of epilepsy from other attack disorders if
these are sufficiently frequent. Management
Indications for imaging are summarised in Box 26.41. It is important to explain the nature and cause of sei-
Imaging cannot establish a diagnosis of epilepsy but zures to patients and their relatives, and to instruct rela-
1182 identifies any structural cause. It is not required if a tives in the first aid management of seizures (Box 26.42).

26.42 How to administer first aid for seizures
• Move person away from danger (fire, water, machinery,
furniture)
• After convulsions cease, turn person into ‘recovery’ position
(semi-prone)
• Ensure airway is clear but do NOT insert anything in mouth
(tongue-biting occurs at seizure onset and cannot be
prevented by observers)
• If convulsions continue for more than 5 mins or recur without
person regaining consciousness, summon urgent medical
attention
• Do not leave person alone until fully recovered (drowsiness
and confusion can persist for up to 1 hr)
26.43 Epilepsy: outcome after 20 years
• 50% are seizure-free, without drugs, for the previous 5 yrs
• 20% are seizure-free for the previous 5 yrs but continue to
take medication
• 30% continue to have seizures in spite of anti-epileptic
therapy
Many people with epilepsy feel stigmatised and may
become unnecessarily isolated from work and social life.
It should be emphasised that epilepsy is a common dis-
order that affects 0.5–1% of the population, and that full
control of seizures can be expected in approximately
70% of patients (Box 26.43).
Immediate care
Little can or needs to be done for a person during a
major seizure except for first aid and common-sense
manœuvres to limit damage or secondary complications
(see Box 26.42). Advice should be given that on no
account should anything be inserted into the patient’s
mouth. The management of status epilepticus is
described on page 1159.
Lifestyle advice
Patients should be advised to avoid activities where
they might place themselves or others at risk if they
have a seizure. This applies at work, at home and
at leisure. At home, only shallow baths (or showers)
should be taken. Prolonged cycle journeys should be
discouraged until reasonable freedom from seizures
has been achieved. Activities requiring prolonged prox-
imity to water (swimming, fishing or boating) should
always be carried out in the company of someone
who is aware of the risks and the potential need for
rescue measures. Driving regulations vary between
countries, and the patient should be made aware of these
(Box 26.44). Certain occupations, such as firefighter or
airline pilot, are not open to anyone who has a previous
or active diagnosis of epilepsy; further information is
available from epilepsy support organisations.
The recognised mortality of epilepsy should be dis-
cussed at around the time of diagnosis. This should be
done with care and sensitivity, and with the aim of moti-
vating the patient to adapt habits and lifestyle to opti-
mise epilepsy control.
Epilepsy
26.44 UK driving regulations
Private use
Single seizure
• Cease driving until at least 6 mths have passed without
recurrence. Driver and Vehicle Licensing Authority (DVLA)
may restore a full licence sooner if recurrence risk is low
Epilepsy (i.e. more than one seizure over the age of 5 yrs)
• Cease driving immediately
• Licence restored when patient is free from all types of
seizure for 1 yr or seizures have occurred exclusively during
sleep for a period of at least 3 yrs
• Licence will require renewal every 3 yrs thereafter until
patient is seizure-free for 10 yrs
Withdrawal of anticonvulsants
• Cease driving during withdrawal period and for 6 mths
thereafter
Vocational drivers (heavy goods and public service vehicles)
• No licence permitted if any seizure has occurred after the
age of 5 yrs until patient is off medication and seizure-free
for more than 10 yrs, and has no potentially epileptogenic
brain lesion
26.45 Guidelines for anticonvulsant therapy 26
• Start with one first-line drug (see Box 26.46)
• Start at a low dose; gradually increase dose until effective
control of seizures is achieved or side-effects develop (drug
levels may be helpful)
• Optimise compliance (use minimum number of doses
per day)
• If first drug fails (seizures continue or side-effects develop),
start second first-line drug, followed if possible by gradual
withdrawal of first
• If second drug fails (seizures continue or side-effects
develop), start second-line drug in combination with
preferred first-line drug at maximum tolerated dose (beware
interactions)
• If this combination fails (seizures continue or side-effects
develop), replace second-line drug with alternative
second-line drug
• If this combination fails, check compliance and reconsider
diagnosis (Are events seizures? Occult lesion? Treatment
compliance/alcohol/drugs confounding response?)
• Consider alternative, non-drug treatments (e.g. epilepsy
surgery, vagal nerve stimulation)
• Use minimum number of drugs in combination at any one time
Anticonvulsant therapy
Anticonvulsant drug treatment (anti-epileptic drugs, or
AEDs) should be considered after more than one unpro-
voked seizure. The decision to start treatment should be
shared with the patient, to enhance compliance. A wide
range of drugs is available. These agents either increase
inhibitory neurotransmission in the brain or alter neuro-
nal sodium channels to prevent abnormally rapid trans-
mission of impulses. In the majority of patients, full
control is achieved with a single drug. Dose regimens
should be kept as simple as possible. Guidelines are
listed in Box 26.45. For seizures of focal onset, one large 1183
 NEUROLOGICAL DISEASE

26 26.46 Guidelines for choice of anti-epileptic drug

Epilepsy type First-line Second-line Third-line
Focal onset and/or Lamotrigine Carbamazepine Clobazam
secondary GTCS Levetiracetam Gabapentin
Sodium valproate Oxcarbazepine
Topiramate Phenobarbital
Zonisamide Phenytoin
Lacosamide Pregabalin
Primidone
Tiagabine
GTCS Sodium valproate Lamotrigine Carbamazepine
Levetiracetam Topiramate Phenytoin
Zonisamide Primidone
Phenobarbital
Acetazolamide
Absence Ethosuximide Sodium valproate Lamotrigine
Clonazepam
Myoclonic Sodium valproate Levetiracetam Lamotrigine
Clonazepam Phenobarbital

N.B. Use as few drugs as possible at the lowest possible dose.

study suggests that lamotrigine is the best-tolerated Withdrawing anticonvulsant therapy

monotherapy, which, alongside its favourable side-
effect profile and relative lack of pharmacokinetic inter-
actions, makes it a good first-line drug, although caution
must be exercised with oral contraceptive use. Unclassi-
fied or specific syndromes respond best to valproate.
Problems in pregnancy mean that sodium valproate
should not be used in women of reproductive age unless
the benefits outweigh the risks. The first choice should
be an established first-line drug (Box 26.46), with more
recently introduced drugs as second choice.
Monitoring therapy
Some practitioners confuse epilepsy care with serum
level monitoring. The newer drugs have much more
predictable pharmacokinetics than the older ones, and
the only indication for measuring serum levels is if there
is doubt that the patient is taking the medication. Blood
levels need to be interpreted carefully, and dose changes
made to treat the patient rather than to bring a serum
level into the ‘therapeutic range’. Some centres advocate
serum level monitoring during pregnancy (notably with
lamotrigine) but the evidence of benefit for this is not
strong.
Epilepsy surgery
Some patients with drug-resistant epilepsy benefit from
surgical resection of epileptogenic brain tissue. Less
invasive treatments, including vagal nerve stimulation
or deep brain stimulation, may also be helpful in some
patients. All those who continue to experience seizures
despite appropriate drug treatment should be consid-
ered for surgical treatment. Planning such interventions
will require intensive specialist assessment and investi-
gation to identify the site of seizure onset and the dis-
pensability of any targets for resection, i.e. whether the
area of brain involved is necessary for a critical function
1184 such as vision or motor function.
Withdrawal of medication may be considered after a
patient has been seizure-free for more than 2 years.
Childhood-onset epilepsy, particularly classical absence
seizures, carries the best prognosis for successful drug
withdrawal. Other epilepsy syndromes, such as juvenile
myoclonic epilepsy, have a marked tendency to recur
after drug withdrawal.
Seizures that begin in adult life, particularly those
with partial features, are also likely to recur, especially
if there is an identified structural lesion. Overall, the
recurrence rate after drug withdrawal depends on the
individual’s epilepsy history. An individualised esti-
mate may be gained from the SIGN guideline tables (see
‘Further information’, p. 1230).
Patients should be advised of the risks of recurrence,
to allow them to decide whether or not they wish to
withdraw. If undertaken, withdrawal should be done
slowly, reducing the drug dose gradually over weeks
or months. Withdrawal may necessitate precautions
around driving or occupation (see Box 26.44).
Contraception
Some AEDs induce hepatic enzymes that metabolise
synthetic hormones, increasing the risk of contraceptive
failure. This is most marked with carbamazepine,
phenytoin and barbiturates, but clinically significant
effects can be seen with lamotrigine and topiramate. If
the AED cannot be changed, this can be overcome by
giving higher-dose preparations of the oral contracep-
tive. Sodium valproate and levetiracetam have no inter-
action with hormonal contraception.
Pregnancy and reproduction
Epilepsy presents specific management problems during
pregnancy (Box 26.47). There is usually great concern
about teratogenesis associated with AEDs. It is impor-
tant to recognise that the background risk of severe fetal

26.47 Epilepsy in pregnancy
• Provision of pre-conception counselling is best practice:
start folic acid 5 mg daily for 2 mths before conception to
reduce the risk of fetal malformations.
• Fetal malformation: risk is minimised if a single drug
is used.
Carbamazepine and lamotrigine have the lowest incidence
of major fetal malformations.
The risk with sodium valproate is higher but should be
carefully balanced against its benefits.
Levetiracetam may be safe, but avoid other newer drugs if
possible.
• Learning difficulties in children: IQ may be lower when
children are exposed to valproate in utero, so its use should
always be considered carefully.
• Haemorrhagic disease of the newborn: anticonvulsants
increase risk. Give oral vitamin K 20 mg daily to the mother
during the last month of pregnancy and give IM vitamin K
1 mg to the infant at birth.
• Increased frequency of seizures: where breakthrough
seizures occur, monitor anticonvulsant levels and adjust the
dose regimen accordingly.
• Pharmacokinetic effects of pregnancy: carbamazepine
levels may fall in the third trimester. Lamotrigine and
levetiracetam levels may fall early in pregnancy. Some
advocate monitoring of levels.
malformation in the population is around 2–3%. The
modern AED most associated with teratogenesis is
sodium valproate, which, at high dose, increases the risk
to around 6–7%. Long-term observational studies show
that most of the commonly used AEDs can be given
safely in pregnancy.
Pre-conception treatment with folic acid (5 mg daily),
along with use of the smallest effective doses of as few
AEDs as possible, may reduce the risk of fetal abnor-
malities. The risks of abrupt AED withdrawal to the
mother should be stressed.
Seizures may become more frequent during preg-
nancy, particularly if pharmacokinetic changes decrease
serum levels of AEDs (see Box 26.47).
Menstrual irregularities and reduced fertility are
more common in women with epilepsy, and are also
increased by sodium valproate. Patients with epilepsy
are at greater risk of osteoporosis, almost independently
of the drug used. Some centres advocate vitamin D sup-
plementation in any patient with epilepsy, but the higher
female risk of osteoporosis makes this most important
in women.
Prognosis
The outcome of newly diagnosed epilepsy is generally
good. Overall, generalised seizures are more readily
controlled than focal seizures. The presence of a struc-
tural lesion reduces the chances of freedom from sei-
zures. The overall prognosis for epilepsy is shown
in Box 26.43.
Status epilepticus
Presentation and management are described on page
1159. While generalised status epilepticus is most easily
recognised, non-convulsive status may be less dramatic
and less easily diagnosed. It may cause only altered
Epilepsy
26.48 Epilepsy in old age
• Incidence and prevalence: late-onset epilepsy is very
common and the annual incidence in those over 60 yrs is
rising.
• Fits and faints: the features that usually differentiate these
may be less definitive than in younger patients.
• Non-convulsive status epilepticus: can present as
confusion in the elderly.
• Cerebrovascular disease: the underlying cause of seizures
in 30–50% of patients over the age of 50 yrs. A seizure may
occur with an overt stroke or with occult vascular disease.
• AED regimens: keep as simple as possible and take care to
avoid interactions with other drugs being prescribed.
• Carbamazepine-induced hyponatraemia: increases
significantly with age; particularly important in patients on
diuretics or those with heart failure.
• Withdrawal of anticonvulsant therapy: late-onset epilepsy
often recurs when drug treatment is stopped, so drug
withdrawal should not be attempted where it was
commenced appropriately.
26.49 Epilepsy in adolescence
• Effect on school/education: seizures, AEDs and
psychological complications of epilepsy may hamper
education. Fear may make some educational institutions
26
unduly restrictive.
• Effect on family relationships: parents may adopt a
protective role, which can lead to epilepsy (and AEDs)
becoming a point of assertion and rebellion.
• Effect on career choice: epilepsy may exclude or restrict
employment in the emergency services and armed forces.
• Alcohol: may affect sleep pattern; excess may be associated
with poor AED compliance.
• Illicit drugs: may affect seizure threshold and be associated
with poor AED compliance.
• Sleep disturbance: may be worsened by social activities
and computer games.
• Oral contraception: interactions with AED can occur. Use
may not always be disclosed to parents.
awareness, confusion or wandering with automatisms.
In an intensive care unit setting, EEG monitoring is
essential to ensure that diagnosis and treatment are
optimised.
Non-epileptic attack disorder
The difficulty with nomenclature is discussed on page
1179. Patients may present with attacks that resemble
epileptic seizures but which are caused by psychological
phenomena and have no abnormal epileptic discharges.
Such attacks may be very prolonged, sometimes mim-
icking status epilepticus. Epileptic and non-epileptic
attacks may coexist, and time and effort are needed to
clarify the relative contribution of each, allowing more
accurate and comprehensive treatment.
Non-epileptic attack disorder (NEAD) may be accom-
panied by dramatic flailing of the limbs and arching of
the back, with side-to-side head movements and vocalis-
ing. Cyanosis and severe biting of the tongue are rare,
but urinary incontinence can occur. Distress and crying 1185
 NEUROLOGICAL DISEASE

26 are common following non-epileptic attacks. The dis-

tinction between epileptic attacks originating in the
frontal lobes and non-epileptic attacks may be especially
difficult, and may require videotelemetry with pro-
longed EEG recordings. Non-epileptic attacks are three
times more common in women than in men and have
been linked with a history of past or ongoing life trauma.
They are not necessarily associated with formal psychi-
atric illness. Patients and carers may need reassurance
that hospital admission is not required for every attack.
Prevention requires psychotherapeutic interventions
rather than drug therapy (p. 246).
VESTIBULAR DISORDERS
Vertigo is the typical symptom caused by vestibular
dysfunction, and most patients with vertigo have acute
vestibular failure, benign paroxysmal positional vertigo
or Ménière’s disease. Central (brain) causes of vertigo
are rare by comparison, with the exception of migraine
(p. 1176).
Acute vestibular failure
Although commonly called ‘labyrinthitis’ or ‘vestibular
neuronitis’, acute vestibular failure is a more accurate
term, as most cases are idiopathic. It usually presents as
isolated severe vertigo with vomiting and unsteadiness.
It begins abruptly, often on waking, and many patients
are initially bed-bound. The vertigo settles within a few
days, though head movement may continue to provoke
transient symptoms (positional vertigo) for some time.
During the acute attack, nystagmus (p. 1171) will be
present for a few days.
Cinnarizine, prochlorperazine or betahistine pro-
vides symptomatic relief but should not be used long-
term as this may delay recovery. A small proportion of
patients fail to recover fully, and complain of ongoing
imbalance and dysequilibrium rather than vertigo; ves-
tibular rehabilitation by a physiotherapist may help.
Benign paroxysmal
positional vertigo
Benign paroxysmal positional vertigo (BPPV) is due to
the presence of otolithic debris from the saccule or
utricle affecting the free flow of endolymph in the
semicircular canals (cupulolithiasis). It may follow
minor head injury but typically is spontaneous. The
history is diagnostic, with transient (seconds) vertigo
precipitated by movement (typically, rolling over in
bed or getting into or out of bed). Although benign,
and usually self-limiting after a few weeks or months,
patients are often very alarmed by the symptoms. The
diagnosis can be confirmed by the ‘Hallpike manœuvre’
to demonstrate positional nystagmus (Fig. 26.25). Treat-
ment comprises explanation and reassurance, along
with positioning procedures designed to return otolithic
debris from the semicircular canal to saccule or utricle
(such as the Epley manœuvre) and/or to re-educate the
brain to cope with the inappropriate signals from the
labyrinth (such as Cawthorne–Cooksey exercises: see
‘Further information’).
Ménière’s disease
This is due to an abnormality of the endolymph that
causes episodes of vertigo accompanied by tinnitus and
fullness in the ear, each attack typically lasting a few
hours. Over the years, patients may develop progressive
deafness (typically low-tone on audiometry). Examina-
tion is typically normal in between attacks. The diagno-
sis is clinical, supported by abnormal audiometry.
Ménière’s disease is idiopathic, but a similar syndrome
may be caused by middle ear trauma or infection. Man-
agement includes a low-salt diet, vestibular sedatives for
acute attacks, and occasionally surgery.

A B

Fig. 26.25 The Hallpike manœuvre for diagnosis of benign paroxysmal positional vertigo (BPPV). Patients are asked to keep their eyes
open and look at the examiner as their head is swung briskly backwards through 120° to overhang the edge of the couch. A Perform first with the
right ear down. B Perform next with the left ear down. The examiner looks for nystagmus (usually accompanied by vertigo). In BPPV, the nystagmus
typically occurs in A or B only and is torsional, the fast phase beating towards the lower ear. Its onset is usually delayed a few seconds, and it lasts
10–20 seconds. As the patient is returned to the upright position, transient nystagmus may occur in the opposite direction. Both nystagmus and vertigo
1186 typically decrease (fatigue) on repeat testing.

DISORDERS OF SLEEP
Sleep disturbances include too much sleep (hypersom-
nolence or excessive daytime sleepiness), insufficient or
poor-quality sleep (insomnia), and abnormal behaviour
during sleep (parasomnias). Insomnia is usually caused
by psychological or psychiatric disorders, shift work and
other environmental causes, pain and so on, and will not
be discussed further. Many symptoms and disorders
may affect sleep and sleep quality (e.g. pain, depression/
anxiety, parkinsonism).
Excessive daytime sleepiness
(hypersomnolence)
There are primary and secondary causes (Box 26.50). The
most common causes are impaired sleep due to lifestyle
issues or sleep-disordered breathing (p. 725). Sleepiness
may be measured using the Epworth Sleepiness Score
(see Box 19.98, p. 726). Most causes will be identified by
a detailed history from the patient and their bed partner,
and a 2-week sleep diary.
Narcolepsy
This has a prevalence of about 1 in 2000, with peak
onset in adolescence and early middle age. The key
symptom is sudden, irresistible ‘sleep attacks’, often in
26.50 Causes of hypersomnolence
Primary causes
• Narcolepsy
• Idiopathic hypersomnolence
• Brain injury
Secondary causes (due to poor-quality sleep)
• Obstructive sleep apnoea
• Pain
• Restless legs/periodic limb movements of sleep
• Parkinsonism and other neurodegenerative diseases
• Depression/anxiety
• Medication
• Environmental factors (noise, temperature etc.)
26.51 Narcolepsy symptoms
Sleep attacks
• Brief, frequent and unlike normal somnolence
Cataplexy
• Sudden loss of muscle tone triggered by surprise, laughter,
strong emotion etc.
Hypnagogic or hypnapompic hallucinations
• Frightening hallucinations experienced during sleep onset or
waking due to intrusion of REM sleep during wakefulness
(can occur in normal people)
Sleep paralysis
• Brief paralysis on waking (can occur in normal people)
Disorders of sleep
inappropriate circumstances such as whilst eating or
talking. Other characteristic features help distinguish
this from excessive daytime sleepiness (Box 26.51).
Symptoms may be due to loss of hypocretin-secreting
hypothalamic neurons. Diagnosis requires sleep study
with sleep latency testing (demonstrating rapid onset
of REM sleep). Treatment is with sodium oxybate,
modafinil, dexamfetamine or methylphenidate. Cata-
plexy may respond to sodium oxybate, clomipramine or
venlafaxine.
Parasomnias
Parasomnias are abnormal motor behaviours that occur
around sleep. They may arise in either REM or non-REM
sleep, with characteristic features and timing. Non-REM
parasomnias tend to occur early in sleep. Parasomnias
should be distinguished from other motor disturbances
(such as periodic limb movements, hypnic jerks or sleep
talking) and sleep-onset epileptic seizures (p. 1182).
History from a sleeping partner or other witness is
essential.
Non-REM parasomnias
These are due to incomplete arousal from non-REM
sleep, and manifest as night terrors, sleep walking and
confusional arousals (sleep drunkenness). They typi- 26
cally occur within an hour or two of sleep onset, are
common in children, and usually of no pathological
significance. Rarely, they persist into adulthood and
may become increasingly complex, including dressing,
moving objects, eating, drinking or even acts of violence.
Patients have little or no recollection of the episodes,
even though they appear ‘awake’. They may be trig-
gered by alcohol or unfamiliar sleeping situations, and
can be familial. Treatment is usually not required, but
clonazepam can be used.
REM sleep behaviour disorder
In REM sleep behaviour disorder (RBD), patients ‘act
out’ their dreams during REM sleep, due to failure of
the usual muscle atonia. Sleep partners provide typical
histories of patients ‘fighting’ or ‘struggling’ in their
sleep, sometimes causing injury to themselves or to their
partner. They are easily roused from this state, with
recollection of their dream, unlike in non-REM states.
RBD is more common in men, and may be an early
symptom of neurodegenerative diseases such as alpha
synucleinopathies (p. 1195), perhaps preceding more
typical symptoms of these conditions by years. Polysom-
nography will confirm absence of atonia during REM
sleep. Clonazepam is the most successful treatment.
Restless legs syndrome
Restless legs syndrome (RLS) is common, with a preva-
lence of up to 10%, but many patients never seek medical
attention. It is characterised by unpleasant leg (and
sometimes arm) sensations that are eased by movement
(motor restlessness); the diagnosis is clinical (Box 26.52).
It has a strong familial tendency and can present with
daytime somnolence due to poor sleep. It is usually idio-
pathic, but may be associated with haematinic defi-
ciency, pregnancy, peripheral neuropathy, Parkinson’s
disease or uraemia. It should be distinguished from 1187
 NEUROLOGICAL DISEASE

26 26.52 Diagnostic criteria for

restless legs syndrome
T lymphocytes in the CSF and increased immunoglobu-
lin synthesis within the CNS.
Initial CNS inflammation in MS involves entry of
A need to move the legs, usually accompanied or caused by activated T lymphocytes across the blood–brain barrier.
uncomfortable, unpleasant sensations in the legs, with the
following features:
• only present or worse during periods of rest or inactivity such A
as lying or sitting
• partially or totally relieved by movement such as walking or
stretching, at least as long as the activity continues
• generally worse or occurs only in the evening or night.

akathisia, the daytime motor restlessness that is an

adverse effect of anti-psychotic drugs. Treatment, if
required, is with dopaminergic drugs (dopamine ago-
nists or levodopa, p. 1196) or benzodiazepines.

Periodic limb movements in sleep

Unlike RLS, period limb movements in sleep (PLMS) B
only occurs during sleep and causes repetitive flexion
movements of the limbs, usually in the early (non-REM)
stages of sleep. Although patients are unaware of the
symptoms, they may disturb sleep quality and often
disturb partners. The pathological significance of PLMS
is uncertain and it often occurs in normal health. There
is an overlap with RLS. Treatment is most successful
with clonazepam or dopaminergic drugs.

NEURO-INFLAMMATORY DISEASES
Multiple sclerosis
Multiple sclerosis (MS) is an important cause of long-
term disability in adults, especially in the UK, where the
prevalence is about 120 per 100 000. The annual inci-
dence is around 7 per 100 000, while the lifetime risk of
developing MS is about 1 in 400. The incidence of MS is C
higher in Northern Europeans, and the disease is about
twice as common in females.

Pathophysiology
There is evidence that both genetic and environmental
factors play a causative role. The prevalence of MS is low
near the equator and increases in the temperate zones of A
both hemispheres. Most importantly, people retain the A A
risk of developing the disease in the zone in which they
grew up, indicating that environmental exposures B B
during growth and development are important. Preva-
lence also correlates with environmental factors, such as
sunlight exposure, vitamin D and exposure to Epstein–
Barr virus (EBV), although causative mechanisms
remain unclear. Genetic factors are also relevant; the risk
of familial recurrence in MS is 15%, with highest risk in
first-degree relatives (age-adjusted risk: 4–5% for sib-
lings and 2–3% for parents or offspring). Monozygotic
Fig. 26.26 Multiple sclerosis. A Photomicrograph from demyelinating
twins have a concordance rate of 30%. The genes
plaque, showing perivascular cuffing of blood vessel by lymphocytes.
that predispose to MS are incompletely defined but B Brain MRI in multiple sclerosis. Multiple high-signal lesions (arrows)
inheritance appears to be polygenic, with influences seen particularly in the paraventricular region on T2 image. C In T1
from genes for human leucocyte antigen (HLA) typing, image with gadolinium enhancement, recent lesions (A arrows) show
interleukin receptors, CLEC16A (C-type lectin domain enhancement, suggesting active inflammation (enhancement persists for
family 16 member A) and CD226 genes. An immune 4 weeks); older lesions (B arrows) show no enhancement but low signal,
1188 hypothesis is supported by increased levels of activated suggesting gliosis.
 Neuro-inflammatory diseases

These recognise myelin-derived antigens on the surface of the disease characterised by progressive and persist-
of the nervous system’s antigen-presenting cells, the ent disability (Fig. 26.27).
microglia, and undergo clonal proliferation. The result-
ing inflammatory cascade releases cytokines and initi- Clinical features
ates destruction of the oligodendrocyte–myelin unit by A diagnosis of MS requires the demonstration of other-
macrophages. Histologically, the resultant lesion is a wise unexplained CNS lesions separated in time and
plaque of inflammatory demyelination, most commonly space (Box 26.53). The peak age of onset of MS is the
in the periventricular regions of the brain, the optic
nerves, and the subpial regions of the spinal cord (Fig.
26.26). This begins as a circumscribed area of disintegra-
tion of the myelin sheath, accompanied by infiltration by
activated lymphocytes and macrophages, often with
conspicuous perivascular inflammation. After the acute Fulminant
attack, gliosis follows, leaving a shrunken grey scar. (< 10%)
Much of the initial acute clinical deficit is caused Primary
by the effect of inflammatory cytokines on transmission progressive

Disability
of the nervous impulse rather than structural disruption (10–20%)
of the myelin, and may explain the rapid recovery of Relapsing-
some deficits and probably the acute benefit from remitting Secondary
corticosteroids. In the long term, accumulating myelin (80%) progressive
loss reduces the efficiency of impulse propagation or
causes complete conduction block, contributing to sus-
tained impairment of CNS functions. Inflammatory
mediators released during the acute attack (particularly
nitric oxide) probably also initiate axonal damage, which
is a feature of the latter stages of the disease. In estab-
lished MS there is progressive axonal loss, probably due
to the successive damage from acute attacks and the
subsequent loss of neurotrophic factors from oligo-
Time 26
Fig. 26.27 The progression of disability in fulminant, relapsing–
dendrocytes. This axonal loss may account for the phase remitting and progressive multiple sclerosis.

26.53 The Macdonald criteria for the diagnosis of multiple sclerosis (2011)1
Clinical presentation2 Additional evidence required for diagnosis of MS
Two or more attacks with either None
Objective clinical evidence of at least
2 lesions
or
Objective clinical evidence of 1 attack with
reasonable evidence (on clinical history) of
at least 1 prior attack
Two or more attacks with objective clinical Dissemination in ‘space’ demonstrated by MRI
evidence of 1 lesion ≥ 1 lesion in at least 2 of the MS-typical regions3 (multiple lesions in different sites) or
Await further clinical attack at different anatomical site
One attack with objective clinical evidence Dissemination in ‘time’ demonstrated by
of ≥ 2 lesions Evolving MRI showing combined enhancing (new) and non-enhancing (old) lesions or
New T2 or enhancing lesion on repeat MRI or
Await further (second) clinical attack at different anatomical site
One attack with clinical evidence of only Dissemination in ‘space’ demonstrated by
1 lesion (clinically isolated syndrome) ≥ 1 T2 lesion in at least 2 MS-typical regions or
Dissemination in ‘time’, demonstrated by simultaneous enhancing and
non-enhancing lesions or
New T2 or enhancing lesions on repeat MRI or
Await further (second) clinical attack
Insidious neurological progression suggestive 1 yr of progression plus 2 of the following:
of MS Evidence for dissemination in space with ≥ 1 T2 lesions in MS-typical regions
Evidence for dissemination in space based on ≥ 2 lesions in the spinal cord
Positive CSF (evidence of oligoclonal band and/or elevated immunoglobulin (Ig) G index)
1
Published by the International Panel on MS Diagnosis (Ann Neurol 2011; 69:292–302). If the clinical presentation in the left-hand column is associated with the
features in the right-hand column, the diagnosis is MS. If there is incomplete association, the diagnosis is ‘possible MS’.
2
Assumes other possible causes for CNS inflammation (e.g. sarcoidosis, SLE) have been excluded.
3
MS-typical regions = periventricular, juxtacortical, infratentorial, spinal cord.
1189
 NEUROLOGICAL DISEASE
26 fourth decade; onset before puberty or after the age of
60 years is rare. Where there is widespread inflamma-
tion, this usually leads to widespread symptoms and/
or signs. Symptoms and signs of MS usually come on
over days or weeks, resolving over weeks or months.
Rarely, a more rapid stroke-like presentation may occur.
Around 80% of patients have a relapsing and remitting
clinical course of episodic dysfunction of the CNS with
variable intervening recovery. Of the remaining 20%,
most follow a slowly progressive clinical course, while
a tiny minority have a fulminant variety leading to
early death (see Fig. 26.27). Frequent relapses with
incomplete recovery indicate a poor prognosis for the
patient. Some milder cases have an interval of years or
even decades between attacks, while in others (particu-
larly if optic neuritis is the initial manifestation) there is
no recurrence of disease. In some individuals, a phase
of secondary progression, caused by secondary axonal
degeneration, supersedes the phase of relapse and
remission.
There are a number of clinical symptoms and syn-
dromes suggestive of MS, occurring either at presenta-
tion or during the course of the illness (Box 26.54). The
physical signs observed in MS are determined by the
anatomical site of demyelination. Combined spinal cord
and brainstem signs are common, although evidence
of previous optic neuritis may be found in the form of
an afferent pupillary deficit. Significant intellectual
impairment only supervenes late in the disease, when
loss of frontal functions and impairment of memory are
common.
The prognosis for patients with MS is difficult to
predict with confidence, especially early in the disease.
About 15% of patients have a single attack of demyelina-
tion and do not suffer further events, whilst those with
relapsing and remitting MS experience, on average, 1–2
events every 2 years. Approximately 5% of patients die
within 5 years of disease onset, whilst others have a
26.54 Clinical features of multiple sclerosis
Common presentations of multiple sclerosis
• Optic neuritis
• Relapsing/remitting sensory symptoms
• Subacute painless spinal cord lesion
• Acute brainstem syndrome
• Subacute loss of function of upper limb (dorsal column
deficit)
• 6th cranial nerve palsy
Other symptoms and syndromes suggestive of
CNS demyelination
• Afferent pupillary defect and optic atrophy (previous optic
neuritis)
• Lhermitte’s symptom (tingling in spine or limbs on neck
flexion)
• Progressive non-compressive paraparesis
• Partial Brown–Séquard syndrome (p. 1221)
• Internuclear ophthalmoplegia with ataxia
• Postural (‘rubral’, ‘Holmes’) tremor
• Trigeminal neuralgia (p. 1178) under the age of 50
• Recurrent facial palsy
1190
benign outcome. Prognosis is good for patients with
optic neuritis and only sensory relapses. Overall, about
one-third of patients are disabled to the point of needing
help with walking after 10 years, and this proportion
rises to about one-half after 15 years. It would appear
likely (though this is as yet unproven) that disease-
modifying drugs will have an effect on future
prognostication.
Investigations
There is no single diagnostic test that is definitive for
MS, and the results of investigation need to be com-
bined with the clinical picture in order to make a diag-
nosis (Box 26.55). Other conditions should be excluded,
and investigations should provide support for the diag-
nosis, with evidence for a chronic widespread inflam-
matory condition. Following the first clinical event,
investigations may help prognosis by confirming the
disseminated nature of the disease. MRI is the most
sensitive technique for imaging lesions in brain and
spinal cord (Fig. 26.28) and in excluding other causes
that have provoked the neurological deficit. However,
the MRI appearances in MS may be confused with those
of small-vessel disease or cerebral vasculitis, and these
diagnoses should be considered and excluded. Visual
evoked potentials (p. 1152) can detect clinically silent
lesions in up to 70% of patients, but auditory and
somatosensory evoked potentials are seldom of diag-
nostic value.
The CSF may show a lymphocytic pleocytosis in the
acute phase and oligoclonal bands of IgG in 70–90% of
patients between attacks. Oligoclonal bands are not spe-
cific for MS and only denote intrathecal inflammation.
These can appear in other disorders, which should be
excluded by examination and other investigations. It is
important to exclude other potentially treatable condi-
tions, such as infection, vitamin B12 deficiency and spinal
cord compression.
26.55 Investigations in a patient suspected of
having multiple sclerosis
Exclude other structural disease and identify plaques
of demyelination
• Image area of clinical involvement (MRI,
myelography)
Demonstrate other sites of involvement
• Imaging (MRI)
• Visual evoked potentials
• Other evoked potentials
Demonstrate inflammatory nature of lesion(s)
• CSF examination
• Cell count
• Protein electrophoresis (oligoclonal bands)
Exclude other conditions
• Chest X-ray
• Serum angiotensin-converting enzyme (ACE) –
sarcoidosis
• Serum B12
• Antinuclear antibodies – SLE
• Antiphospholipid antibodies

A
B
Fig. 26.28 Multiple sclerosis: demyelinating lesion in cervical
spinal cord, high-signal T2 images (arrow). A Sagittal plane.
B Axial plane.
Management
The management of MS involves four different strands:
treatment of the acute episode, prevention of future
relapses, treatment of complications and management of
the patient’s disability.
The acute episode
In a function-threatening exacerbation of MS, pulses of
high-dose steroid, given either intravenously or orally
over 3–5 days, will shorten the duration of the acute
episode (Box 26.56). Prolonged administration of ster-
oids does not alter the long-term outcome and causes
severe adverse effects and should therefore be avoided.
Pulses of steroids can be given up to three times in a year
but use should be restricted to those individuals with
significant function-threatening deficits. Prophylaxis to
prevent the occurrence of steroid-induced osteoporosis
(p. 1120) should be considered in patients requiring mul-
tiple courses of corticosteroids.
Disease-modifying treatment
Despite its immune basis, the administration of long-
term steroids, standard chemotherapies and immuno-
globulin is not practical or helpful in established MS.
This motivated the search for innovative immuno-active
treatments.
Neuro-inflammatory diseases
26.56 Corticosteroids in multiple sclerosis
‘There is evidence favouring corticosteroids (methylprednisolone)
for acute exacerbations of multiple sclerosis, but there are
insufficient data to estimate reliably the effect of corticosteroids
on prevention of new exacerbations and reduction of long-term
disability.’
‘There is currently no evidence that long-term corticosteroid
treatment delays progression of long-term disability in multiple
sclerosis.’
• Filippini G, et al. Corticosteroids or ACTH for acute exacerbations in multiple
sclerosis. Cochrane Database of Systematic Reviews, 2000, issue 4. Art. no.:
CD001331.
• Ciccone A, et al. Corticosteroids for long term treatment in multiple sclerosis.
Cochrane Database of Systematic Reviews, 2008, issue 1. Art. no.: CD006264.
For further information: www.cochrane.org/cochrane-reviews
26.57 Disease-modifying therapies in
multiple sclerosis
‘Beta-interferons have a modest effect on exacerbations and
disease progression in relapsing–remitting MS but do not
prevent the development of permanent physical disability on
slowly progressive multiple sclerosis.’
‘Natalizumab reduces relapses and disability at 2 years in
relapsing–remitting multiple sclerosis.’ 26
• Rice GP, et al. Interferon in relapsing remitting multiple sclerosis. Cochrane
Database of Systematic Reviews, 2001, issue 4. Art. no.: CD002002.
• La Mantia L, et al. Interferon beta for secondary progressive multiple sclerosis.
Cochrane Database of Systematic Reviews, 2011, issue 1. Art. no.: CD005181.
• Pucci E, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane
Database of Systematic Reviews, 2011, issue 10. Art. no.: CD007621.
For further information: www.cochrane.org/cochrane-reviews
In relapsing and remitting MS, an increasing number
of beta-interferons have been used to reduce relapse
rates and improve long-term outlook. Their pharmaco-
logical properties tend to vary, but there has been no
good trial evidence clinically separating the licensed
compounds. Subcutaneous or intramuscular interferon-
beta reduces the number of relapses by some 30%, with
a small effect on long-term disability (Box 26.57). Long-
term effects are usually local and development of anti-
bodies should be sought; their development should
preclude further long-term treatment. Other treatments
are shown in Box 26.58.
Glatiramer acetate is a parenterally administered
oligopeptide that may act as a competitor antigen,
but in addition it increases numbers of regulatory
CD4 T cells in relapsing–remitting MS, thereby helping
to reduce relapse rates. Unlike other immunomodula-
tory treatments used for MS, glatiramer antibodies
do not block function and actually appear to enhance
efficacy.
Mitoxantrone was initially developed as a chemo-
therapeutic agent and has been shown to decrease the
relapse rate in MS, as well as lowering the number of
MRI lesions and reducing disability with long-term use.
Its similarity to doxorubicin is reflected in its adverse
effects, the most notable of which is cardiotoxicity.
1191
 NEUROLOGICAL DISEASE

26 26.58 Disease-modifying treatments in multiple sclerosis

Treatment Mode of action Comment
Interferon-beta Immune modulation In widespread use for reducing relapse rate (RCT
evidence)
Glatiramer acetate Immune modulation Similar efficacy to interferon-beta (RCT evidence)
Fingolimod Immune modulation Superior efficacy to interferon-beta in RCTs
Monoclonal antibody Immune modulation (blocks Recently introduced. Possibly more effective than
to alpha4-integrin lymphocyte entry into CNS) interferon-beta and glatiramer acetate (RCT evidence)
(natalizumab)
Mitoxantrone Immune suppression Trials favour early use in aggressive disease
(cytotoxic)

(RCT = randomised controlled clinical trial)

Natalizumab is a monoclonal antibody to an antigen 26.59 Treatment of complications in

expressed on activated T cells and monocytes, and has multiple sclerosis
been associated with a dramatic fall in the number of
lesions evident on MRI, with a corresponding decrease Spasticity
in the number of relapses and reduction in axonal • Physiotherapy • Tizanidine
damage. Rarely, neutralising antibodies block its effi- • Baclofen (usually oral) • Intrathecal baclofen
cacy and indicate that the drug should be withdrawn. • Dantrolene • Local (IM) injection of
Progressive multifocal leucoencephalopathy (PML) has • Gabapentin botulinum toxin
been seen in some natalizumab-treated patients. Occa- • Sativex® • Chemical neuronectomy
sional cases of CNS lymphoma and toxoplasmosis may Ataxia
be related to drug use. • Isoniazid • Clonazepam
Other newer immunomodulatory treatments have
been developed, including fingolimod, which is derived Dysaesthesia
from the ascomycete metabolite ISP-1 (myriocin) and • Carbamazepine • Phenytoin
can be given orally. Further studies are needed to predict • Gabapentin • Amitriptyline
which immune treatment should be tried in which Bladder symptoms
patients. • See Box 26.31, p. 1175
Special diets, including a gluten-free diet or linoleic
acid supplements, and hyperbaric oxygen therapy are Fatigue
popular with patients but their efficacy has not yet been • Amantadine • Amitriptyline
proven. • Modafinil
Treatment of symptoms, complications Impotence
and disability • Sildenafil 50–100 mg/24 hrs • Tadalafil
Treatments for the complications of MS are summa-
rised in Box 26.59. It is important to provide patients
with a careful explanation of the nature of the disease
and its outcome. When and if disability occurs, patients 26.60 Multiple sclerosis in pregnancy
and their relatives need appropriate support. Specialist
• Counselling: provision of pre-conception counselling is best
nurses working in a multidisciplinary team of health-
practice.
care professionals are of great value in managing the
• Relapse risk: endocrine effects on the immune system
chronic phase of the disease. Periods of physiotherapy ensure that relapse risk drops during pregnancy.
and occupational therapy may improve functional • Disease-modifying drugs: risk of teratogenicity means that
capacity in those patients who become disabled, and all disease-modifying drugs should ideally be stopped
guidance can be provided on the provision of aids at 6–8 wks before conception and recommenced after
home, reducing handicap. Care of the bladder is particu- breastfeeding has stopped.
larly important. Urgency and frequency can be treated • Post-partum relapse rate: rebound of immune system
pharmacologically (see Box 26.31, p. 1175), but this may activity means that the highest risk of relapse is in the first
lead to a degree of retention with an attendant risk of year after delivery.
infection. Retention can be managed initially by inter-
mittent urinary catheterisation (performed by the
patient, if possible), but an in-dwelling catheter may
become necessary. Sexual dysfunction is a frequent Acute disseminated encephalomyelitis
source of distress. Sildenafil or tadalafil helps impotence
in men, and skilled counselling and prosthetic aids are This is an acute monophasic demyelinating condition in
1192 often beneficial. which there are areas of perivenous demyelination

widely disseminated throughout the brain and spinal
cord. The illness may apparently arise spontaneously
but often occurs a week or so after a viral infection,
especially measles and chickenpox, or following vacci-
nation, suggesting that it is immunologically mediated.
Clinical features
Headache, vomiting, pyrexia, confusion and meningism
may be presenting features, often with focal or multi-
focal brain and spinal cord signs. Seizures or coma may
occur. A minority of patients who recover have further
episodes.
Investigations
MRI shows multiple high-signal areas in a pattern
similar to that of MS, although often with large confluent
areas of abnormality. The CSF may be normal or show
an increase in protein and lymphocytes (occasionally
over 100 × 106 cells/L); oligoclonal bands may be found
in the acute episode but, unlike in MS, will not persist
beyond clinical recovery. The clinical picture may be
very similar to a first relapse of MS.
Management
The disease may be fatal in the acute stages but is other-
wise self-limiting. Treatment with high-dose intra-
venous methylprednisolone, using the same regimen as
for a relapse of MS, is recommended.
Transverse myelitis
Transverse myelitis is an acute, usually monophasic,
demyelinating disorder affecting the spinal cord. It is
usually thought to be post-infectious in origin. It occurs
at any age and presents with a subacute paraparesis
with a sensory level, accompanied by severe pain in the
neck or back at the onset. MRI should distinguish this
from an external lesion affecting the spinal cord. CSF
examination shows cellular pleocytosis, often with poly-
morphs at the onset. Oligoclonal bands are usually
absent. Treatment is with high-dose intravenous methyl-
prednisolone. The outcome is variable: one-third have
static deficit, one-third go on to develop MS and one-
third recover with no subsequent relapse. Some clinical
features may predict the development of MS after trans-
verse myelitis (Box 26.61).
26.61 Prognostic features predicting
multiple sclerosis after transverse myelitis
Increased risk
• Severe weakness • Spinal shock
• Catastrophic onset • Incontinence
• Initial lancinating pain • Presence of 14-3-3 protein
• Sensory disturbance at in CSF
cervical level
Decreased risk
• Subacute onset over days • Retained tendon reflexes
• Young onset • Early recovery
• Retained posterior column
function
Paraneoplastic neurological disorders
Neuromyelitis optica
Neuromyelitis optica (also known as Devic’s disease) is
the occurrence of transverse myelitis and bilateral optic
neuritis. The disease has been recognised for many
years, particularly in Asia. The majority of cases are
associated with an antibody to a neuronal membrane
channel, aquaporin 4. If changes are seen on brain MRI
(this is variable), they are typically high-signal lesions
restricted to periventricular regions. Spinal MRI scans
show lesions that are typically longer than three spinal
segments (unlike the shorter lesions of MS). Clinical
deficits tend to recover less well than in MS, and the
disease may be more aggressive with more frequent
relapses. Treatment with older immunosuppressive
agents, such as steroids, azathioprine or cyclophospha-
mide, and/or plasmapheresis seems to be more effective
than in MS.
PARANEOPLASTIC NEUROLOGICAL
DISORDERS
Neurological disease may occur with systemic malig-
26
nant tumours in the absence of cerebral metastases.
It is now recognised that, in the majority of these
cases, antigen production in the body of the tumour
leads to development of antibodies to parts of the
CNS. Paraneoplastic conditions are increasingly recog-
nised, and the number of antibodies identified is also
increasing (Boxes 26.62 and 26.63). These syndromes
are particularly associated with small-cell carcinoma
of lung, ovarian tumours, and lymphomas. Autoanti-
bodies are found in the serum and/or CSF, and biopsy
will show a lymphocytic infiltrate of the neural tissue
affected.
Clinical presentations
These are summarised in Boxes 26.62 and 26.63. In most
instances, the neurological condition progresses quite
rapidly over a few months, preceding the malignant
disease in around half of cases. The range of clinical pat-
terns is so wide that paraneoplastic disease should be
considered in the diagnosis of any unusual progressive
neurological syndrome. The paraneoplastic disorders of
the peripheral nervous system particularly affect the
synaptic cleft (p. 1141).
Investigations and management
The presence of characteristic autoantibodies in the
context of a suspicious clinical picture may be diagnos-
tic. The causative tumour may be very small and there-
fore CT of the chest or abdomen or PET scanning may
be necessary to find it. These investigations should only
be pursued when paraneoplastic disease has been
proven, rather than when it is suspected. The CSF often
shows an increased protein and lymphocyte count with
oligoclonal bands.
Treatment is directed at the primary tumour. Occa-
sionally, successful therapy of the tumour is associated
with improvement of the paraneoplastic syndrome.
Some improvement may occur following administration
of intravenous immunoglobulin. 1193
 NEUROLOGICAL DISEASE

26 26.62 Paraneoplastic disorders of the central nervous system

Clinical presentation
Limbic encephalitis
Myelopathy
Motor neuron disease
Stiff-person syndrome
Cerebellar degeneration
Multifocal encephalomyelitis
Opsoclonus–myoclonus
Extrapyramidal encephalitis
Optic neuritis
Retinal degeneration
Associated tumour Antibodies demonstrated
SCLC Anti-Hu, anti-CV2, PCA-2, anti-VGKC, anti-Ma1,
anti-amphiphysin, anti-Ri, ANNA-3, anti-VGCC, anti-Zic4,
anti-GluR1/2, anti-GABAR
Testicular, breast Anti-Ma2, anti-GluR1/2
Thymoma Anti-VGKC, anti-CV2, anti-GluR1/2
Ovarian/testicular teratoma Anti-NMDAR
SCLC, thymoma, others Anti-CV2, anti-amphiphysin, anti-aquaporin
SCLC, others Anti-Hu
Breast, SCLC, thymoma, others Anti-amphiphysin, anti-Ri, anti-GAD, anti-GlyR
Breast, ovarian, others Anti-Yo, anti-Ma1, anti-Ri
SCLC, others Anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-amphiphysin, anti-VGCC,
anti-Ri, anti-Zic4, anti-GAD
Lymphoma Anti-Tr, anti-mGluR1
SCLC, thymoma Anti-Hu, anti-CV2, anti-VGKC, anti-Ma1, anti-amphiphysin, anti-Ri,
ANNA-3
Breast, ovarian Anti-Ri, anti-Yo, anti-amphiphysin
SCLC Anti Hu, anti-Ri, anti-CV2, anti-amphiphysin, anti-VGCC
Neuroblastoma Anti-Hu
Testicular Anti-Ma1/2, anti-CV2
SCLC, thymoma, testicular Anti-CV2, anti-Hu, anti-VGKC, anti-Ma
SCLC Anti-CV2, anti-aquaporin
SCLC Anti-recoverin

(ANNA = anti-neuronal nucleolar antibody; GABAR = GABA receptor; GAD = glutamic acid decarboxylase; GluR = glutamate receptor; PCA = Purkinje cell
antibody; SCLC = small-cell lung cancer; VGCC = voltage-gated calcium channel; VGKC = voltage-gated potassium channel)

26.63 Paraneoplastic disorders of the peripheral nervous system

Clinical presentation Associated tumour Antibodies demonstrated
Neuromyotonia Thymoma, SCLC, others Anti-VGKC
Myasthenia gravis Thymoma Anti-Achr, anti-MuSK
Sensorimotor polyneuropathy Lymphoma, SCLC, others Anti-HU, anti-CV2, ANNA-3, anti-Ma1, anti-amphiphysin
Lambert–Eaton syndrome SCLC Anti-VGCC
Motor neuropathy Lymphoma, SCLC, others Anti-Hu, anti-Yo, anti-CV2
Sensory neuropathy Lymphoma, SCLC, others Anti-Hu, anti-Yo, anti-CV2
Polymyositis/dermatomyositis Lung, breast Anti-Jo1

(MuSK = muscle-specific kinase; for other abbreviations, see Box 26.62)

NEURODEGENERATIVE DISEASES Movement disorders

Whilst MS is the most common cause of disability
in young people in the UK, vascular and neuro-
degenerative diseases are increasingly important in
later life. The neurodegenerative diseases are united
in having a pathological process that leads to specific
neuronal death, causing relentlessly progressive
symptoms that increase in incidence in older age.
The precise causes are not yet known. Alzheimer’s
disease (p. 251) and Parkinson’s disease are the most
1194 common.
Movement disorders present with a wide range of
symptoms. They may be genetic or acquired, and the
most important is Parkinson’s disease. Most movement
disorders are categorised clinically, with few confirma-
tory investigations available other than for those with a
known gene abnormality.
Idiopathic Parkinson’s disease
Parkinsonism is a clinical syndrome characterised prima-
rily by bradykinesia (p. 1165), with associated increased

26.64 Causes of parkinsonism
Idiopathic Parkinson’s disease (at least 80% of parkinsonism)
Cerebrovascular disease
Drugs and toxins
• Antipsychotic drugs (older • Sodium valproate
and ‘atypical’) • Lithium
• Metoclopramide, • Manganese
prochlorperazine • MPTP
• Tetrabenazine
Other degenerative diseases
• Dementia with Lewy bodies • Multiple system atrophy
• Progressive supranuclear • Corticobasal degeneration
palsy • Alzheimer’s disease
Genetic
• Huntington’s disease • Spinocerebellar ataxias
• Fragile X tremor ataxia (particularly SCA 3)
syndrome • Wilson’s disease
• Dopa-responsive dystonia
Anoxic brain injury
(MPTP = methyl-phenyl-tetrahydropyridine)
tone (rigidity), tremor and loss of postural reflexes. There
are many causes (Box 26.64) but the most common is
Parkinson’s disease (PD). PD has an annual incidence of
about 18/100 000 in the UK and a prevalence of about
180/100 000. Age has a critical influence on incidence and
prevalence, the latter rising to 300–500/100 000 after 80
years of age. Average age of onset is about 60 years, and
fewer than 5% of patients present under the age of 40.
Genetic factors are increasingly recognised and several
single genes causing parkinsonism have been identified,
although they only account for a very small proportion
of cases overall. Having a first-degree relative with PD
confers a 2–3 times increased risk of developing PD. It is
a progressive and incurable condition, with a variable
prognosis. Whilst motor symptoms are the most common
presenting features, non-motor symptoms (particularly
cognitive impairment, depression and anxiety) become
increasingly common as the disease progresses, and sig-
nificantly reduce quality of life.
Pathophysiology
Although mutations in several genes have been
identified in a few cases, in most patients the cause
remains unknown. The discovery that methyl-phenyl-
tetrahydropyridine (MPTP) caused severe parkinsonism
in young drug users suggested that PD might be due to
an environmental toxin but none has been convincingly
identified. The pathological hallmarks of PD are deple-
tion of the pigmented dopaminergic neurons in the sub-
stantia nigra and the presence of α-synuclein and other
protein inclusions in nigral cells (Lewy bodies – Fig.
26.29). It is thought that environmental or genetic factors
alter the α-synuclein protein, rendering it toxic and
leading to Lewy body formation within the nigral cells.
Lewy bodies are also found in the basal ganglia, brain-
stem and cortex, and increase with disease progression.
PD is recognised as a synucleinopathy alongside multi-
ple system atrophy and dementia with Lewy bodies. The
loss of dopaminergic neurotransmission is responsible
for many of the clinical features.
Neurodegenerative diseases
Fig. 26.29 Parkinson’s disease. High power (× 400) of substantia
nigra of a patient with Parkinson’s disease showing classical Lewy body
(haematoxylin and eosin).
Clinical features
Non-motor symptoms, including reduction in sense
of smell (hyposmia), constipation and REM sleep
behavioural disturbance (RBD), may precede the devel-
opment of typical motor features by many years, but
patients rarely present at this stage. The motor symp-
toms are almost always initially asymmetrical. The hall-
mark is bradykinesia, leading to classic symptoms such
as increasingly small handwriting, difficulty with tying 26
shoelaces or buttoning, and difficulty rolling over in bed.
Tremor is an early feature but may not be apparent in at
least 20% of people with PD. It is typically a unilateral
rest tremor (p. 1165) affecting limbs, jaw and chin, but
not the head. In some patients, tremor remains the domi-
nant symptom for many years. Rigidity causes stiffness
and a flexed posture. Although postural righting reflexes
are impaired early on in the disease, falls tend not to
occur until later. As the disease advances, speech
becomes softer and indistinct. There are a number of
abnormalities on neurological examination (Box 26.65).
Although the features are initially unilateral, gradual
bilateral involvement evolves with time. Cognition is
spared in early disease; if impaired, it should trigger
consideration of alternative diagnoses, such as dementia
with Lewy bodies.
Non-motor symptoms
Some non-motor symptoms (NMS) precede the onset of
more typical symptoms by many years (see above).
Depression or anxiety may also be presenting features
of PD. For most patients, however, NMS become increas-
ingly common and disabling as PD progresses. Cogni-
tive impairment, including dementia, is the symptom
most likely to impair quality of life for patients and
their carers. Estimates of dementia frequency range
from 30 to 80%, depending on definitions and length
of follow-up. Other distressing NMS include other
neuropsychiatric features (anxiety, depression, apathy,
hallucinosis/psychosis), sleep disturbance and hyper-
somnolence, fatigue, pain, sphincter disturbance and
constipation, sexual problems (erectile failure, loss of
libido or hypersexuality) and drooling.
Investigations
The diagnosis is clinical. Structural imaging (CT or MRI)
is usually normal for age and thus rarely helpful, 1195
 NEUROLOGICAL DISEASE

26 26.65 Physical signs in Parkinson’s disease

Management
Drug therapy
General Drug treatment for PD remains symptomatic rather than
• Expressionless face • Flexed (stooped) posture curative, and there is no evidence that any of the cur-
(hypomimia) • Impaired postural rently available drugs are neuroprotective. Levodopa
• Soft, rapid, indistinct reflexes (LD) remains the most effective treatment available,
speech (dysphonia) but other agents include dopamine agonists, anti-
cholinergics, inhibitors of monoamine oxidase (MAOI)-B
Gait
and catechol-O-methyl-transferase (COMT), and aman-
• Slow to start walking • Reduction of arm tadine. Debate continues about when to start treatment,
(failure of gait ignition) swing and with which drug. In general, most specialists recom-
• Rapid, short stride length, • Impaired balance on mend initiating treatment when symptoms are impact-
tendency to shorten turning ing on everyday life; whether it is best to start with LD,
(festination) a dopamine agonist or MAOI-B remains unclear, but
Tremor most accept that the most effective, best-tolerated and
Resting (3–4 Hz, moderate amplitude): most common cheapest drug is LD. Many motor symptoms, such as
• Asymmetric, usually first in arm/hand (‘pill rolling’) tremor, freezing, falling, head-drop and abnormal
• May affect legs, jaw and chin, but not head flexion, are quite resistant to treatment. Some NMS, such
• Intermittent, present at rest, often briefly abolished by as anxiety or depression, may respond to drug or non-
movement of the limb, exacerbated by walking drug treatments. In the UK, rivastigmine is licensed for
Postural (6–8 Hz, moderate amplitude) use in PD-associated dementia, although its effect is
• Present immediately on stretching out arms modest at best. Many other NMS are resistant to treat-
ment. Evidence-based statements regarding diagnosis
Re-emergent tremor (3–4 Hz, moderate amplitude)
and drug management of PD are listed in Box 26.66.
• Initially no tremor on stretching arms out, rest tremor
re-emerges after a few seconds Levodopa. LD is the precursor to dopamine. When
administered orally, more than 90% is decarboxylated to
Rigidity dopamine peripherally in the gastrointestinal tract and
• Cogwheel type, mostly upper limbs (due to tremor blood vessels, and only a small proportion reaches the
superimposed upon rigidity) brain. This peripheral conversion is responsible for the
• Lead pipe type high frequency of adverse effects, and to avoid this, LD
Akinesia (fundamental feature) is combined with a dopa decarboxylase inhibitor (DDI);
the inhibitor does not cross the blood–brain barrier, thus
• Slowness of movement
• Fatiguing and decrease in size of repetitive movements avoiding unwanted decarboxylation-blocking in the
brain. Two DDIs, carbidopa and benserazide, are avail-
Normal findings (if abnormal, consider other causes) able as combination preparations with LD, as Sinemet®
• Power, deep tendon reflexes, plantar responses and Madopar®, respectively.
• Eye movements LD is most effective at relieving the akinesia and
• Sensory and cerebellar examination rigidity; tremor response is often less satisfactory, and it
has no effect on many motor (posture, freezing) and
non-motor symptoms. Failure of akinesia/rigidity to
respond to LD 1000 mg/day should prompt reconsid-
although it may support a suspected vascular cause. eration of the diagnosis. Although controlled-release
Functional dopaminergic imaging (SPECT or PET) is versions of LD exist, these are usually best reserved for
abnormal, even at early stages (Fig. 26.30), but does not use overnight, as their variable bioavailability makes
differentiate between the different forms of degenerative them difficult to use throughout the day. Madopar® is
parkinsonism (see Box 26.64) and so is not specific for also available as a dispersible tablet for more rapid-onset
PD. In younger patients, specific investigations may effect.
be appropriate (e.g. exclusion of Huntington’s and Adverse effects include postural hypotension, nausea
Wilson’s diseases). Some patients with family histories and vomiting, which may be offset by domperidone.
may wish to consider genetic testing, although the role LD may exacerbate or trigger hallucinations, and abnor-
of genetic counselling is uncertain at present. mal LD-seeking behaviour may occur uncommonly

A B

Fig. 26.30 Imaging in Parkinson’s disease. A SPECT scan in

Parkinson’s disease showing reduced dopamine activity in the basal
1196 ganglia. B Normal.

26.66 Management of Parkinson’s disease
Early treatment
‘Patients with early PD may be considered for treatment with:
• levodopa plus dopa decarboxylase inhibitor or
• oral or transdermal dopamine agonists or
• monoamine oxidase B inhibitors.’
‘Ergot-derived dopamine agonists should not be used as
first-line treatment.’
‘Anticholinergic drugs should not be used as first-line
treatment.’
Motor fluctuations
‘Motor fluctuations may be treated with either monoamine
oxidase B inhibitors or dopamine agonists.’
‘Dopamine agonists may be used to manage motor
complications in patients with advanced PD. The non-ergot
agonists are preferable to the ergot agonists.’
‘Intermittent or infusions of subcutaneous apomorphine may
be used to manage advanced PD.’
‘Catechol-O-methyl-transferase (COMT) inhibitors may be
used to reduce off-time in patients with advanced PD.’
• SIGN 113. Diagnosis and pharmacological management of Parkinson’s disease,
2010.
For further information: www.sign.ac.uk
(dopamine dysregulation syndrome) in which the
patient takes excessive doses of LD.
As PD progresses, the response to LD becomes less
predictable in many patients, leading to motor fluctua-
tions. This end-of-dose deterioration is due to progres-
sive loss of dopamine storage capacity by dwindling
numbers of striatonigral neurons. LD-induced involun-
tary movements (dyskinesia) may occur as a peak-dose
phenomenon or as a biphasic phenomenon (occurring
during both the build-up and wearing-off phases). More
complex fluctuations present as sudden, unpredictable
changes in response, in which periods of parkinsonism
(‘off’ phases) alternate with improved mobility but with
dyskinesias (‘on’ phases). Motor complication manage-
ment is difficult; wearing-off effects may respond to
increased dose or frequency of LD or the addition of a
COMT inhibitor (see below). More complex fluctuations
may be improved by the addition of dopamine agonists
(including continuous infusion of apomorphine), use of
intrajejunal LD via a percutaneous endoscopic jejunos-
tomy, or deep brain stimulator implantation.
Dopamine receptor agonists. Originally introduced in
the hope of delaying the initiation of LD, and thus delay-
ing motor complications, several dopamine agonists are
available, and may be delivered orally, transdermally or
subcutaneously (Box 26.67).
The ergot-derived agonists are no longer recom-
mended because of rare but serious fibrotic effects. With
the exception of apomorphine, all the agonists are con-
siderably less powerful than LD in relieving parkinson-
ism, have more adverse effects (nausea, vomiting,
confusion and hallucinations, impulse control disorders)
and are more expensive. Their role in the management
of PD (monotherapy or adjunctive) remains uncertain,
Neurodegenerative diseases
26.67 Dopamine agonists*
Ergot-derived
• Bromocriptine
• Lisuride
• Pergolide
• Cabergoline
Non-ergot-derived
• Ropinirole
• Pramipexole
• Rotigotine (transdermal patch)
• Apomorphine (subcutaneous)
*Oral unless otherwise stated.
and evidence is accruing to suggest that their usefulness
as initial monotherapy is short-lasting.
MAOI-B inhibitors. Monoamine oxidase type B facili-
tates breakdown of excess dopamine in the synapse.
Two inhibitors are used in PD: selegiline and rasagiline.
The effects of both are modest, although usually well
tolerated. Neither is neuroprotective, despite initial
hopes.
26
COMT inhibitors. Catechol-O-methyl-transferase (along
with dopa decarboxylase) is involved in peripheral
breakdown of LD. Two inhibitors are available: enta-
capone and tolcapone (which also inhibits central
COMT). Entacapone has a modest effect and is most
useful for early wearing-off. It is available either as a
single tablet taken with each LD/DDI dose, or as a
combination tablet with LD and DDI. The more potent
tolcapone is less used because of rare but serious
hepatotoxicity.
Amantadine. This has a mild, usually short-lived effect
on bradykinesia and is rarely used unless patients are
unable to tolerate other drugs. It is more commonly
employed as a treatment for LD-induced dyskinesias,
although again benefit is modest and short-lived.
Adverse effects include livedo reticularis, peripheral
oedema, confusion and other anticholinergic effects.
Anticholinergic drugs. These were the main treatment
for PD prior to the introduction of LD. Their role now
is limited by lack of efficacy (apart from an effect on
tremor sometimes) and adverse effects, including dry
mouth, blurred vision, constipation, urinary retention,
confusion and hallucinosis. Several anticholinergics
are available, including trihexyphenidyl (benzhexol)
and orphenadrine.
Surgery
Destructive neurosurgery was commonly used before
the introduction of LD. In the last 20 years, stereotactic
surgery has emerged and most commonly involves
deep brain stimulation (DBS), rather than the destruc-
tive approach of previous eras. Various targets have
been identified, including the thalamus (though this is
only effective for tremor), globus pallidus and subtha-
lamic nucleus. DBS is usually reserved for patients with
medically refractory tremor or motor fluctuations, and
careful patient selection is vital to success. Intracranial
delivery of fetal grafts or specific growth factors remains
experimental. 1197
 NEUROLOGICAL DISEASE
26 Physiotherapy, occupational therapy
and speech therapy
Patients at all stages of PD benefit from physiotherapy,
which helps reduce rigidity and corrects abnormal
posture. Occupational therapists can provide equipment
to help overcome functional limitations, such as rails
for stairs and the toilet, and bathing equipment. Speech
therapy can help where dysarthria and dysphonia
interfere with communication, and advice may also
be provided to those with dysphagia on the use of
altered-texture diets. As with many complex neuro-
logical disorders, patients with PD should ideally be
managed by a multidisciplinary team, including PD
specialist nurses.
Other parkinsonian syndromes
Cerebrovascular disease and drug-induced parkinson-
ism are the most common alternative causes of parkin-
sonism (see Box 26.64). There are several degenerative
conditions that cause parkinsonism, including multiple
system atrophy, progressive supranuclear palsy and
corticobasal degeneration. They typically have a more
rapid progression than PD and tend to be resistant to
treatment with LD. They are defined pathologically and
identification during life is difficult. There are other
conditions that may rarely manifest as parkinsonism,
including Huntington’s and Wilson’s diseases.
Multiple system atrophy
Multiple system atrophy (MSA) is characterised by par-
kinsonism, autonomic failure and cerebellar symptoms,
with either parkinsonism (MSA-P) or cerebellar features
(MSA-C) predominating. It is much less common than
PD, with a prevalence of about 4/100 000. Although
early distinction between PD and MSA-P may be diffi-
cult, early falls, postural instability and lack of response
to LD are clues. The pathological hallmark is α-synuclein-
containing glial cytoplasmic inclusions found in the
basal ganglia, cerebellum and motor cortex. Manage-
ment is symptomatic and the prognosis is less good than
for PD, with mean survival from symptom onset of
fewer than 10 years, and early disability. Cognition is
preserved.
Progressive supranuclear palsy
Progressive supranuclear palsy (PSP) presents with
symmetrical parkinsonism, cognitive impairment, early
falls and bulbar symptoms. The characteristic eye move-
ment disorder, with slowed vertical saccades leading to
impairment of up and down gaze, may take years to
emerge. PSP has different pathological features, being
associated with abnormal accumulation of tau (τ) pro-
teins and degeneration of the substantia nigra, subtha-
lamic nucleus and mid-brain. It is therefore a tauopathy
rather than synucleinopathy. The prevalence is about
5/100 000, with average survival similar to that in MSA.
There is no treatment, and the parkinsonism usually
does not respond to LD.
Corticobasal degeneration
Corticobasal degeneration (CBD) is less common than
MSA or PSP, and the clinical manifestations are variable,
1198 including parkinsonism, dystonia, myoclonus and ‘alien
limb’ phenomenon, whereby a limb (usually upper)
moves about or interferes with the other limb without
apparent conscious control. Cortical symptoms, espe-
cially apraxia, are common and may be the only features
in some cases, including dementia. A number of other
diseases may present with a corticobasal syndrome,
including other dementias. CBD is a tauopathy with
widespread deposition throughout the brain, and has
similar survival rates to MSA and PSP.
Wilson’s disease
This is an autosomal recessive disorder causing a defect
of copper metabolism (p. 973). It is a treatable cause of
various movement disorders, including tremor, dysto-
nia, parkinsonism and ataxia; psychiatric symptoms
may also occur. Wilson’s should always be excluded
in younger patients presenting with any movement
disorder.
Huntington’s disease
Huntington’s disease (HD) is an autosomal dominant
disorder, usually presenting in adults but occasionally
children. It is due to expansion of a trinucleotide CAG
repeat in the Huntingtin gene on chromosome 4 (p. 65).
The disease frequently demonstrates the phenomenon
of anticipation, in which there is a younger age at onset
as the disease is passed through generations, due to
progressive expansion of the repeat. The prevalence is
about 4–8/100 000.
Clinical features
HD typically presents with a progressive behavioural
disturbance, abnormal movements (usually chorea), and
cognitive impairment leading to dementia. Onset under
18 years is rare, but patients may then present with
parkinsonism rather than chorea (the ‘Westphal variant’).
There is always a family history, although this may be
concealed.
Investigations and management
The diagnosis is confirmed by genetic testing; pre-
symptomatic testing for other family members is avail-
able but must be preceded by appropriate counselling
(p. 67). Brain imaging may show caudate atrophy but is
not a reliable test. There are a number of HD mimics.
Management is symptomatic. The chorea may
respond to neuroleptics such as risperidone or sulpi-
ride, or other drugs such as tetrabenazine. Depression
and anxiety are common, and may be helped by
medication.
Ataxias
The ataxias are a heterogeneous group of inherited and
acquired disorders, presenting either with pure ataxia
or in association with other neurological and non-
neurological features. The differential is wide (Boxes
26.68 and 26.69), and diagnosis is guided by age of onset,
evolution and clinical features. A significant proportion
of cases remain idiopathic despite investigation.
The hereditary ataxias are a group of inherited disor-
ders in which degenerative changes occur to varying

26.68 Causes of acquired ataxia
Structural lesions
• Brain tumour
Toxic
• Drugs: lithium, phenytoin, amiodarone, toluene,
5-fluorouracil, cytosine arabinoside
• Alcohol
• Heavy metals/chemicals: mercury, lead, thallium
Infection/post-infectious
• HIV
• Varicella zoster
• Whipple’s disease
Degenerative
• Multiple system atrophy
• Sporadic Creutzfeldt–Jakob
disease
Inflammatory/immune-mediated
• Multiple sclerosis
• Gluten ataxia (coeliac
disease)
Metabolic
• Vitamin B1 or E deficiency
• Hypothyroidism
Vascular
• Stroke (ischaemic or
haemorrhagic)
26.69 Inherited ataxias
Inheritance pattern
Autosomal dominant
Episodic ataxias
Spinocerebellar ataxias
(SCA)
Dentato-rubro-pallidoluysian
atrophy (DRPLA)
Autosomal recessive
Friedreich’s ataxia
Ataxia telangiectasia
Abetalipoproteinaemia
Hereditary ataxia with
vitamin E deficiency
Others
X-linked
Fragile X tremor ataxia
syndrome
Adrenoleucodystrophy
Mitochondrial disease
(MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibres)
• Brain abscess
• Miller Fisher syndrome
(p. 1224)
• Idiopathic (or sporadic)
late-onset cerebellar ataxia
• Paraneoplastic ataxia
• Hashimoto encephalopathy
• Hypoparathyroidism
• Vascular malformations
• Superficial siderosis
Age of onset
Childhood and early
adulthood
Childhood to middle age
Childhood to middle age
Childhood/adolescence
(late onset possible)
Childhood
Childhood
< 20 yrs
Usually young onset
> 50 yrs
Childhood to adult
Various
Neurodegenerative diseases
extents in the cerebellum, brainstem, pyramidal tracts,
spinocerebellar tracts, and optic and peripheral nerves,
and which influence the clinical manifestations. Onset
ranges from infancy to adulthood, with recessive, sex-
linked or dominant inheritance (see Box 26.69). Whilst
the genetic abnormality has been identified for some,
allowing diagnostic testing, this is not currently the case
for many of the hereditary ataxias.
Tremor disorders
Tremor (p. 1165) is a feature of many disorders, but the
most important clinical syndromes are PD, essential
tremor, drug-induced tremors (Box 26.70) and func-
tional (psychogenic) tremors.
Essential tremor
This has a prevalence of about 300/100 000 and may
display a dominant pattern of inheritance, although no
genes have thus far been identified. It may present at
any age with a bilateral arm tremor (8–10 Hz), rarely
at rest but typical with movement. The head and voice
may be involved. The tremor improves in about 50% of
patients with small amounts of alcohol. There are no
specific tests, and it should be distinguished from other
tremor syndromes, including dystonic tremor. Beta- 26
blockers and primidone are sometimes helpful, and
DBS of the thalamus is an effective treatment for
severe cases.
Clinical features
Brief episodes of ataxia, sometimes induced by stress or startle. May develop
progressive ataxia
Over 30 subtypes identified thus far. Progressive ataxia, sometimes associated
with other features, including retinitis pigmentosa, pyramidal tract
abnormalities, peripheral neuropathy and cognitive deficits
Children present with myoclonic epilepsy and progressive ataxia. Adults have
progressive ataxia with psychiatric features, dementia and choreoathetosis
Ataxia, nystagmus, dysarthria, spasticity, areflexia, proprioceptive impairment,
diabetes mellitus, optic atrophy, cardiac abnormalities. Usually chair-bound
Progressive ataxia, athetosis, telangiectasia on conjunctivae, impaired DNA
repair, immune deficiency, tendency to malignancies
Steatorrhoea, sensorimotor neuropathy, retinitis pigmentosa, malabsorption of
vitamins A, D, E, K
Similar to Friedreich’s ataxia, visual loss or retinitis pigmentosa, chorea
Numerous, with genes only identified in some
Tremor, ataxia, parkinsonism, autonomic failure, cognitive impairment and
dementia
Impaired adrenal and cognitive function, sometimes spastic paraparesis
Ataxia features in several mitochondrial diseases, including Kearns–Sayre
syndrome, MELAS, MERRF, Leigh’s syndrome (p. 46)
1199
 NEUROLOGICAL DISEASE
26 26.70 Drug-induced tremor (usually postural)*
• β-agonists (e.g. salbutamol) • Tricyclic antidepressants
• Theophylline • Recreational drugs (e.g.
• Sodium valproate amphetamines)
• Thyroxine • Alcohol
• Lithium • Caffeine
*Drugs causing parkinsonism and associated tremor are listed in
Box 26.64.
Dystonia
Dystonia is characterised by a focal increase in tone
affecting muscles in the limbs or trunk. It may be a
feature of a number of neurological conditions (PD,
Wilson’s disease), or occur secondary to brain damage
(trauma, stroke) or drugs (tardive syndromes). Dystonia
also occurs as a primary disorder. In childhood onset,
the cause is usually genetic and dystonia is generalised
but adult onset is usually focal; examples include a
twisted neck (torticollis), repetitive blinking (blepharo-
spasm) or tremor. Task-specific symptoms (e.g. writer’s
cramp, musician’s dystonia) are often dystonic. Treat-
ment is difficult but botulinum toxin injections or DBS
may be useful.
Hemifacial spasm
This usually presents after middle age with intermittent
twitching around one eye, spreading ipsilaterally to
other facial muscles. The spasms are exacerbated by
talking, eating and stress. Hemifacial spasm is usually
idiopathic (similarly to trigeminal neuralgia, it has been
suggested that it is due to an aberrant arterial loop irri-
tating the 7th nerve just outside the pons), but may be
symptomatic and secondary to structural lesions or MS.
Drug treatment is not effective but injections of botuli-
num toxin into affected muscles help, although these
usually have to be repeated every 3 months or so. In
refractory cases, microvascular decompression may be
considered.
Motor neuron disease
Motor neuron disease (MND) is a neurodegenerative
condition caused by loss of upper and lower motor
neurons in the spinal cord, cranial nerve nuclei and
motor cortex. Annual incidence is about 2/100 000, with
a prevalence of about 7/100 000. Most cases are sporadic
but between 5 and 10% of cases are familial. Abnormali-
ties in the superoxide dismutase (SOD1) gene account
for about 20% of such cases, and recently an expanded
repeat sequence in the C9ORF72 gene on chromosome 9
has been associated with MND and frontotemporal
dementia. The most common form of MND is amyo-
trophic sclerosis (ALS), and many use the terms MND
and ALS interchangeably. ALS is characterised by a
combination of upper and lower motor neuron signs;
there are rarer, pure lower (progressive muscular
1200 atrophy) or upper (progressive lateral sclerosis) motor
26.71 Clinical features of motor neuron disease
Onset
• Usually after the age of 50 yrs
• Very uncommon before the age of 30 yrs
• Affects males more commonly than females
Symptoms
• Limb muscle weakness, cramps, occasionally
fasciculation
• Disturbance of speech/swallowing (dysarthria/dysphagia)
Signs
• Wasting and fasciculation of muscles
• Weakness of muscles of limbs, tongue, face and palate
• Pyramidal tract involvement, causing spasticity, exaggerated
tendon reflexes, extensor plantar responses
• External ocular muscles and sphincters usually remain intact
• No objective sensory deficit
Course
• Symptoms often begin focally in one part and spread
gradually but relentlessly to become widespread
26.72 Patterns of involvement in
motor neuron disease
Progressive muscular atrophy
• Predominantly spinal motor neurons affected
• Weakness and wasting of distal limb muscles at first
• Fasciculation in muscles
• Tendon reflexes may be absent
Progressive bulbar palsy
• Early involvement of tongue, palate and pharyngeal muscles
• Dysarthria/dysphagia
• Wasting and fasciculation of tongue
• Pyramidal signs may also be present
Amyotrophic lateral sclerosis (ALS)
• Combination of distal and proximal muscle-wasting and
weakness, fasciculation
• Spasticity, exaggerated reflexes, extensor plantars
• Bulbar and pseudobulbar palsy follow eventually
• Pyramidal tract features may predominate
neuron variants of MND. The average age of onset is 65,
with 10% presenting before 45 years.
Clinical features
MND typically presents focally, either with limb onset
(e.g. foot drop) or with bulbar symptoms; respiratory
onset is rare but respiratory failure is a common terminal
event. Sensory, autonomic and visual symptoms do not
occur, although cramp is common (Box 26.71). Examina-
tion reveals a combination of lower and upper motor
neuron signs (e.g. brisk reflexes in wasted, fasciculating
muscles) without sensory involvement (Box 26.72). Cog-
nitive impairment is under-recognised in MND: up to
50% will have a mainly executive impairment on formal
testing, and around 10% develop a frontotemporal
dementia (FTD). About 10% of patients presenting with
FTD will develop ALS within a few years of dementia
onset. MND is relentlessly progressive and up to 50%
die within 2 years of diagnosis.
 Infections of the nervous system

Investigations
26.74 Infections of the nervous system
Clinical features are often typical but alternative diag-
noses should be excluded. Exclusion of treatable causes, Bacterial infections
such as immune-mediated multifocal motor neuropathy
• Meningitis • Neurosyphilis
with conduction block (p. 1224) and cervical myelo-
• Suppurative encephalitis • Leprosy (peripheral
radiculopathy, is essential. Blood tests are usually • Brain abscess nerves)*
normal, other than a mildly raised creatine kinase. • Paravertebral (epidural) • Diphtheria (peripheral
Sensory and motor nerve conduction studies are normal abscess nerves)*
but there may be reduction in amplitude of motor action • Tuberculosis (Ch. 19) • Tetanus (motor cells)
potentials due to axonal loss. Electromyography will
Viral infections
usually confirm the typical features of widespread
denervation and re-innervation. Spinal fluid analysis is • Meningitis • Subacute sclerosing
not usually necessary. DNA testing may become more • Encephalitis panencephalitis (late
important as genetic factors become clearer. • Transverse myelitis sequel)
• Progressive multifocal • Rabies
Management leucoencephalopathy • HIV infection (Ch. 14)
Patients should be managed within a multidisciplinary • Poliomyelitis
service, including physiotherapists, speech and occu- Prion diseases
pational therapists, dietitians, ventilatory and feeding • Creutzfeldt–Jakob disease • Kuru
support, and palliative care teams, with neurological
Protozoal infections
and respiratory input. Riluzole is licensed for ALS but
has only a modest effect (Box 26.73). Non-invasive ven- • Malaria* • Trypanosomiasis*
tilatory support and/or feeding by percutaneous gas- • Toxoplasmosis (in • Amoebic abscess*
trostomy may improve quality of life in selected patients. immune-suppressed)*
Rapid access to palliative care teams is essential for Helminthic infections
patients as they enter the terminal stages of MND. • Schistosomiasis (spinal • Hydatid disease*
cord)*
• Cysticercosis*
• Strongyloidiasis*
26
26.73 Effective treatments for amyotrophic Fungal infections
lateral sclerosis/motor neuron disease
• Candida meningitis or brain • Cryptococcal meningitis
‘Riluzole 100 mg daily is reasonably safe and may prolong abscess
median survival by about 2–3 months in patients with ALS.’
‘Non-invasive ventilation significantly prolongs survival and *These infections are discussed in Chapter 13.
improves or maintains quality of life in people with ALS. Survival
and some measures of quality of life were significantly improved
in the subgroup of people with better bulbar function, but not in
those with severe bulbar impairment.’ The major infections of the nervous system are listed in
Box 26.74. The frequency of these varies geographically.
• Radunovic A, et al. Mechanical ventilation for amyotrophic lateral sclerosis/motor Helminthic infections, such as cysticercosis and hydatid
neuron disease. Cochrane Database of Systematic Reviews, 2009, issue 4. Art.
no.: CD004427. disease, and protozoal infections are described in
• Miller RG, et al. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron Chapter 13.
disease (MND). Cochrane Database of Systematic Reviews, 2012, issue 3. Art.
no.: CD001447.

For further information: www.cochrane.org/cochrane-reviews Meningitis

Spinal muscular atrophy
This is a group of genetically determined disorders
affecting spinal and cranial lower motor neurons, char-
acterised by proximal and distal wasting, fasciculation
and weakness of muscles. Involvement is usually sym-
metrical but occasional localised forms occur. With the
exception of the infantile form, progression is slow and
the prognosis better than for MND.
INFECTIONS OF THE NERVOUS SYSTEM
The clinical features of nervous system infections
depend on the location of the infection (the meninges
or the parenchyma of the brain and spinal cord), the
causative organism (virus, bacterium, fungus or para-
site), and whether the infection is acute or chronic.
Acute infection of the meninges presents with a charac-
teristic combination of pyrexia, headache and menin-
gism. Meningism consists of headache, photophobia and
stiffness of the neck, often accompanied by other signs
of meningeal irritation, including Kernig’s sign (exten-
sion at the knee with the hip joint flexed causes spasm
in the hamstring muscles) and Brudzinski’s sign (passive
flexion of the neck causes flexion of the hips and knees).
Meningism is not specific to meningitis and can occur in
patients with subarachnoid haemorrhage. The severity
of clinical features varies with the causative organism,
as does the presence of other features such as a rash.
Abnormalities in the CSF (see Box 26.5, p. 1154) are
important in distinguishing the cause of meningitis.
Causes of meningitis are listed in Box 26.75.
Viral meningitis
Viruses are the most common cause of meningitis,
usually resulting in a benign and self-limiting illness
requiring no specific therapy. It is much less serious 1201
 NEUROLOGICAL DISEASE

26 26.75 Causes of meningitis 26.76 Bacterial causes of meningitis

Infective Age of onset Common Less common

Bacteria (see Box 26.76) Neonate Gram-negative bacilli Listeria monocytogenes

(Escherichia coli,
Viruses Proteus)
• Enteroviruses (echo, • Epstein–Barr Group B streptococci
Coxsackie, polio) • HIV
• Mumps • Lymphocytic Pre-school Haemophilus Mycobacterium
• Influenza choriomeningitis child influenzae tuberculosis
• Herpes simplex • Mollaret’s meningitis (herpes Neisseria meningitidis
• Varicella zoster simplex virus type 2) Streptococcus
pneumoniae
Protozoa and parasites
• Cysticerci • Amoeba Older child Neisseria meningitidis Listeria monocytogenes
and adult Streptococcus Mycobacterium
Fungi
pneumoniae tuberculosis
• Cryptococcus neoformans • Blastomyces
Staphylococcus aureus
• Candida • Coccidioides
(skull fracture)
• Histoplasma • Sporothrix
Haemophilus
Non-infective (‘sterile’) influenzae
Malignant disease
• Breast cancer • Leukaemia
• Bronchial cancer • Lymphoma
Inflammatory disease (may be recurrent) Bacterial meningitis is usually part of a bacteraemic
• Sarcoidosis • Behçet’s disease illness, although direct spread from an adjacent focus
• SLE of infection in the ear, skull fracture or sinus can be
causative. Antibiotics have rendered this less common
but mortality and morbidity remain significant. An
than bacterial meningitis unless there is associated important factor in determining prognosis is early diag-
encephalitis (which is rare). A number of viruses can nosis and the prompt initiation of appropriate therapy.
cause meningitis (see Box 26.75), the most common The meningococcus and other common causes of men-
being enteroviruses. Where specific immunisation is ingitis are normal commensals of the upper respiratory
not employed, the mumps virus is a common cause. tract. New and potentially pathogenic strains are
acquired by the air-borne route but close contact is nec-
Clinical features essary. Epidemics of meningococcal meningitis occur
Viral meningitis occurs mainly in children or young particularly in cramped living conditions or where the
adults, with acute onset of headache and irritability and climate is hot and dry. The organism invades through
the rapid development of meningism. The headache is the nasopharynx, producing septicaemia and leading to
usually the most severe feature. There may be a high meningitis.
pyrexia but focal neurological signs are rare.
Pathophysiology
Investigations The meningococcus (Neisseria meningitidis) is now the
The diagnosis is made by lumbar puncture. The CSF most common cause of bacterial meningitis in Western
usually contains an excess of lymphocytes but glucose Europe after Streptococcus pneumoniae, whilst in the
and protein levels are commonly normal; the protein USA Haemophilus influenzae remains common. In India,
level may be raised. It is extremely important to verify H. influenzae B and Strep. pneumoniae are probably the
that the patient has not received antibiotics (for what- most common causes of bacterial meningitis, especially
ever cause) prior to the lumbar puncture, as this picture in children. Strep. suis is a rare zoonotic cause of menin-
can also be found in partially treated bacterial gitis associated with contact with pigs. The infection
meningitis. stimulates an immune response, causing the pia–
arachnoid membrane to become congested and infil-
Management trated with inflammatory cells. Pus then forms in layers,
There is no specific treatment and the condition is which may later organise to form adhesions. These may
usually benign and self-limiting. The patient should be obstruct the free flow of CSF, leading to hydrocephalus,
treated symptomatically in a quiet environment. Recov- or they may damage the cranial nerves at the base of the
ery usually occurs within days, although a lymphocytic brain. Hearing loss is a frequent complication. The CSF
pleocytosis may persist in the CSF. Meningitis may also pressure rises rapidly, the protein content increases, and
occur as a complication of a systemic viral infection such there is a cellular reaction that varies in type and severity
as mumps, measles, infectious mononucleosis, herpes according to the nature of the inflammation and the
zoster and hepatitis. Whatever the virus, complete causative organism. An obliterative endarteritis of the
recovery without specific therapy is the rule. leptomeningeal arteries passing through the meningeal
exudate may produce secondary cerebral infarction.
Bacterial meningitis Pneumococcal meningitis is often associated with a very
Many bacteria can cause meningitis but geographical purulent CSF and a high mortality, especially in older
1202 patterns vary, as does age-related sensitivity (Box 26.76). adults.
 Infections of the nervous system

26.77 Complications of meningococcal Resuscitate and stabilise patient

septicaemia
• Meningitis
• Rash (morbilliform,
petechial or purpuric)
• Shock
• Intravascular coagulation
Initial tests
(blood culture and polymerase
• Renal failure chain reaction, throat swab)
• Peripheral gangrene
• Arthritis (septic or reactive)
• Pericarditis (septic or
reactive)
Empirical antibiotics (Box 26.78)
Transfer to critical care facility

Clinical features
Headache, drowsiness, fever and neck stiffness are the
usual presenting features. In severe bacterial meningitis
the patient may be comatose and later there may be focal
neurological signs. Ninety percent of patients with
meningococcal meningitis will have two of the follow-
ing: fever, neck stiffness, altered consciousness and rash.
When accompanied by septicaemia, it may present very
rapidly, with abrupt onset of obtundation due to cere-
bral oedema. Complications of meningococcal septicae-
mia are listed in Box 26.77. Chronic meningococcaemia
is a rare condition in which the patient can be unwell for
weeks or even months with recurrent fever, sweating,
joint pains and transient rash. It usually occurs in the
middle-aged and elderly, and in those who have previ-
ously had a splenectomy. In pneumococcal and Haemo-
philus infections there may be an associated otitis media.
Pneumococcal meningitis may be associated with pneu-
monia and occurs especially in older patients and alco-
holics, as well as those without functioning spleens.
Listeria monocytogenes is an increasing cause of meningi-
tis and rhombencephalitis (brainstem encephalitis) in
the immunosuppressed, people with diabetes, alcoholics
and pregnant women (p. 339). It can also cause menin-
gitis in neonates.
Investigations
Lumbar puncture is mandatory unless there are contra-
indications (p. 1154). If the patient is drowsy and has
focal neurological signs or seizures, is immunosup-
pressed, has undergone recent neurosurgery or has suf-
fered a head injury, it is wise to obtain a CT to exclude
a mass lesion (such as a cerebral abscess) before lumbar
puncture because of the risk of coning. This should not,
however, delay treatment of a presumptive meningitis.
If lumbar puncture is deferred or omitted, it is essential
to take blood cultures and to start empirical treatment
(Fig. 26.31). Lumbar puncture will help differentiate the
causative organism: in bacterial meningitis the CSF is
cloudy (turbid) due to the presence of many neutrophils
(often > 1000 × 106 cells/L), the protein content is signifi-
cantly elevated and the glucose reduced. Gram film and
culture may allow identification of the organism. Blood
cultures may be positive. PCR techniques can be used
on both blood and CSF to identify bacterial DNA. These
methods are useful in detecting meningococcal infection
and in typing the organism.
Management
There is an untreated mortality rate of around 80%, so
action must be swift. If bacterial meningitis is suspected,
the patient should be given parenteral benzylpenicillin
immediately (intravenous is preferable) and prompt
hospital admission should be arranged. The only contra-
indication is a history of penicillin anaphylaxis.
Drowsy, focal signs?
(possible mass lesion, hydrocephalus
or cerebral oedema)
No Yes
No other CT
contraindication
to lumbar puncture brain
No mass lesion,
hydrocephalus
or other 26
contraindication
to lumbar
puncture seen
Lumbar
puncture
Fig. 26.31 The investigation of meningitis.
Recommended empirical therapy before the cause of
meningitis is known is given in Box 26.78, and the pre-
ferred antibiotic when the organism is known after
CSF examination is stipulated in Box 26.79. Adjunctive
corticosteroid therapy is useful in both children and
adults (Box 26.80) in developed countries where the inci-
dence of penicillin resistance is low, but its role in set-
tings where there are high rates of resistance or in
under-developed countries where there are high rates of
untreated HIV is unclear.
In meningococcal disease, mortality is doubled if the
patient presents with features of septicaemia rather than
meningitis. Individuals likely to require intensive care
facilities and expertise include those with cardiac,
respiratory or renal involvement, and those with CNS
depression prejudicing the airway. Early endotracheal
intubation and mechanical ventilation protect the airway
and may prevent the development of the acute respira-
tory distress syndrome (ARDS, p. 192). Adverse prog-
nostic features include hypotensive shock, a rapidly
developing rash, a haemorrhagic diathesis, multisystem
failure and age over 60 years.
Prevention of meningococcal infection
Close contacts of patients with meningococcal infection
(Box 26.81) should be given 2 days of oral rifampicin. In 1203
 NEUROLOGICAL DISEASE

26 26.78 Treatment of pyogenic meningitis of

unknown cause
26.80 Adjunctive dexamethasone for
bacterial meningitis
1. Adults aged 18–50 yrs with or without a typical Corticosteroids significantly reduce hearing loss and neurological
meningococcal rash sequelae, but do not reduce overall mortality.
• Cefotaxime 2 g IV 4 times daily or • Brouwer MC, et al. Corticosteroids for acute bacterial meningitis. Cochrane
• Ceftriaxone 2 g IV twice daily Database of Systematic Reviews, 2010, issue 9. Art. no.: CD004405.
2. Patients in whom penicillin-resistant pneumococcal For further information: www.cochrane.org/cochrane-reviews
infection is suspected, or in areas with a significant
incidence of penicillin resistance in the community
As for (1) but add:
• Vancomycin 1 g IV twice daily or 26.81 Chemoprophylaxis following
• Rifampicin 600 mg IV twice daily meningococcal exposure
3. Adults aged > 50 yrs and those in whom Listeria Close contacts warranting chemoprophylaxis
monocytogenes infection is suspected (brainstem signs,
immunosuppression, diabetic, alcoholic) • Household contacts (including persons who ate or slept in
the same dwelling as the patient during the 7 days prior to
As for (1) but add: disease onset)
• Ampicillin 2 g IV 6 times daily or • Child-care and nursery-school contacts
• Co-trimoxazole 50 mg/kg IV daily in two divided doses • Persons having contact with patient’s oral secretions during
4. Patients with a clear history of anaphylaxis to β-lactams the 7 days prior to disease onset
Kissing
• Chloramphenicol 25 mg/kg IV 4 times daily plus Sharing of toothbrushes
• Vancomycin 1 g IV twice daily Sharing of eating utensils
5. Adjunctive treatment (see text) Mouth-to-mouth resuscitation
• Dexamethasone 0.15 mg/kg 4 times daily for 2–4 days Unprotected contact during endotracheal intubation
• Aircraft contacts for persons seated next to the patient
for > 8 hrs
Persons at low risk in whom chemoprophylaxis is
26.79 Chemotherapy of bacterial meningitis not recommended
when the cause is known • Casual contact (e.g. at school or work) without direct
Alternative exposure to patient’s oral secretions
Pathogen Regimen of choice agents • Indirect contact only (contact with a high-risk contact and not
N. meningitidis Benzylpenicillin Cefuroxime, a case)
2.4 g IV 6 times ampicillin • Health-care worker without direct exposure to patient’s oral
daily for 5–7 days Chloramphenicol* secretions
Strep. pneumoniae Cefotaxime 2 g IV Chloramphenicol*
(sensitive to 4 times daily or
β-lactams, MIC ceftriaxone 2 g IV
< 1 mg/L) twice daily for adults, a single dose of ciprofloxacin is an alternative.
10–14 days If not treated with ceftriaxone, the index case should
Strep. pneumoniae As for sensitive Vancomycin plus be given similar treatment to clear infection from the
(resistant to strains but add rifampicin* nasopharynx before hospital discharge. Vaccines are
β-lactams) vancomycin 1 g IV Moxifloxacin available for most meningococcal subgroups but not
twice daily or Gatifloxacin group B, which is among the most common serogroup
rifampicin 600 mg isolated in many countries.
IV twice daily
H. influenzae Cefotaxime 2 g IV Chloramphenicol* Tuberculous meningitis
4 times daily or Tuberculous meningitis is now uncommon in developed
ceftriaxone 2 g IV countries in previously healthy individuals, although it
twice daily for is still seen in those born in endemic areas and in the
10–14 days immunocompromised. It remains common in develop-
L. monocytogenes Ampicillin 2 g IV Ampicillin 2 g IV ing countries and is seen more frequently as a secondary
6 times daily plus 4-hourly plus infection in patients with the acquired immunodefi-
gentamicin 5 mg/ co-trimoxazole ciency syndrome (AIDS).
kg IV daily 50 mg/kg daily in
two divided doses Pathophysiology
Strep. suis Cefotaxime 2 g IV Chloramphenicol* Tuberculous meningitis most commonly occurs shortly
4 times daily or after a primary infection in childhood or as part of
ceftriaxone 2 g IV miliary tuberculosis (p. 689). The usual local source of
twice daily for infection is a caseous focus in the meninges or brain
10–14 days substance adjacent to the CSF pathway. The brain is
covered by a greenish, gelatinous exudate, especially
*For patients with a history of anaphylaxis to β-lactam antibiotics.
(MIC = minimum inhibitory concentration)
around the base, and numerous scattered tubercles are
1204 found on the meninges.

26.82 Clinical features and staging of
tuberculous meningitis
Symptoms
• Headache • Depression
• Vomiting • Confusion
• Low-grade fever • Behaviour changes
• Lassitude
Signs
• Meningism (may be absent) • Depression of conscious
• Oculomotor palsies level
• Papilloedema • Focal hemisphere signs
Staging of severity
• Stage I (early): non-specific symptoms and signs without
alteration of consciousness
• Stage II (intermediate): altered consciousness without coma
or delirium + minor focal neurological signs
• Stage III (advanced): stupor or coma, severe neurological
deficits, seizures or abnormal movements
Clinical features
The clinical features and staging criteria are listed in Box
26.82. Onset is much slower than in other bacterial men-
ingitis – over 2–8 weeks. If untreated, it is fatal in a few
weeks but complete recovery is usual if treatment is
started at stage I (see Box 26.82). When treatment is initi-
ated later, the rate of death or serious neurological
deficit may be as high as 30%.
Investigations
Lumbar puncture should be performed if the diagnosis
is suspected. The CSF is under increased pressure. It
is usually clear but, when allowed to stand, a fine
clot (‘spider web’) may form. The fluid contains up to
500 × 106 cells/L, predominantly lymphocytes, but can
contain neutrophils. There is a rise in protein and a
marked fall in glucose. The tubercle bacillus may be
detected in a smear of the centrifuged deposit from
the CSF but a negative result does not exclude the diag-
nosis. The CSF should be cultured but, as this result will
not be known for up to 6 weeks, treatment must be
started without waiting for confirmation. Brain imaging
may show hydrocephalus, brisk meningeal enhance-
ment on enhanced CT or MRI, and/or an intracranial
tuberculoma.
Management
As soon as the diagnosis is made or strongly suspected,
chemotherapy should be started using one of the regi-
mens that include pyrazinamide, described on page 693.
The use of corticosteroids in addition to anti-tuberculous
therapy has been controversial. Recent evidence sug-
gests that it improves mortality, especially if given early,
but not focal neurological damage. Surgical ventricular
drainage may be needed if obstructive hydrocephalus
develops. Skilled nursing is essential during the acute
phase of the illness, and adequate hydration and nutri-
tion must be maintained.
Other forms of meningitis
Fungal meningitis (especially cryptococcosis – p. 384)
usually occurs in patients who are immunosuppressed
and is a recognised complication of HIV infection
Infections of the nervous system
(p. 401). The CSF findings are similar to those of tuber-
culous meningitis, but the diagnosis can be confirmed
by microscopy or specific serological tests.
In some areas, meningitis may be caused by spiro-
chaetes (leptospirosis, Lyme disease and syphilis –
pp. 336, 334 and 419), rickettsiae (typhus fever – p. 350)
or protozoa (amoebiasis – p. 367).
Meningitis can also be due to non-infective patholo-
gies. This is seen in recurrent aseptic meningitis due to
SLE, Behçet’s disease or sarcoidosis, as well as a condi-
tion of previously unknown origin known as Mollaret’s
syndrome, in which the recurrent meningitis is associ-
ated with epithelioid cells in the spinal fluid (‘Mollaret’
cells). Recent evidence suggests that this condition may
be due to human herpes virus type 2, and is therefore
infective after all. Meningitis can also be seen due to
direct invasion of the meninges by neoplastic cells
(‘malignant meningitis’ – see Box 26.75, p. 1202).
Parenchymal viral infections
Infection of the substance of the nervous system
will produce symptoms of focal dysfunction (deficits
and/or seizures) with general signs of infection, depend-
ing on the acuteness of the infection and the type of
organism.
26
Viral encephalitis
A range of viruses can cause encephalitis but only a
minority of patients have a history of recent viral infec-
tion. In Europe, the most serious cause of viral encepha-
litis is herpes simplex (p. 325), which probably reaches
the brain via the olfactory nerves. Varicella zoster is
also an important cause. The development of effective
therapy for some forms of encephalitis has increased the
importance of clinical diagnosis and virological exami-
nation of the CSF. In some parts of the world, viruses
transmitted by mosquitoes and ticks (arboviruses) are an
important cause of encephalitis. The epidemiology of
some of these infections is changing. Japanese encepha-
litis (p. 328) has spread relentlessly across Asia to
Australia, and there have been outbreaks of West
Nile encephalitis in Romania, Israel and New York. HIV
may cause encephalitis with a subacute or chronic pres-
entation, but occasionally has an acute presentation with
seroconversion.
Pathophysiology
The infection provokes an inflammatory response that
involves the cortex, white matter, basal ganglia and
brainstem. The distribution of lesions varies with the
type of virus. For example, in herpes simplex encepha-
litis, the temporal lobes are usually primarily affected,
whereas cytomegalovirus can involve the areas adjacent
to the ventricles (ventriculitis). Inclusion bodies may
be present in the neurons and glial cells and there is
an infiltration of polymorphonuclear cells in the
perivascular space. There is neuronal degeneration and
diffuse glial proliferation, often associated with cerebral
oedema.
Clinical features
Viral encephalitis presents with acute onset of head-
ache, fever, focal neurological signs (aphasia and/or 1205
 NEUROLOGICAL DISEASE
26 hemiplegia, visual field defects) and seizures. Distur-
bance of consciousness ranging from drowsiness to deep
coma supervenes early and may advance dramatically.
Meningism occurs in many patients. Rabies presents a
distinct clinical picture and is described below.
Investigations
Imaging by CT scan may show low-density lesions in
the temporal lobes but MRI is more sensitive in detecting
early abnormalities. Lumbar puncture should be per-
formed once imaging has excluded a mass lesion. The
CSF usually contains excess lymphocytes but poly-
morphonuclear cells may predominate in the early
stages. The CSF may be normal in up to 10% of cases.
Some viruses, including the West Nile virus, may cause
a sustained neutrophilic CSF. The protein content may
be elevated but the glucose is normal. The EEG is usually
abnormal in the early stages, especially in herpes simplex
encephalitis, with characteristic periodic slow-wave
activity in the temporal lobes. Virological investigations
of the CSF, including PCR for viral DNA, may reveal the
causative organism but treatment initiation should not
await this.
Management
Optimum treatment for herpes simplex encephalitis (aci-
clovir 10 mg/kg IV 3 times daily for 2–3 weeks) has
reduced mortality from 70% to around 10%. This should
be given early to all patients suspected of suffering from
viral encephalitis.
Some survivors will have residual epilepsy or cogni-
tive impairment. For details of post-infectious encephalo-
myelitis, see page 1192. Anticonvulsant treatment may
be needed (p. 1183) and raised intracranial pressure may
indicate the need for dexamethasone.
Brainstem encephalitis
This presents with ataxia, dysarthria, diplopia or other
cranial nerve palsies. The CSF is lymphocytic, with a
normal glucose. The causative agent is presumed to be
viral. However, Listeria monocytogenes may cause a
similar syndrome with meningitis (and often a poly-
morphonuclear CSF pleocytosis) and requires specific
treatment with ampicillin 500 mg 4 times daily (see
Box 26.79).
Rabies
Rabies is caused by a rhabdovirus that infects the central
nervous tissue and salivary glands of a wide range of
mammals, and is usually conveyed by saliva through
bites or licks on abrasions or on intact mucous mem-
branes. Humans are most frequently infected from dogs
and bats. In Europe, the maintenance host is the fox. The
incubation period varies in humans from a minimum of
9 days to many months but is usually between 4 and
8 weeks. Severe bites, especially if on the head or neck,
are associated with shorter incubation periods. Human
rabies is a rare disease, even in endemic areas. However,
because it is usually fatal, major efforts are directed at
limiting its spread and preventing its importation into
uninfected countries, such as the UK.
Clinical features
At the onset there may be fever, and paraesthesia at the
1206 site of the bite. A prodromal period of 1–10 days, during
which the patient becomes increasingly anxious, leads
to the characteristic ‘hydrophobia’. Although the patient
is thirsty, attempts at drinking provoke violent contrac-
tions of the diaphragm and other inspiratory muscles.
Delusions and hallucinations may develop, accompa-
nied by spitting, biting and mania, with lucid intervals
in which the patient is markedly anxious. Cranial nerve
lesions develop and terminal hyperpyrexia is common.
Death ensues, usually within a week of the onset of
symptoms.
Investigations
During life, the diagnosis is usually made on clinical
grounds but rapid immunofluorescent techniques can
detect antigen in corneal impression smears or skin
biopsies.
Management
Established disease
Only a few patients with established rabies have sur-
vived. All received some post-exposure prophylaxis (see
below) and needed intensive care facilities to control
cardiac and respiratory failure. Otherwise, only pallia-
tive treatment is possible once symptoms have appeared.
The patient should be heavily sedated with diazepam,
supplemented by chlorpromazine if needed. Nutrition
and fluids should be given intravenously or through a
gastrostomy.
Pre-exposure prophylaxis
Pre-exposure prophylaxis is required by those who
handle potentially infected animals professionally,
those who work with rabies virus in laboratories and
those who live at special risk in rabies-endemic areas.
Protection is afforded by intradermal injections of
human diploid cell strain vaccine, or two intramuscular
injections given 4 weeks apart, followed by yearly
boosters.
Post-exposure prophylaxis
The wounds should be thoroughly cleaned, preferably
with a quaternary ammonium detergent or soap;
damaged tissues should be excised and the wound left
unsutured. Rabies can usually be prevented if treatment
is started within a day or two of biting. Delayed treat-
ment may still be of value. For maximum protection,
hyperimmune serum and vaccine are required.
The safest antirabies antiserum is human rabies
immunoglobulin. The dose is 20 U/kg body weight; half
is infiltrated around the bite and half is given intramus-
cularly at a different site from the vaccine. Hyper-
immune animal serum may be used but hypersensitivity
reactions, including anaphylaxis, are common.
The safest vaccine, free of complications, is human
diploid cell strain vaccine; 1.0 mL is given intramuscu-
larly on days 0, 3, 7, 14, 30 and 90. In developing
countries, where human rabies globulin may not be
obtainable, 0.1 mL of vaccine may be given intrader-
mally into eight sites on day 1, with single boosters on
days 7 and 28. Where human products are not available
and when risk of rabies is slight (licks on the skin, or
minor bites of covered arms or legs), it may be justifiable
to delay starting treatment while observing the biting
animal or awaiting examination of its brain, rather than
use the older vaccine.

Poliomyelitis
Pathophysiology
Disease is caused by one of three polioviruses, which
constitutes a subgroup of the enteroviruses. Poliomyeli-
tis has become much less common in developed coun-
tries following the widespread use of oral vaccines but
is still a problem in the developing world, especially
parts of Africa. Infection usually occurs through the
nasopharynx.
The virus causes a lymphocytic meningitis and infects
the grey matter of the spinal cord, brainstem and cortex.
There is a particular propensity to damage anterior horn
cells, especially in the lumbar segments.
Clinical features
The incubation period is 7–14 days. Figure 26.32 illus-
trates the various features of the infection. Many patients
recover fully after the initial phase of a few days of mild
fever and headache. In other individuals, after a week
of well-being, there is a recurrence of pyrexia, headache
and meningism. Weakness may start later in one muscle
group and can progress to widespread paresis. Respira-
tory failure may supervene if intercostal muscles are
paralysed or the medullary motor nuclei are involved.
Epidemics vary widely in terms of the incidence of non-
paralytic cases and in mortality rate. Death occurs from
respiratory paralysis. Muscle weakness is maximal at
the end of the first week and gradual recovery may then
take place over several months. Muscles showing no
signs of recovery after a month will probably not regain
useful function. Second attacks are very rare but occa-
sionally patients show late deterioration in muscle bulk
and power many years after the initial infection (this is
termed the ‘post-polio syndrome’).
Infection
1 2 3 The CSF may show a mild lymphocytic pleocytosis
Asymptomatic Aseptic meningitis Febrile
seroconversion (encephalitis) illness
Anterior horn Recovery
cell infection
Lower motor
neuron paralysis
Death Recovery
Complete Residual
disability
Late
deterioration
Fig. 26.32 Poliomyelitis. Possible consequences of infection.
Infections of the nervous system
Investigations
The CSF shows a lymphocytic pleocytosis, a rise in
protein and a normal sugar content. Poliomyelitis virus
may be cultured from CSF and stool.
Management
Established disease
In the early stages, bed rest is imperative because exer-
cise appears to worsen the paralysis or precipitate it. At
the onset of respiratory difficulties, a tracheostomy and
ventilation are required. Subsequent treatment is by
physiotherapy and orthopaedic measures.
Prophylaxis
Prevention of poliomyelitis is by immunisation with
live (Sabin) vaccine. In developed countries where
polio is now very rare, the live vaccine has been replaced
by the killed vaccine in childhood immunisation
schedules.
Herpes zoster (shingles)
Herpes zoster is the result of reactivation of the varicella
zoster virus that has lain dormant in a nerve root gan-
glion following chickenpox earlier in life. Reactivation
may be spontaneous (as usually occurs in the middle-
aged or elderly) or due to immunosuppression (as in
patients with diabetes, malignant disease or AIDS). Full 26
details are given on page 318.
Subacute sclerosing
panencephalitis
This is a rare, chronic, progressive and eventually
fatal complication of measles, presumably a result of
an inability of the nervous system to eradicate the
virus. It occurs in children and adolescents, usually
many years after the primary virus infection. There
is generalised neurological deterioration and onset is
insidious, with intellectual deterioration, apathy and
clumsiness, followed by myoclonic jerks, rigidity and
dementia.
and the EEG demonstrates characteristic periodic bursts
of triphasic waves. Although there is persistent measles-
specific IgG in serum and CSF, antiviral therapy is inef-
fective and death ensues within a few years.
Progressive multifocal
leucoencephalopathy
This was originally described as a rare complication
of lymphoma, leukaemia or carcinomatosis, but has
become more frequent as a feature of AIDS (p. 402). It is
an infection of oligodendrocytes by human polyoma-
virus JC, which causes widespread demyelination of
the white matter of the cerebral hemispheres. Clinical
signs include dementia, hemiparesis and aphasia, which
progress rapidly, usually leading to death within weeks
or months. Areas of low density in the white matter are
seen on CT but MRI is more sensitive, showing diffuse
high signal in the cerebral white matter on T2-weighted
images. The only treatment available is to restore the
immune response (by treating AIDS or any other cause
of immunosuppression). 1207
 NEUROLOGICAL DISEASE

26 Parenchymal bacterial infections

A

Cerebral abscess
Bacteria may enter the cerebral substance through pen-
etrating injury, by direct spread from paranasal sinuses
or the middle ear, or secondary to septicaemia. The site
of abscess formation and the likely causative organism
are both related to the source of infection (Box 26.83).
Initial infection leads to local suppuration followed by
loculation of pus within a surrounding wall of gliosis,
which in a chronic abscess may form a tough capsule.
Haematogenous spread may lead to multiple abscesses.
Clinical features
A cerebral abscess may present acutely with fever, head-
ache, meningism and drowsiness, but more commonly
presents over days or weeks as a cerebral mass lesion
with little or no evidence of infection. Seizures, raised
intracranial pressure and focal hemisphere signs occur
alone or in combination. Distinction from a cerebral
tumour may be impossible on clinical grounds. B

Investigations
Lumbar puncture is potentially hazardous in the pres-
ence of raised intracranial pressure and CT should
always precede it. CT reveals single or multiple low-
density areas, which show ring enhancement with
contrast and surrounding cerebral oedema (Fig. 26.33).
There may be an elevated white blood cell count and
ESR in patients with active local infection. The possibil-
ity of cerebral toxoplasmosis or tuberculous disease
secondary to HIV infection (p. 402) should always be
considered.
Management and prognosis
Antimicrobial therapy is indicated once the diagnosis is
made. The likely source of infection should guide the
choice of antibiotic (see Box 26.83). In neurosurgical
patients, the addition of vancomycin should be consid-
ered. Surgical drainage by burr-hole aspiration or exci- Fig. 26.33 Right temporal cerebral abscess (arrows), with
sion may be necessary, especially where the presence of surrounding oedema and midline shift to the left. A Unenhanced
a capsule may lead to a persistent focus of infection. CT image. B Contrast-enhanced CT image.

26.83 Aetiology and treatment of bacterial cerebral abscess

Site of abscess Source of infection Likely organisms Recommended treatment
Frontal lobe Paranasal sinuses Streptococci Cefotaxime 2–3 g IV 4 times daily plus
Teeth Anaerobes Metronidazole 500 mg IV 3 times daily
Temporal lobe Middle ear Streptococci Ampicillin 2–3 g IV 3 times daily plus
Enterobacteriaceae Metronidazole 500 mg IV 3 times daily plus either Ceftazidime
Cerebellum Sphenoid sinus Pseudomonas spp. 2 g IV 3 times daily or
Mastoid/middle ear Anaerobes Gentamicin* 5 mg/kg IV daily
Any site Penetrating trauma Staphylococci Flucloxacillin 2–3 g IV 4 times daily or
Cefuroxime 1.5 g IV 3 times daily
Multiple Metastatic and Streptococci Benzylpenicillin 1.8–2.4 g IV 4 times daily if endocarditis or
cryptogenic Anaerobes cyanotic heart disease
Otherwise cefotaxime 2–3 g IV 4 times daily plus
Metronidazole 500 mg IV 3 times daily

*Monitor gentamicin levels.

1208
 Infections of the nervous system

Epilepsy frequently develops and is often resistant to 26.84 Clinical and pathological features of
treatment. neurosyphilis
Despite advances in therapy, the mortality rate
Type Pathology Clinical features
remains at 10–20% and this may partly relate to delay in
diagnosis and initiation of treatment. Meningovascular Endarteritis Stroke
(5 yrs)* obliterans Cranial nerve
Subdural empyema Meningeal exudate palsies
This is a rare complication of frontal sinusitis, osteo- Granuloma Seizures/mass
(gumma) lesion
myelitis of the skull vault or middle ear disease. A col-
lection of pus in the subdural space spreads over the General Degeneration in Dementia
surface of the hemisphere, causing underlying cortical paralysis of cerebral cortex/ Tremor
oedema or thrombophlebitis. Patients present with the insane cerebral atrophy Bilateral upper
severe pain in the face or head and pyrexia, often with (5–15 yrs)* Thickened motor signs
a history of preceding paranasal sinus or ear infection. meninges
The patient then becomes drowsy, with seizures and Tabes dorsalis Degeneration of Lightning pains
focal signs such as a progressive hemiparesis. (5–20 yrs)* sensory neurons Sensory ataxia
The diagnosis rests on a strong clinical suspicion in Wasting of dorsal Visual failure
patients with a local focus of infection. Careful assess- columns Abdominal crises
ment with contrast-enhanced CT or MRI may show a Optic atrophy Incontinence
subdural collection with underlying cerebral oedema. Trophic changes
Management requires aspiration of pus via a burr-hole Any of the above Argyll Robertson
and appropriate parenteral antibiotics. Any local source pupils (p. 1172)
of infection must be treated to prevent re-infection.
*Interval from primary infection.
Spinal epidural abscess
The characteristic clinical features are pain in a root
distribution and progressive transverse spinal cord
syndrome with paraparesis, sensory impairment and and irregular pupils that react to convergence but not
light, as described by Argyll Robertson (see Box 26.28,
26
sphincter dysfunction. Features of the primary focus of
infection may be less obvious and thus can be over- p. 1172), may accompany any neurosyphilitic syndrome,
looked. The resurgence of resistant staphylococcal infec- but most commonly tabes dorsalis.
tion and intravenous drug misuse has contributed to a
recent marked rise in incidence. Investigations
X-ray changes occur late if present, so MRI or mye- Routine screening for syphilis is warranted in many
lography should precede urgent neurosurgical interven- neurological patients. Serological tests (p. 420) are posi-
tion. Decompressive laminectomy with draining of the tive in the serum in most patients, but CSF examination
abscess relieves the pressure on the dura. Organisms is essential if neurological involvement is suspected.
may be grown from the pus or blood. Surgery, together Active disease is suggested by an elevated cell count,
with appropriate antibiotics, may prevent complete and usually lymphocytic, and the protein content may be
irreversible paraplegia. elevated to 0.5–1.0 g/L with an increased gamma globu-
lin fraction. Serological tests in the CSF are usually posi-
Lyme disease tive, but progressive disease can occur with negative
This can cause numerous neurological problems, includ- CSF serology.
ing polyradiculopathy, meningitis, encephalitis and Management
mononeuritis multiplex (p. 334).
The injection of procaine benzylpenicillin (procaine pen-
Neurosyphilis icillin) and probenecid for 17 days is essential in the
treatment of neurosyphilis of all types (p. 421). Further
Neurosyphilis may present as an acute or chronic
courses of penicillin must be given if symptoms are not
process and may involve the meninges, blood vessels
relieved, if the condition continues to advance or if the
and/or parenchyma of the brain and spinal cord. The
CSF continues to show signs of active disease. The cell
decade to 2008 saw a ten-fold increase in the incidence
count returns to normal within 3 months of completion
of syphilis, mostly as a result of misguided relaxation
of treatment, but the elevated protein takes longer to
of safe sex measures with the advent of effective anti-
subside and some serological tests may never revert to
retroviral treatments for AIDS. Parallel increases in
normal. Evidence of clinical progression at any time is
neurosyphilis are inevitable. The clinical manifestations
an indication for renewed treatment.
are diverse and early diagnosis and treatment remain
important.
Clinical features Diseases caused by bacterial toxins
The clinical and pathological features of the three most
common presentations are summarised in Box 26.84. Tetanus
Neurological examination reveals signs indicative of This disease results from infection with Clostridium
the anatomical localisation of lesions. Delusions of gran- tetani, a commensal in the gut of humans and domestic
deur suggest general paresis of the insane, but more animals that is found in soil. Infection enters the body
commonly there is simply progressive dementia. Small through wounds, which may be trivial. It is rare in the 1209
 NEUROLOGICAL DISEASE
26 UK, occurring mostly in gardeners and farmers, but a
recent increase has been seen in intravenous drug mis-
users. By contrast, the disease is common in many devel-
oping countries, where dust contains spores derived
from animal and human excreta. Unhygienic practices
soon after birth may lead to infection of the umbilical
stump or site of circumcision, causing tetanus neonato-
rum. Tetanus is still one of the major killers of adults,
children and neonates in developing countries, where
the mortality rate can be nearly 100% in the newborn
and around 40% in others.
In circumstances unfavourable to the growth of the
organism, spores are formed and these may remain
dormant for years in the soil. Spores germinate and
bacilli multiply only in the anaerobic conditions that
occur in areas of tissue necrosis or if the oxygen tension
is lowered by the presence of other organisms, particu-
larly if aerobic. The bacilli remain localised but produce
an exotoxin with an affinity for motor nerve endings and
motor nerve cells.
The anterior horn cells are affected after the exotoxin
has passed into the blood stream and their involvement
results in rigidity and convulsions. Symptoms first
appear from 2 days to several weeks after injury – the
shorter the incubation period, the more severe the attack
and the worse the prognosis.
Clinical features
By far the most important early symptom is trismus –
spasm of the masseter muscles, which causes difficulty
in opening the mouth and in masticating; hence the
name ‘lockjaw’. Lockjaw in tetanus is painless, unlike
the spasm of the masseters due to dental abscess, septic
throat or other causes. Conditions that can mimic tetanus
include hysteria and phenothiazine overdosage, or over-
dose in intravenous drug misusers.
In tetanus, the tonic rigidity spreads to involve the
muscles of the face, neck and trunk. Contraction of the
frontalis and the muscles at the angles of the mouth
leads to the so-called ‘risus sardonicus’. There is rigidity
of the muscles at the neck and trunk of varying degree.
The back is usually slightly arched (‘opisthotonus’) and
there is a board-like abdominal wall.
In the more severe cases, violent spasms lasting for a
few seconds to 3–4 minutes occur spontaneously, or may
be induced by stimuli such as movement or noise. These
convulsions are painful, exhausting and of very serious
significance, especially if they appear soon after the
onset of symptoms. They gradually increase in fre-
quency and severity for about 1 week and the patient
may die from exhaustion, asphyxia or aspiration pneu-
monia. In less severe illness, convulsions may not com-
mence until a week or so after the first sign of rigidity,
and in very mild infections they may never appear.
Autonomic involvement may cause cardiovascular com-
plications, such as hypertension. Rarely, the only mani-
festation of the disease may be ‘local tetanus’ – stiffness
or spasm of the muscles near the infected wound – and
the prognosis is good if treatment is commenced at
this stage.
Investigations
The diagnosis is made on clinical grounds. It is rarely
possible to isolate the infecting organism from the origi-
1210 nal locus of entry.
26.85 Treatment of tetanus
Neutralise absorbed toxin
• IV injection of 3000 U of human tetanus antitoxin
Prevent further toxin production
• Débridement of wound
• Benzylpenicillin 600 mg IV 4 times daily (metronidazole if
patient is allergic to penicillin)
Control spasms
• Nurse in a quiet room
• Avoid unnecessary stimuli
• IV diazepam
• If spasms continue, paralyse patient and ventilate
General measures
• Maintain hydration and nutrition
• Treat secondary infections
Management
Established disease
Management of established disease should begin as
soon as possible, as shown in Box 26.85.
Prevention
Tetanus can be prevented by immunisation and prompt
treatment of contaminated wounds by débridement and
antibiotics. In patients with a contaminated wound, the
immediate danger of tetanus can be greatly reduced by
the injection of 1200 mg of penicillin followed by a 7-day
course of oral penicillin. For those allergic to penicillin,
erythromycin should be used. When the risk of tetanus
is judged to be present, an intramuscular injection of
250 U of human tetanus antitoxin should be given, along
with toxoid which should be repeated 1 month and
6 months later. For those already immunised, only a
booster dose of toxoid is required.
Botulism
Botulism is caused by the neurotoxins of Clostridium
botulinum, which are extremely potent and cause disease
after ingestion of even picogram amounts. Its classical
form is an acute onset of bilateral cranial neuropathies
associated with symmetric descending weakness.
Anaerobic conditions are necessary for the organ-
ism’s growth. It may contaminate and thrive in many
foodstuffs, where sealing and preserving provide the
requisite conditions. Contaminated honey has been
implicated in infant botulism, in which the organism
colonises the gastrointestinal tract. Wound botulism is a
growing problem in injection drug-users.
The toxin causes predominantly bulbar and ocular
palsies (difficulty in swallowing, blurred or double
vision, ptosis), progressing to limb weakness and respi-
ratory paralysis. Criteria for the clinical diagnosis are
shown in Box 26.86.
Management includes assisted ventilation and
general supportive measures until the toxin eventually
dissociates from nerve endings 6–8 weeks following
ingestion. A polyvalent antitoxin is available for post-
exposure prophylaxis and for the treatment of suspected
botulism. It specifically neutralises toxin types A, B and
E and is not effective against infantile botulism (in which
 Intracranial mass lesions and raised intracranial pressure

26.86 The US Centers for Disease Control (CDC)

definition of botulism
Three main syndromes
1. Infantile
2. Food-borne
3. Wound infection
Clinical features
• Absence of fever
• Symmetrical neurological deficits
• Patient remains responsive
• Normal or slow heart rate and normal blood pressure
• No sensory deficits with the exception of blurred vision

active growth of the organism allows continued toxin

production).

Transmissible spongiform
encephalopathies
Transmissible spongiform encephalopathies (TSEs)
include a number of veterinary and medical conditions
that are characterised by the histopathological triad of
cortical spongiform change, neuronal cell loss and
gliosis. Associated with these changes, there is deposi-
tion of amyloid made up of an altered form of a nor-
mally occurring protein, the prion protein.
The precise nature of the infective agent is not yet
clear but almost certainly involves the cascade formation
of an abnormal prion protein. TSEs may also occur spon-
taneously or as an inherited disorder. Diseases affecting
animals include bovine and feline spongiform encepha-
lopathies (BSE and FSE). These diseases achieved media
prominence in the 1990s, when a form of Creutzfeldt–
Jakob disease emerged that was associated with prion
protein ingestion.
Creutzfeldt–Jakob disease
Creutzfeldt–Jakob disease (CJD) is the best-characterised
human TSE. Some 10% of cases arise due to a mutation
in the gene coding for the prion protein. The sporadic
form is the most common, occurring in middle-aged
to elderly patients. Clinical features usually involve
a rapidly progressive dementia, with myoclonus and
a characteristic EEG pattern (repetitive slow-wave
complexes), although a number of other features, such
as visual disturbance or ataxia, may also be seen. These
are particularly common in CJD transmitted by inocula-
tion (e.g. by infected dura mater grafts). Death occurs
after a mean of 4–6 months. There is no effective
treatment.
Variant Creutzfeldt–Jakob disease
A variant of CJD (vCJD) emerged in the late 1990s,
affecting a small number of patients in the UK. The
causative agent appears to be identical to that causing
BSE in cows, and the disease may have been a result of
the epidemic of BSE in the UK a decade earlier. Patients
affected by vCJD are typically younger than those with
sporadic CJD and present with neuropsychiatric changes
and sensory symptoms in the limbs, followed by ataxia,
dementia and death. Progression is slightly slower than
Fig. 26.34 MRI in variant Creutzfeldt–Jakob disease. Arrows
26
indicate bilateral pulvinar hyperintensity.
in patients with sporadic CJD (mean time to death is
over a year). Characteristic EEG changes are not present,
but MRI brain scans show characteristic high-signal
changes in the pulvinar in a high proportion of cases
(Fig. 26.34). Brain histology is distinct, with very florid
plaques containing the prion proteins. Abnormal prion
protein has been identified in tonsil specimens from suf-
ferers of vCJD, leading to the suggestion that the disease
could be transmitted by reticulo-endothelial tissue (like
TSEs in animals but unlike sporadic CJD in humans).
This has caused great concern in the UK, leading to
precautionary measures such as leucodepletion of all
blood used for transfusion, and the mandatory use of
disposable surgical instruments wherever possible for
tonsillectomy, appendicectomy and ophthalmological
procedures. The incidence of vCJD has now declined
dramatically but surveillance and research continue.
Other TSE syndromes
Other extremely rare, inherited human TSEs include
Gerstmann–Sträussler–Scheinker disease, fatal familial
insomnia and kuru. Kuru occurred only in members of
a cannibalistic New Guinea tribe and was probably
transmitted by people eating the brains of dead tribal
members. Clinical features include progressive ataxia
and dementia.
INTRACRANIAL MASS LESIONS AND
RAISED INTRACRANIAL PRESSURE
Many different types of mass lesion may arise within the
intracranial cavity (Box 26.87). In developing countries,
tuberculoma and other infections are frequent causes,
but in the West, intracranial haemorrhage and brain 1211
 NEUROLOGICAL DISEASE

26 26.87 Common causes of raised

intracranial pressure
26.88 Clinical features of intracranial
mass lesions
Mass lesions Presentation Features
• Intracranial haemorrhage (traumatic or spontaneous) Seizures Focal onset ± generalised spread
Extradural haematoma
Focal symptoms Progressive loss of function
Subdural haematoma
Weakness
Intracerebral haemorrhage
Numbness
• Cerebral tumour (particularly posterior fossa lesions or
Dysphasia
high-grade gliomas: see Box 26.89)
Cranial neuropathy
• Infective
Cerebral abscess False localising signs Unilateral/bilateral 6th nerve
Tuberculoma palsies
Cysticercosis (p. 380) Contralateral 3rd nerve (usually
Hydatid cyst (p. 380) pupil first)
• Colloid cyst (in ventricles) Raised intracranial Headache worse on lying/straining
Disturbance of CSF circulation pressure Vomiting
• Obstructive (non-communicating) hydrocephalus: obstruction (usually aggressive Diplopia (6th nerve involvement)
within ventricular system tumours causing Papilloedema
• Communicating hydrocephalus: site of obstruction outside vasogenic oedema or Bradycardia, raised blood pressure
ventricular system obstructive hydrocephalus) Impaired conscious level

Obstruction to venous sinuses

Stroke/TIA-like Acute haemorrhage into tumour
symptoms Paroxysmal ‘tumour attacks’
• Cerebral venous thrombosis
• Trauma (depressed fractures overlying sinuses) Cognitive/behavioural Usually frontal mass lesions
change
Diffuse brain oedema or swelling
Endocrine abnormalities Pituitary tumours
• Meningo-encephalitis
• Trauma (diffuse head injury, near-drowning) Incidental finding Asymptomatic but identified on
• Subarachnoid haemorrhage imaging (meningiomas commonly)
• Metabolic (e.g. water intoxication)
• Idiopathic intracranial hypertension (TIA = transient ischaemic attack)

tumours are more common. The clinical features depend

on the site of the mass, its nature and its rate of expan-
Mid-brain
sion. Symptoms and signs (see Box 26.88) are produced distorted 3rd nerve
by a number of mechanisms. deformed

Raised intracranial pressure

Tentorial
margin Cerebral
Raised intracranial pressure (RIP) may be caused by mass tumour
lesions, cerebral oedema, obstruction to CSF circulation
causing hydrocephalus, impaired CSF absorption and
cerebral venous obstruction (see Box 26.87).

Clinical features
In adults, intracranial pressure is less than 10–15 mmHg.
The features of RIP are listed in Box 26.88. The speed of
pressure increase influences presentation. If slow, com-
pensatory mechanisms may occur, including alteration
in the volume of fluid in CSF spaces and venous sinuses,
which minimise symptoms. Rapid pressure increase (as
in aggressive tumours) does not permit these compensa-
tory mechanisms to occur, leading to early symptoms,
including sudden death. Papilloedema is not always
present, either because the pressure rise has been too
rapid or because of anatomical anomalies of the menin-
geal sheath of the optic nerve.
A false localising sign is one in which the pathology
is remote from the site of the expected lesion; in RIP, the
6th cranial nerve (unilateral or bilateral) is most com-
monly affected, but the 3rd, 5th and 7th nerves may also
be involved. Sixth nerve palsies are thought to be due
either to stretching of the long slender nerve or to
1212 compression against the petrous temporal bone ridge.
Fig. 26.35 Cerebral tumour displacing medial temporal lobe and
causing pressure on the mid-brain and 3rd cranial nerve.
Trans-tentorial herniation of the uncus may compress
the ipsilateral 3rd nerve and usually involves the pupil-
lary fibres first, causing a dilated pupil; however, a false
localising contralateral 3rd nerve palsy may also occur,
perhaps due to extrinsic compression by the tentorial
margin. Vomiting, coma, bradycardia and arterial
hypertension are later features of RIP.
The rise in intracranial pressure from a mass lesion
may cause displacement of the brain. Downward dis-
placement of the medial temporal lobe (uncus) through
the tentorium due to a large hemisphere mass may cause
‘temporal coning’ (Fig. 26.35). This may stretch the 3rd
and/or 6th cranial nerves, or cause pressure on the
contralateral cerebral peduncle (causing ipsilateral
upper motor neuron signs), and is usually accompanied
by progressive coma. Downward movement of the
 Intracranial mass lesions and raised intracranial pressure

26.89 Primary brain tumours

Histological type Common site Age
Fourth Malignant
ventricle Glioma Cerebral Adulthood
(astrocytoma) hemisphere Childhood/adulthood
Level of foramen Cerebellum Childhood/young
magnum Brainstem adulthood
Oligodendroglioma Cerebral Adulthood
Atlas hemisphere
Cerebellar
tonsil Axis Medulloblastoma Posterior fossa Childhood
Ependymoma Posterior fossa Childhood/
Fig. 26.36 Tonsillar cone. Downward displacement of the cerebellar adolescence
tonsils below the level of the foramen magnum. Cerebral Cerebral Adulthood
lymphoma hemisphere
Benign
cerebellar tonsils through the foramen magnum may Meningioma Cortical dura Adulthood (often
compress the medulla – ‘tonsillar coning’ (Fig. 26.36). Parasagittal incidental finding)
This may result in brainstem haemorrhage and/or acute Sphenoid ridge
obstruction of the CSF pathways. As coning progresses, Suprasellar
coma and death occur unless the condition is rapidly Olfactory groove
treated.
Neurofibroma Acoustic Adulthood
Management neuroma
Primary management of RIP should be targeted at Craniopharyngioma Suprasellar Childhood/
relieving the cause (e.g. surgical decompression of mass
lesion, steroids to reduce vasogenic oedema or shunt Pituitary adenoma Pituitary fossa
adolescence
Adulthood
26
procedure to relieve hydrocephalus). Supportive treat- Colloid cyst Third ventricle Any age
ment includes maintenance of fluid balance, blood pres-
sure control, head elevation, and use of diuretics such as Pineal tumours Quadrigeminal Childhood (teratomas)
mannitol. Intensive care support may be needed (p. 199). cistern Young adulthood
(germ cell)

Brain tumours
Primary brain tumours are a heterogeneous collection of
neoplasms arising from the brain tissue or meninges,
and vary from benign to highly malignant. Primary
malignant brain tumours (Box 26.89) are rare, account-
ing for 1% of all adult tumours but a higher proportion
in children. The most common benign brain tumour is a
meningioma. Primary brain tumours do not metastasise
due to the absence of lymphatic drainage in the brain.
There are rare pathological subtypes, however, such as
medulloblastoma, which do have a propensity to metas-
tasise; the reasons for this are not clear. Most cerebral
tumours are sporadic but may be associated with genetic
syndromes such as neurofibromatosis or tuberous scle-
rosis. Brain tumours are not classified by the usual TNM
system but by the WHO grading I–IV; this is based
on histology (e.g. nuclear pleomorphism, presence of
mitoses and presence of necrosis), with grade I being the
most benign and grade IV the most malignant. Gliomas
account for 60% of brain tumours, with the aggressive
glioblastoma multiforme (WHO grade IV) being the
most common glioma, followed by meningiomas (20%)
and pituitary tumours (10%). Although the lower-grade
gliomas (I and II) may be very indolent, with prognosis
measured in terms of many years, these tumours may
transform to higher-grade disease at any time, with a
resultant sharp decline in life expectancy.
Most malignant brain tumours are due to metastases,
with intracranial metastases complicating about 20%
of extracranial malignancies. The rate is higher with
primaries in the bronchus, breast and gastrointestinal
tract (Fig. 26.37). Metastases usually occur in the white
matter of the cerebral or cerebellar hemispheres, but
there are diffuse leptomeningeal types.
Clinical features
The presentation is variable and usually influenced by
the rate of growth. High-grade disease (WHO grade III
and IV) tends to present with a short 4–6-week history of
mass effect (headache, nausea secondary to RIP), while
more indolent tumours can present with slowly progres-
sive focal neurological deficits, depending on their loca-
tion (see Box 26.88); generalised or focal seizures are
common. Headache, if present, is usually accompanied
by focal deficits or seizures, and isolated stable headache
is almost never due to intracranial tumour.
The size of the primary tumour is of far less prognos-
tic significance than its location within the brain.
Tumours within the brainstem will result in early neu-
rological deficits, while those in the frontal region may
be quite large before symptoms occur.
Investigations
Diagnosis is by neuroimaging (Figs 26.38 and 26.39)
and pathological grading following biopsy or resection
where this is possible. The more malignant tumours are
more likely to demonstrate contrast enhancement on
imaging. If the tumour appears to be metastatic, further
investigation to find the primary will be required. 1213
 NEUROLOGICAL DISEASE
26
Fig. 26.37 Contrast-enhanced CT head showing a large
metastasis within the left hemisphere (large arrow). There is
surrounding cerebral oedema, and a smaller metastasis (small arrow)
within the wall of the right lateral ventricle. The primary lesion was a lung
carcinoma.
B Fig. 26.39 MRI of an acoustic neuroma (arrows) in the posterior
Fig. 26.38 MRI showing a meningioma in the frontal lobe
(arrow A) with associated oedema (arrow B).
Management
Brain tumours are treated with a combination of surgery,
radiotherapy and chemotherapy, depending on the type
of tumour and the patient. Advancing age is the most
powerful negative prognostic factor in CNS tumours, so
best supportive care (including steroid therapy) may be
1214 most appropriate in older patients with metastases or
A
fossa compressing the brainstem. A Axial image. B Coronal image.
high-grade disease. Treatment may not always be indi-
cated in indolent (low-grade, WHO I or II) disease, and
watchful waiting after surgery is often appropriate in
such situations.
Dexamethasone given orally (or intravenously where
RIP is acutely or severely raised) may reduce the
vasogenic oedema typically associated with metastases
and high-grade gliomas.
Prolactin- or growth hormone-secreting pituitary
adenomas (p. 789) may respond well to treatment with
dopamine agonists (such as bromocriptine, cabergoline
or quinagolide); in this situation, imaging and hormone
levels may be all that is required to establish a formal
diagnosis, precluding the need for surgery.
Surgical
The mainstay of primary treatment is surgery, either
resective (full or partial debulking) or biopsy, depend-
ing on the site and likely radiological diagnosis. Clearly,
if a tumour occurs in an area of brain that is highly

important for normal function (e.g. motor strip), then
biopsy may be the only safe surgical intervention but, in
general, maximal safe resection is the optimal surgical
management. Meningiomas and acoustic neuromas
offer the best prospects for complete removal
and thus cure. Some meningiomas can recur, however,
particularly those of the sphenoid ridge when partial
excision is often all that is possible. Thereafter, post-
operative surveillance may be required, as radiotherapy
is effective at preventing further growth of residual
tumour. Pituitary adenomas may be removed by a trans-
sphenoidal route, avoiding the need for a craniotomy.
Unfortunately, gliomas, which account for the majority
of brain tumours, cannot be completely excised, since
infiltration spreads well beyond the apparent radiologi-
cal boundaries of the intracranial mass. Recurrence
is therefore the rule, even if the mass of the tumour
is apparently removed completely; partial excision
(‘debulking’) may be useful in alleviating symptoms
caused by RIP, but although there is increasing evidence
that the degree of surgical excision may have a positive
influence on survival, this has not yet been demon-
strated in a randomised study.
Radiotherapy and chemotherapy
In the majority of primary CNS tumours, radiation
and chemotherapy are used to control disease and
extend survival rather than for cure. Meningioma and
pituitary adenoma offer the best chance of life-long
remission. The gliomas are incurable; high-grade, WHO
IV disease still carries a median survival of just over a
year. In this situation, patient and family should always
be involved in decisions regarding treatment. The diag-
nosis, and often the symptoms, are devastating, and
support from palliative care and social work is crucial at
an early stage. In WHO grade III disease, prognosis is
a little better (2–4 years) and in rarer, more indolent
tumours, very prolonged survival is possible.
Advances have been made recently in terms of thera-
peutic outcome. Standard care for WHO grade IV glio-
blastoma multiforme is now combination radiotherapy
with oral temozolomide chemotherapy; although this
improves median survival of the population from only
12 to 14.5 months, up to 25% of patients survive for
more than 2 years (compared to approximately 10% with
radiotherapy alone). Ten percent will survive more than
5 years with temozolomide (virtually unheard of with
radiotherapy alone). Benefits are more likely in well-
debulked patients who are younger and fitter. Implanta-
tion of chemotherapy gives a small survival benefit.
Understanding of the molecular biology of brain
tumours has allowed the use of biomarkers to guide
therapy and prognostic discussions. In patients with
methylation of the promoter region of the MGMT
(methyl guanine methyl transferase) gene (about 30% of
the population), 2-year survival is almost 50%. MGMT
reduces the cytotoxicity of temozolomide, and this
mutation also reduces the enzyme’s activity, rendering
the tumour more sensitive to chemotherapy. In grade II
and III gliomas, the presence of the loss of heterozygo-
city (LOH) 1p19q chromosomal abnormality confers
chemosensitivity and thus improves prognosis. The
presence of a rare mutation in the IDH-1 (isocitrate
dehydrogenase) gene confers a very favourable progno-
sis in patients with glioblastoma.
Intracranial mass lesions and raised intracranial pressure
There is a small group of highly malignant grade IV
tumours that can be cured with aggressive therapy.
Patients with medulloblastomas have a good chance of
long-term survival with maximal surgery followed by
irradiation of the whole brain and spine; younger
patients may also benefit from concomitant and adju-
vant chemotherapy. Older patients do not tolerate this,
however.
Once tumours relapse, chemotherapy response rates
are low and survival is short in high-grade disease. In
the more uncommon low-grade tumours, repeated
courses of chemotherapy can result in much more pro-
longed survival.
In metastatic disease, radiotherapy offers a modest
improvement in survival but with costs in terms of
quality of life; treatment therefore needs careful discus-
sion with the patient. Benefits may be superior in breast
cancer but there is little to separate other pathologies.
Occasional chemosensitive cancers, such as small-cell
lung cancer, may benefit from systemic chemotherapy,
but intracerebral metastases represent a late stage of
disease and have a short prognosis.
Prognosis
The WHO histological grading system is a powerful pre-
dictor of prognosis in primary CNS tumours, though it
does not yet take account of individual biomarkers. For
each tumour type and grade, advancing age and deterio-
rating functional status are the next most important
26
negative prognostic features. The overall 5-year survival
rate of about 14% in adults masks a wide variation that
depends on tumour type.
Acoustic neuroma
This is a benign tumour of Schwann cells of the 8th
cranial nerve, which may arise in isolation or as part of
neurofibromatosis type 2 (see below). When sporadic,
acoustic neuroma occurs after the third decade and is
more frequent in females. The tumour commonly arises
near the nerve’s entry point into the medulla or in the
internal auditory meatus, usually on the vestibular divi-
sion. Acoustic neuromas account for 80–90% of tumours
at the cerebellopontine angle.
Clinical features
Acoustic neuroma typically presents with unilateral pro-
gressive hearing loss, sometimes with tinnitus. Vertigo
is an unusual symptom, as slow growth allows com-
pensatory brainstem mechanisms to develop. In some
cases, progressive enlargement leads to distortion of
the brainstem and/or cerebellar peduncle, causing
ataxia and/or cerebellar signs in the limbs. Distortion
of the fourth ventricle and cerebral aqueduct may
cause hydrocephalus (see below), which may be the
presenting feature. Facial weakness is unusual at pres-
entation but facial palsy may follow surgical removal of
the tumour. The tumour may be identified incidentally
on cranial imaging.
Investigations
MRI is the investigation of choice (see Fig. 26.39).
Management
Surgery is the treatment of choice. If the tumour can be
completely removed, the prognosis is excellent, although 1215
 NEUROLOGICAL DISEASE

26 deafness is a common complication of surgery. Stereo-

tactic radiosurgery (radiotherapy) may be appropriate
26.90 Neurofibromatosis types 1 and 2:
clinical features
for some lesions.
Neurofibromatosis 1 Neurofibromatosis 2
Neurofibromatosis Skin
Neurofibromatosis encompasses two clinically and Cutaneous/subcutaneous Much less commonly affected
genetically separate conditions, with an autosomal dom- neurofibromas than NF1
Angiomas Café au lait patches (usually
inant pattern of inheritance. The more common neuro-
Café au lait patches (> 6) < 6)
fibromatosis type 1 (NF1) is caused by mutations in
Axillary/groin freckling Cutaneous schwannomas:
the NF1 gene on chromosome 17, half of which are Hypopigmented patches plaque lesions
new mutations. NF1 is characterised by neurofibromas Subcutaneous schwannomas
(benign peripheral nerve sheath tumours) and skin
involvement (Fig. 26.40), and may affect numerous Eyes
Lisch nodules (iris fibromas) Cataracts
systems (Box 26.90). Neurofibromatosis type 2 (NF2) is
Glaucoma Retinal hamartoma
caused by mutations of the NF2 gene on chromosome
Congenital ptosis Optic nerve meningioma
22, and is characterised by schwannomas (benign
peripheral nerve sheath tumours comprising Schwann Nervous system
cells only), with little skin involvement; the clinical Plexiform neurofibromas Vestibular schwannomas
manifestations are more restricted to the eye and nervous Malignant peripheral nerve Cranial nerve schwannomas
system (see Box 26.90). Malignant change may occur in sheath tumours (not 1 and 2)
Aqueduct stenosis Spinal schwannomas
NF1 neurofibromas but is rare in NF2 schwannomas.
Slight tonsillar descent Peripheral nerve
The prevalence of NF1 and NF 2 is about 20–50 per
Cognitive impairment schwannomas
100 000 and 1.5 per 100 000 respectively. Epilepsy Cranial meningiomas
Spinal meningiomas
Spinal/brainstem
ependymomas
Spinal/cranial astrocytoma
Bone
Scoliosis
Osteoporosis
Pseudoarthrosis
Cardiorespiratory systems
B Pulmonary stenosis
Hypertension
Renal artery stenosis
Compression from
neurofibroma causing
restrictive lung defect
B Gastrointestinal system
Gastrointestinal stromal
tumour
Dysplasia
Duodenal carcinoid tumour

Paraneoplastic neurological disease

Fig. 26.40 A café au lait spot (arrow A) and subcutaneous
nodules (arrows B) on the forearm of a patient with
neurofibromatosis type 1.
Paraneoplastic neurological syndromes often present
before the underlying tumour declares itself and cause
considerable disability. They are discussed in full on
page 1193.

Von Hippel–Lindau disease Hydrocephalus

This rare autosomal dominant disease is caused by
mutations of the VHL tumour suppressor gene on chro-
mosome 3. It promotes development of tumours affect-
ing the kidney, adrenal gland, CNS, eye, inner ear,
epididymis and pancreas, which may undergo malig-
nant change. Benign haemangiomas and haemangio-
blastomas affect about 80% of patients, mostly in the
1216 cerebellum and retina.
Hydrocephalus is the excessive accumulation of CSF
within the brain, and may be caused either by increased
CSF production, by reduced CSF absorption, or by
obstruction of the circulation (Fig. 26.41). Symptoms
range from none to sudden death, depending upon the
speed at which and degree to which hydrocephalus
develops. The causes are listed in Box 26.91. The terms
 Intracranial mass lesions and raised intracranial pressure

Choroid plexus

Fig. 26.41 The circulation of cerebrospinal fluid. (1) CSF is

synthesised in the choroid plexus of the ventricles, and flows from the
lateral and third ventricles through the aqueduct to the fourth ventricle.
(2) At the foramina of Luschka and Magendie it exits the brain, flowing
over the hemispheres (3) and down around the spinal cord and roots in the
subarachnoid space. (4) It is then absorbed into the dural venous sinuses
B
via the arachnoid villi.

26.91 Causes of hydrocephalus

Congenital malformations
• Aqueduct stenosis
• Chiari malformations
• Dandy–Walker syndrome
• Benign intracranial cysts
Acquired causes
• Mass lesions (especially
those in the posterior
fossa)
Tumour
Colloid cyst of third
ventricle
Abscess
Haematoma
26
• Vein of Galen aneurysms
• Congenital CNS infections
• Craniofacial anomalies
• Absorption blockages
due to:
Inflammation (e.g.
meningitis, sarcoidosis)
Intracranial haemorrhage
Fig. 26.42 MRI of hydrocephalus due to aqueduct stenosis.
A Axial T2-weighted image (CSF appears white): note the dilated lateral
ventricles. B Sagittal T2-weighted image (CSF appears black): note the
dilated ventricles (top arrow) and narrowed aqueduct (bottom arrow).

‘communicating’ and ‘non-communicating’ (also known

as obstructive) hydrocephalus refer to blockage either
outside or within the ventricular system respectively
(Fig. 26.42).
Normal pressure hydrocephalus
Normal pressure hydrocephalus (NPH) is a controver-
sial entity, said to involve intermittent rises in CSF pres-
sure, particularly at night. It is described in old age as
being associated with a triad of gait apraxia, dementia
and urinary incontinence.
Management
Diversion of the CSF by means of a shunt placed between
the ventricular system and the peritoneal cavity or right
atrium may result in rapid relief of symptoms in obstruc-
tive hydrocephalus. The outcome of shunting in NPH is
much less predictable and, until a good response can be
predicted, the management of individual cases will
remain uncertain.
Idiopathic intracranial hypertension
This usually occurs in obese young women. The
annual incidence is about 3 per 100 000. RIP occurs in
the absence of a structural lesion, hydrocephalus or
other identifiable cause. The aetiology is uncertain
but there may be a defect of CSF reabsorption by the
arachnoid villi. It may be associated with a number of
drugs, including tetracycline, and with vitamin A and
its derivatives.
Clinical features
The usual presentation is with headache, sometimes
accompanied by diplopia and visual disturbance (most
commonly transient obscurations of vision associated
with changes in posture). Clinical examination reveals
papilloedema but little else. False localising cranial
nerve palsies (usually of the 6th nerve) may be present. 1217
 NEUROLOGICAL DISEASE

26 It is important to record visual fields accurately for

future monitoring.
Inflammatory changes in the cerebellum may cause
symptoms in the aftermath of some infections (espe-
cially herpes zoster) or as a paraneoplastic phenomenon.
Investigations The hereditary spinocerebellar ataxias are described on
Brain imaging is required to exclude a structural or other page 1198; they manifest as progressive ataxias in middle
(e.g. cerebral venous sinus thrombosis, p. 1247) cause. and old age, often with other neurological features that
The ventricles are typically normal in size or small (‘slit’ aid specific diagnosis.
ventricles). The diagnosis may be confirmed by lumbar
puncture, which shows raised CSF pressure (usually
> 30 cm CSF) but normal CSF constituents. DISORDERS OF THE SPINE AND
Management SPINAL CORD
Management can be difficult and there is no evidence to
The spinal cord and spinal roots may be affected by
support any specific treatment. Weight loss in over-
intrinsic disease or by disorders of the surrounding
weight patients may be helpful but is difficult to achieve.
meninges and bones. The clinical presentation of
Acetazolamide or topiramate may help to lower intra-
these conditions depends on the anatomical level at
cranial pressure, the latter perhaps aiding weight loss in
which the cord or roots are affected, as well as the
some patients. Repeated lumbar puncture is an effective
nature of the pathological process involved. It is impor-
treatment for headache, but may be technically difficult
tant to recognise when the spinal cord is at risk of com-
in obese patients and is often poorly tolerated. Patients
pression (p. 1220) so that urgent action can be taken.
failing to respond, in whom chronic papilloedema
threatens vision, may require optic nerve sheath fenes-
tration or a lumbo-peritoneal shunt. Cervical spondylosis
Cervical spondylosis is the result of osteoarthritis in the
Head injury cervical spine. It is characterised by degeneration of the
intervertebral discs and osteophyte formation. Such
Diagnosis of head trauma is usually clear – either from ‘wear and tear’ is extremely common and radiological
the history or from signs of external trauma to the head. changes are frequently found in asymptomatic individu-
Brain injury is more likely with skull fracture but can als over the age of 50. Spondylosis may be associated
occur without. Individual cranial nerves may be with neurological dysfunction. In order of frequency,
damaged in fractures of the facial bones or skull base. the C5/6, C6/7 and C4/5 vertebral levels affect C6, C7
Intracranial effects can be substantial and take several and C5 roots, respectively (Fig. 26.43).
forms: extradural haematoma (collection of blood
between the skull and dura); subdural haematoma (col- Cervical radiculopathy
lection of blood between the dura and the surface of the
brain); and intracerebral haematoma or diffuse axonal Acute onset of compression of a nerve root occurs when
injury. a disc prolapses laterally. More gradual onset may be
Whatever pathology occurs, the resultant RIP may due to osteophytic encroachment of the intervertebral
lead to coning (see Figs 26.35 and 26.36). Haematomas foramina.
are identified by CT and management is by surgical
drainage, usually via a burr-hole. Penetrating skull frac-
tures lead to increased infection risk. Long-term seque-
lae include headache, cognitive decline and depression,
all contributing to significant social, work, personality
and family difficulties.
Subdural haematoma may occur spontaneously,
particularly in patients on anticoagulants, in old age,
and with alcohol misuse. There may or may not be
a history of trauma. Patients present with subacute
impairment of brain function, both globally (obtunda-
tion and coma) and focally (hemiparesis, seizures).
Headache may not be present. The diagnosis should
always be considered in those who present with reduced
conscious level.

DISORDERS OF CEREBELLAR FUNCTION

Cerebellar dysfunction can manifest as incoordination
of limb function, gait ataxia (p. 1168), speech or eye
movements. Acute dysfunction may be caused by
alcohol or prescription drugs (especially the sodium
channel-blocking anti-epileptic drugs, phenytoin and Fig. 26.43 MRI showing cervical cord compression (arrow) in
1218 carbamazepine). cervical spondylosis.
 Disorders of the spine and spinal cord

Management
26.92 Physical signs in cervical root compression
Surgical procedures, including laminectomy and ante-
Muscle rior discectomy, may arrest progression of disability but
Root weakness Sensory loss Reflex loss neurological improvement is not the rule. The decision
C5 Biceps, deltoid, Upper lateral Biceps as to whether surgery should be undertaken may be
spinati arm difficult. Manual manipulation of the cervical spine is of
no proven benefit and may precipitate acute neurologi-
C6 Brachioradialis Lower lateral Supinator cal deterioration.
arm, thumb,
index finger Prognosis
C7 Triceps, finger Middle finger Triceps The prognosis of cervical myelopathy is variable. In
and wrist many patients, the condition stabilises or even improves
extensors without intervention. If progression results in sphincter
dysfunction or pyramidal signs, surgical decompression
should be considered.

Clinical features
The patient complains of pain in the neck that may
Lumbar spondylosis
radiate in the distribution of the affected nerve root. The
This term covers degenerative disc disease and osteo-
neck is held rigidly and neck movements may exacer-
arthritic change in the lumbar spine. Pain in the distribu-
bate pain. Paraesthesia and sensory loss may be found
tion of the lumbar or sacral roots (‘sciatica’) is almost
in the affected segment and there may be lower motor
always due to disc protrusion but can be a feature of
neuron signs, including weakness, wasting and reflex
other rare but important disorders, including spinal
impairment (Box 26.92).
tumour, malignant disease in the pelvis and tuberculosis
of the vertebral bodies.
Investigations
Where there is no trauma, imaging should not be Lumbar disc herniation 26
carried out for isolated cervical pain. X-rays offer limited
benefit, except in excluding destructive lesions. MRI is While acute lumbar disc herniation is often precipitated
the investigation of choice in those with radicular symp- by trauma (usually lifting heavy weights while the
toms. Electrophysiological studies rarely add to clinical spine is flexed), genetic factors may also be important.
examination and have become less important with the The nucleus pulposus may bulge or rupture through the
emergence of MRI. annulus fibrosus, giving rise to pressure on nerve
endings in the spinal ligaments, changes in the vertebral
Management joints or pressure on nerve roots.
Conservative treatment with analgesics and physio- Pathophysiology
therapy results in resolution of symptoms in the great
majority of patients, but a few require surgery in the The altered mechanics of the lumbar spine result in loss
form of discectomy or radicular decompression. of lumbar lordosis and there may be spasm of the para-
spinal musculature. Root pressure is suggested by limi-
Cervical myelopathy tation of flexion of the hip on the affected side if the
straight leg is raised (Lasègue’s sign). If the third or
Dorsomedial herniation of a disc and the development fourth lumbar root is involved, Lasègue’s sign may be
of transverse bony bars or posterior osteophytes may negative, but pain in the back may be induced by hyper-
result in pressure on the spinal cord or the anterior extension of the hip (femoral nerve stretch test). The
spinal artery, which supplies the anterior two-thirds of roots most frequently affected are S1, L5 and L4; the
the cord (see Fig. 26.43). signs of root pressure at these levels are summarised in
Clinical features Box 26.93.
The onset is usually insidious and painless, but acute
deterioration may occur after trauma, especially hyper-
extension injury. Upper motor neuron signs develop
in the limbs, with spasticity of the legs usually appearing 26.93 Physical signs in lumbar root compression
before the arms are involved. Sensory loss in the
upper limbs is common, producing tingling, numbness Disc
and proprioception loss in the hands, with progressive level Root Sensory loss Weakness Reflex loss
clumsiness. Sensory manifestations in the legs are much L3/L4 L4 Inner calf Inversion of Knee
less common. Neurological deficit usually progresses foot
gradually and disturbance of micturition is a very late L4/L5 L5 Outer calf Dorsiflexion
feature. and dorsum of hallux/
of foot toes
Investigations
L5/S1 S1 Sole and Plantar Ankle
MRI (see Fig. 26.43) (or rarely myelography) will direct
lateral flexion
surgical intervention. MRI also provides information on foot
the state of the spinal cord at the level of compression. 1219
 NEUROLOGICAL DISEASE

26 Clinical features
The onset may be sudden or gradual. Alternatively,
Spinal cord compression
repeated episodes of low back pain may precede sciatica
Spinal cord compression is one of the more common
by months or years. Constant aching pain is felt in the
neurological emergencies encountered in clinical prac-
lumbar region and may radiate to the buttock, thigh, calf
tice and the usual causes are listed in Box 26.94. A
and foot. Pain is exacerbated by coughing or straining
space-occupying lesion within the spinal canal may
but may be relieved by lying flat.
damage nerve tissue either directly by pressure or
indirectly by interfering with blood supply. Oedema
Investigations from venous obstruction impairs neuronal function, and
Plain X-rays of the lumbar spine are of little value in the ischaemia from arterial obstruction may lead to necrosis
diagnosis of lumbar disc disease, although they may of the spinal cord. The early stages of damage are revers-
show other conditions such as malignant infiltration of ible but severely damaged neurons do not recover;
a vertebral body. While CT can provide helpful images hence the importance of early diagnosis and treatment.
of the disc protrusion and/or narrowing of the exit
foramina, MRI is the investigation of choice if available, Clinical features
since soft tissues are well imaged. The onset of symptoms of spinal cord compression
is usually slow (over weeks) but can be acute as a
Management result of trauma or metastases, especially if there is asso-
Some 90% of patients with sciatica recover following ciated arterial occlusion. The symptoms are shown in
conservative treatment with analgesia and early mobi- Box 26.95.
lisation; bed rest does not help recovery. The patient Pain and sensory symptoms occur early, while weak-
should be instructed in back-strengthening exercises ness and sphincter dysfunction are usually late manifes-
and advised to avoid physical manœuvres likely to tations. The signs vary according to the level of the cord
strain the lumbar spine. Injections of local anaesthetic compression and the structures involved. There may be
or corticosteroids may be useful adjunctive treatment
if symptoms are due to ligamentous injury or joint
dysfunction. Surgery may have to be considered if
there is no response to conservative treatment or if 26.94 Causes of spinal cord compression
progressive neurological deficits develop. Central disc
Site Frequency Causes
prolapse with bilateral symptoms and signs and distur-
bance of sphincter function requires urgent surgical Vertebral 80% Trauma (extradural)
decompression. Intervertebral disc prolapse
Metastatic carcinoma (e.g.
breast, prostate, bronchus)
Lumbar canal stenosis Myeloma
This occurs with a congenitally narrowed lumbar spinal Tuberculosis
canal, exacerbated by the degenerative changes that Meninges 15% Tumours (e.g. meningioma,
commonly occur with age. (intradural, neurofibroma, ependymoma,
extramedullary) metastasis, lymphoma,
Pathophysiology leukaemia)
The symptoms of spinal stenosis are thought to be due Epidural abscess
to local vascular compromise secondary to the canal ste- Spinal cord 5% Tumours (e.g. glioma,
nosis, rendering the nerve roots ischaemic and intolerant (intradural, ependymoma, metastasis)
of the increased demand that occurs on exercise. intramedullary)

Clinical features
Patients, who are usually elderly, develop exercise-
induced weakness and paraesthesia in the legs (‘spinal
claudication’). These symptoms progress with contin- 26.95 Symptoms of spinal cord compression
ued exertion, often to the point that the patient can no Pain
longer walk, but are quickly relieved by a short period
• Localised over the spine or in a root distribution, which may
of rest. Physical examination at rest shows preservation
be aggravated by coughing, sneezing or straining
of peripheral pulses with absent ankle reflexes. Weak-
ness or sensory loss may only be apparent if the patient Sensory
is examined immediately after exercise. • Paraesthesia, numbness or cold sensations, especially in the
lower limbs, which spread proximally, often to a level on the
Investigations trunk
The investigation of first choice is MRI, but contraindica- Motor
tions (body habitus, metallic implants) may make CT or • Weakness, heaviness or stiffness of the limbs, most
myelography necessary. commonly the legs
Sphincters
Management
• Urgency or hesitancy of micturition, leading eventually to
Lumbar laminectomy may provide relief of symptoms urinary retention
1220 and recovery of normal exercise tolerance.
 Disorders of the spine and spinal cord

26.96 Signs of spinal cord compression

Cervical, above C5
• Upper motor neuron signs and sensory loss in all four limbs
• Diaphragm weakness (phrenic nerve) N
Cervical, C5–T1 SC
• Lower motor neuron signs and segmental sensory loss in the
arms; upper motor neuron signs in the legs
• Respiratory (intercostal) muscle weakness
Thoracic cord
• Spastic paraplegia with a sensory level on the trunk
• Weakness of legs, sacral loss of sensation and extensor
plantar responses
Cauda equina
• Spinal cord ends approximately at the T12/L1 spinal
level and spinal lesions below this level can only cause
lower motor neuron signs by affecting the cauda Fig. 26.44 Axial MRI of thoracic spine. A neurofibroma (N) is
equina compressing the spinal cord (SC) and emerging in a ‘dumbbell’ fashion
through the vertebral foramen into the paraspinal space.

26.97 Investigation of acute spinal cord

syndrome
• MRI of spine or • Chest X-ray
myelography
• Plain X-rays of spine
• CSF
• Serum B12
26

tenderness to percussion over the spine if there is verte-

bral disease and this may be associated with a local
kyphosis. Involvement of the roots at the level of the
compression may cause dermatomal sensory impair-
ment and corresponding lower motor signs. Interrup-
tion of fibres in the spinal cord causes sensory loss
(p. 1164) and upper motor neuron signs below the level
of the lesion, and there is often disturbance of sphincter
function. The distribution of these signs varies with the
level of the lesion (Box 26.96).
The Brown–Séquard syndrome (see Fig. 26.19E,
p. 1164) results if damage is confined to one side of the
cord; the findings are explained by the anatomy of the
sensory tracts (see Fig. 26.10, p. 1147). With compressive
lesions, there is usually a band of pain at the level of the
lesion in the distribution of the nerve roots subject to
compression.
Investigations
Patients with a history of acute or subacute spinal cord
syndrome should be investigated urgently, as listed in
Box 26.97. The investigation of choice is MRI (Fig. 26.44),
as it can define the extent of compression and associated
soft-tissue abnormality (Fig. 26.45). Plain X-rays may
show bony destruction and soft-tissue abnormalities.
Routine investigations, including chest X-ray, may
provide evidence of systemic disease. If myelography is
performed, CSF should be taken for analysis; in cases of
complete spinal block, this shows a normal cell count
with a very elevated protein causing yellow discolora-
tion of the fluid (Froin’s syndrome). The risk of acute
deterioration after myelography in spinal cord compres-
sion means that the neurosurgeons should be alerted
Fig. 26.45 CT myelogram of cervical spine at the level of C2
showing bony erosion of vertebra by a metastasis (arrow).
before it is undertaken. Where a secondary tumour is
causing the compression, needle biopsy may be required
to establish a tissue diagnosis.
Management
Treatment and prognosis depend on the nature of
the underlying lesion. Benign tumours should be surgi-
cally excised, and a good functional recovery can be
expected unless a marked neurological deficit has devel-
oped before diagnosis. Extradural compression due to
malignancy is the most common cause of spinal cord
compression in developed countries and has a poor
prognosis. Useful function can be regained if treatment,
such as radiotherapy, is initiated within 24 hours of the
onset of severe weakness or sphincter dysfunction; man-
agement should involve close cooperation with both
oncologists and neurosurgeons.
Spinal cord compression due to tuberculosis is
common in some areas of the world, and may require
surgical treatment. This should be followed by appro-
priate antituberculous chemotherapy (p. 693) for an 1221
 NEUROLOGICAL DISEASE

26 extended period. Traumatic lesions of the vertebral

column require specialised neurosurgical treatment.

Intrinsic diseases of the spinal cord

There are many disorders that interfere with spinal
cord function due to non-compressive involvement of B
the spinal cord itself. A list of these disorders is given in
Box 26.98. The symptoms and signs are generally similar
to those that would occur with extrinsic compression
(see Boxes 26.95 and 26.96), although a suspended
A
sensory loss (see Fig. 26.19F, p. 1164) can only occur with
intrinsic disease such as syringomyelia. Urinary symp-
toms usually occur earlier in the course of an intrinsic
cord disorder than with compressive disorders. A
Investigation of intrinsic disease starts with imaging
to exclude a compressive lesion. MRI provides most
information about structural lesions such as diastemato-
myelia, syringomyelia (Fig. 26.46) or intrinsic tumours.
Non-specific signal change may be seen in the spinal
cord in inflammatory (see Fig. 26.28, p. 1191) or infective
conditions and other disorders such as vitamin B12 defi-
ciency. Lumbar puncture or blood tests may be required Fig. 26.46 MRI scan showing syrinx (arrows A), with herniation
to make a specific diagnosis. of cerebellar tonsils (arrow B).

26.98 Intrinsic diseases of the spinal cord

Type of disorder Condition Clinical features
Congenital Diastematomyelia (spina Features variably present at birth and deteriorate thereafter
bifida) LMN features, deformity and sensory loss of legs
Impaired sphincter function
Hairy patch or pit over low back
Incidence reduced by increased maternal intake of folic acid during pregnancy
Hereditary spastic paraplegia Onset usually in adult life
Autosomal dominant inheritance usual
Slowly progressive UMN features affecting legs > arms
Little or no sensory loss
Infective/ Transverse myelitis due to Weakness and sensory loss, often with pain, developing over hours to days
inflammatory viruses (HZV), schistosomiasis, UMN features below lesion
HIV, MS, sarcoidosis Impaired sphincter function
Vascular Anterior spinal artery infarct Abrupt onset
Intervertebral disc embolus Anterior horn cell loss (LMN) at level of lesion
UMN features below it
Spinothalamic sensory loss below lesion but dorsal column sensation spared
Spinal AVM/dural fistula Onset variable (acute to slowly progressive)
Variable LMN, UMN, sensory and sphincter disturbance
Symptoms and signs often not well localised to site of AVM
Neoplastic Glioma, ependymoma Weakness and sensory loss often with pain, developing over months to years
UMN features below lesion in cord; additional LMN features in conus
Impaired sphincter function
Metabolic Vitamin B12 deficiency Progressive spastic paraparesis with proprioception loss
(subacute combined Absent reflexes due to peripheral neuropathy
degeneration) ± Optic nerve and cerebral involvement (p. 129)
Degenerative Motor neuron disease Relentlessly progressive LMN and UMN features, associated bulbar weakness
No sensory involvement (p. 1200)
Syringomyelia Gradual onset over months or years, pain in cervical segments
Anterior horn cell loss (LMN) at level of lesion, UMN features below it
Suspended spinothalamic sensory loss at level of lesion, dorsal columns
preserved. See Figures 26.19F (p. 1164) and 26.46

(AVM = arteriovenous malformation; HIV = human immunodeficiency virus; HZV = herpes zoster virus; LMN = lower motor neuron; MS = multiple sclerosis;
UMN = upper motor neuron)
1222
 Diseases of peripheral nerves

important, as only demyelinating neuropathies are

DISEASES OF PERIPHERAL NERVES usually susceptible to treatment; making the distinction
requires neurophysiology (nerve conduction studies
Disorders of the peripheral nervous system are common and electromyography, pp. 1151 and 1152). Neuropa-
and may affect the motor, sensory or autonomic compo- thies can occur in association with many systemic dis-
nents, either in isolation or combination. The site of eases, toxins and drugs (Box 26.100).
pathology may be nerve root (radiculopathy), nerve
plexus (plexopathy) or nerve (neuropathy). Neuro- Clinical features
pathies may present as mononeuropathy (single nerve Motor nerve involvement produces features of a lower
affected), multiple mononeuropathies (‘mononeuritis motor neuron lesion (p. 1162). Symptoms and signs of
multiplex’) or a symmetrical polyneuropathy (Box sensory nerve involvement depend on the type of
26.99). Cranial nerves 3–12 share the same tissue charac- sensory nerve involved (p. 1164); small-fibre neuropa-
teristics as peripheral nerves elsewhere and are subject thies are often painful. Autonomic involvement may
to the same range of diseases. cause postural hypotension, disturbance of sweating,
cardiac rhythm, and gastrointestinal, bladder and sexual
Pathophysiology functions; isolated autonomic neuropathies are rare, and
Damage may occur to the nerve cell body (axon) or more commonly complicate other neuropathies.
the myelin sheath (Schwann cell), leading to axonal
or demyelinating neuropathies. The distinction is Investigations
The investigations required reflect the wide spectrum of
causes (Box 26.101). Neurophysiological tests are key in
discriminating between demyelinating and axonal neu-
26.99 Causes of polyneuropathy ropathies, and in identifying entrapment neuropathies.
Most neuropathies are of the chronic axonal type.
Genetic
• Charcot–Marie–Tooth disease (CMT)
• Hereditary neuropathy with liability to pressure palsies (HNPP)
•
•
Hereditary sensory ± autonomic neuropathies (HSN, HSAN)
Familial amyloid polyneuropathy
26.100 Common causes of axonal and 26
demyelinating chronic polyneuropathies
• Hereditary neuralgic amyotrophy
Axonal
Drugs • Diabetes mellitus • Drugs and toxins
• Amiodarone • Alcohol (see Box 26.99)
• Antibiotics (dapsone, isoniazid, metronidazole, ethambutol) • Uraemia • Deficiency states
• Antiretrovirals • Cirrhosis (see Box 26.99)
• Chemotherapy (cisplatin, vincristine, thalidomide) • Amyloid • Hereditary
• Phenytoin • Myxoedema • Infection (see Box 26.99)
Toxins • Acromegaly • Idiopathic
• Paraneoplastic
• Alcohol
• Nitrous oxide (recreational use) Demyelinating
• Rarely: lead, arsenic, mercury, organophosphates, solvents • Chronic inflammatory demyelinating polyradiculoneuropathy
Vitamin deficiencies • Multifocal motor neuropathy
• Paraprotein-associated demyelinating neuropathy
• Thiamin • Vitamin B12 • Charcot–Marie–Tooth disease type I and type X
• Pyridoxine • Vitamin E
Infections
• HIV • Brucellosis
• Leprosy
Inflammatory 26.101 Investigation of peripheral neuropathy
• Guillain–Barré syndrome
Initial tests
• Chronic inflammatory demyelinating polyradiculoneuropathy
• Vasculitis (polyarteritis nodosa, granulomatosis with • Glucose (fasting) • Serum protein
polyangiitis (also known as Wegener’s granulomatosis), • Erythrocyte sedimentation electrophoresis
rheumatoid arthritis, SLE) rate, C-reactive protein • Vitamin B12, folate
• Paraneoplastic (antibody-mediated) • Full blood count • ANA, ANCA
• Urea and electrolytes • Chest X-ray
Systemic medical conditions
• Liver function tests • HIV testing
• Diabetes • Sarcoidosis
If initial tests are negative
• Renal failure
• Nerve conduction studies • Lyme serology (p. 335)
Malignant disease
• Vitamins E and A • Serum ACE
• Infiltration • Genetic testing (see • Serum amyloid
Others Box 26.99)
• Paraproteinaemias • Critical illness (ACE = angiotensin-converting enzyme; ANCA = antineutrophil cytoplasmic
• Amyloidosis polyneuropathy/myopathy antibody; ANA = antineutrophil antibody)
1223
 NEUROLOGICAL DISEASE
26 26.102 Symptoms and signs in common entrapment neuropathies
Nerve Symptoms
Median (at wrist) Pain and paraesthesia on palmar aspect of
(carpal tunnel hands and fingers, waking the patient from
syndrome) sleep. Pain may extend to arm and shoulder
Ulnar (at elbow) Paraesthesia on medial border of hand,
wasting and weakness of hand muscles
Radial Weakness of extension of wrist and fingers,
often precipitated by sleeping in abnormal
posture, e.g. arm over back of chair
Common peroneal Foot drop, trauma to head of fibula
Lateral cutaneous Tingling and dysaesthesia on lateral border
nerve of the thigh of thigh
(meralgia paraesthetica)
Entrapment neuropathy
Focal compression or entrapment is the usual cause of a
mononeuropathy. Symptoms and signs of entrapment
neuropathy are listed in Box 26.102. Entrapment neu-
ropathies may affect anyone, but diabetes, excess alcohol
or toxins, or genetic syndromes may be predisposing
causes. Unless axonal loss has occurred, entrapment
neuropathies will recover, provided the primary cause
is removed, either by avoiding the precipitation of activ-
ity or by surgical decompression.
Multifocal neuropathy
Multifocal neuropathy (mononeuritis multiplex) is char-
acterised by lesions of multiple nerve roots, peripheral
nerves or cranial nerves (Box 26.103). Vasculitis is a
common cause, either as part of a systemic disease or
isolated to the nerves, or it may arise on a background
of a polyneuropathy (e.g. diabetes). Multifocal motor
neuropathy (MMN) with conduction block is a rare
pure motor neuropathy, typically affecting the arms; it
26.103 Causes of multifocal mononeuropathy
Axonal (defined on nerve conduction studies)
• Vasculitis (systemic or non-systemic)
• Diabetes mellitus
• Sarcoidosis
• Infection (HIV, hepatitis C, Lyme disease, leprosy,
diphtheria)
Focal demyelination with/without conduction block
• Multifocal motor neuropathy
• Multiple compression neuropathies (usually in association
with underlying disease, such as diabetes or alcoholism)
• Multifocal acquired demyelinating sensory and motor
neuropathy (MADSAM)
• Hereditary neuropathy with a predisposition to pressure
palsy (autosomal dominant, peripheral myelin protein
22 gene)
• Lymphoma
1224
Muscle weakness/
muscle-wasting Area of sensory loss
Abductor pollicis brevis Lateral palm and thumb,
index, middle and lateral
half 4th finger
All small hand muscles, Medial palm and little
excluding abductor pollicis finger, and medial half
brevis 4th finger
Wrist and finger extensors, Dorsum of thumb
supinator
Dorsiflexion and eversion of foot Nil or dorsum of foot
Nil Lateral border of thigh
is associated with anti-GM1 antibodies in about 50%,
and responds to intravenous immunoglobulin.
Polyneuropathy
A polyneuropathy is typically associated with a ‘length-
dependent’ pattern, occurring in the longest peripheral
nerves first and affecting the distal lower limbs before
the upper limbs. Sensory symptoms and signs develop
in an ascending ‘glove and stocking’ distribution
(p. 1164). In inflammatory demyelinating neuropathies,
the pathology may be more patchy, affecting the
upper rather than lower limbs.
Guillain–Barré syndrome
Guillain–Barré syndrome (GBS) is a heterogeneous
group of immune-mediated conditions with an inci-
dence of 1–2/100 000/year. In Europe and North
America, the most common variant is an acute inflam-
matory demyelinating polyneuropathy (AIDP). Axonal
variants, either motor (acute motor axonal neuropathy,
AMAN) or sensorimotor (acute motor and sensory
axonal neuropathy, AMSAN), are more common in
China and Japan, and account for 10% of GBS in Western
countries (often associated with Campylobacter jejuni).
The hallmark is an acute paralysis evolving over days or
weeks with loss of tendon reflexes. About two-thirds of
those with AIDP have a prior history of infection, and
an autoimmune response triggered by the preceding
infection causes demyelination. A number of GBS vari-
ants have been described, associated with specific
anti-ganglioside antibodies; the best-recognised is
Miller Fisher syndrome, which involves anti-GQ1b
antibodies.
Clinical features
Distal paraesthesia and pain precede muscle weakness
that ascends rapidly from lower to upper limbs, and
is more marked proximally than distally. Facial and
bulbar weakness commonly develops, and respiratory
weakness requiring ventilatory support occurs in 20% of
cases. Weakness progresses over a maximum of 4 weeks

(usually less). Rapid deterioration to respiratory failure
can develop within hours. Examination shows diffuse
weakness with loss of reflexes. Miller Fisher syndrome
presents with internal and external ophthalmoplegia,
ataxia and areflexia.
Investigations
The CSF protein is raised, but may be normal in the first
10 days. There is usually no increase in CSF white cell
count (> 10 × 106 cells/L suggests an alternative diagno-
sis). Electrophysiological changes may emerge after a
week or so, with conduction block and multifocal motor
slowing, sometimes most evident proximally as delayed
F waves (p. 1152). Antibodies to the ganglioside GM1
are found in about 25%, usually the motor axonal form.
Other causes of an acute neuromuscular paralysis
should be excluded (e.g. poliomyelitis, botulism, diph-
theria, spinal cord syndromes or myasthenia), via the
history and examination rather than investigations.
Management
Supportive measures to prevent pressure sores and deep
venous thrombosis are essential. Regular monitoring of
respiratory function (vital capacity) is needed in the
acute phase, as respiratory failure may develop with
little warning. Active treatment with plasma exchange
or intravenous immunoglobulin therapy shortens the
duration of ventilation and improves prognosis (Box
26.104). Overall, 80% of patients recover completely
within 3–6 months, 4% die and the remainder suffer
residual neurological disability, which can be severe.
Adverse prognostic features include older age, rapid
26.104 Intravenous immunoglobulin and
plasma exchange in Guillain–Barré syndrome
‘In severe Guillain–Barré syndrome (GBS), intravenous
immunoglobulin (IVIg) started within 2 weeks of onset hastens
recovery as much as plasma exchange (PE). Adverse events are
not significantly more frequent with either treatment, but IVIg is
significantly much more likely to be completed than PE.’
‘In mild GBS, 2 sessions of PE are significantly superior to none;
in moderate disease, 4 sessions are significantly superior to 2;
and in severe disease, 6 sessions are not significantly better
than 4. PE is more beneficial when started within 7 days of
disease onset rather than later, but is still beneficial in patients
treated up to 30 days after disease onset.’
• Hughes RAC, et al. Intravenous immunoglobulin for Guillain–Barré syndrome.
Cochrane Database of Systematic Reviews, 2012, issue 7. Art. no.: CD002063.
• Raphaël JC, et al. Plasma exchange for Guillain–Barré syndrome. Cochrane
Database of Systematic Reviews, 2012, issue 7. Art. no.: CD001798.
For further information: www.cochrane.org/cochrane-reviews
26.105 Physical signs in brachial plexus lesions
Site Affected muscles
Upper plexus Biceps, deltoid, spinati, rhomboids, brachioradialis
(Erb–Duchenne) (triceps, serratus anterior)
Lower plexus All small hand muscles, claw hand (ulnar wrist flexors)
(Déjerine–Klumpke)
Thoracic outlet syndrome Small hand muscles, ulnar forearm
Diseases of peripheral nerves
deterioration to ventilation and evidence of axonal loss
on EMG.
Chronic polyneuropathy
The most common axonal and demyelinating causes of
polyneuropathy are shown in Box 26.100. A chronic
symmetrical axonal polyneuropathy, evolving over
months or years, is the most common form of chronic
neuropathy. Diabetes mellitus is the most common
cause but in about 25–50% no cause can be found.
Hereditary neuropathy
Charcot–Marie–Tooth disease (CMT) is an umbrella
term for the inherited neuropathies. This group of syn-
dromes has different clinical and genetic features. The
most common CMT is the autosomal dominantly inher-
ited CMT type 1, usually caused by duplication of the
PMP-22 gene on chromosome 17. Common signs are
distal wasting (‘inverted champagne bottle’ legs), often
with pes cavus, and predominantly motor involvement.
X-linked and recessively inherited forms of CMT,
causing demyelinating or axonal neuropathies, also
occur.
Chronic demyelinating
polyneuropathy 26
The acquired chronic demyelinating neuropathies
include chronic inflammatory demyelinating peripheral
neuropathy (CIDP), multifocal motor neuropathy (see
above) and paraprotein-associated demyelinating neu-
ropathy. CIDP typically presents with relapsing or
progressive motor and sensory changes, evolving over
more than 8 weeks (in distinction to the more acute
GBS). It is important to recognise, as it usually responds
to corticosteroids, plasma exchange or intravenous
immunoglobulin.
Some 10% of patients with acquired demyelinating
polyneuropathy have an abnormal serum paraprotein,
sometimes associated with a lymphoproliferative malig-
nancy. They may also demonstrate positive antibodies to
myelin-associated glycoprotein (anti-MAG antibodies).
Brachial plexopathy
Trauma usually damages either the upper or the lower
parts of the brachial plexus, according to the mechanics
of the injury. The clinical features depend on the ana-
tomical site of the damage (Box 26.105). Lower parts of
the brachial plexus are vulnerable to infiltration from
breast or apical lung tumours (Pancoast tumour, p. 701)
Sensory loss
Patch over deltoid
Ulnar border of hand/forearm
Ulnar border of hand/forearm/upper arm
1225
 NEUROLOGICAL DISEASE
26 or damage by therapeutic irradiation; they may also be
compressed by a cervical rib or fibrous band between C7
and the first rib at the thoracic outlet.
An acute brachial plexopathy of probable inflamma-
tory origin may present with ‘neuralgic amyotrophy’.
Severe shoulder pain precedes the appearance of a
patchy upper brachial plexus lesion, with motor and/or
sensory involvement. There is no specific treatment and
recovery is often incomplete; it may recur in about 25%,
and there is a rare autosomal dominant hereditary form.
The appearance of vesicles should indicate the alterna-
tive diagnosis of motor zoster.
Lumbosacral plexopathy
Lumbosacral plexus lesions may be caused by neoplastic
infiltration or compression by retroperitoneal haemato-
mas. A small-vessel vasculopathy can produce a unilat-
eral or bilateral lumbar plexopathy in association with
type 2 diabetes mellitus (‘diabetic amyotrophy’) or an
idiopathic form in non-diabetic patients. This presents
with painful wasting of the quadriceps with weakness
of knee extension and an absent knee reflex.
Spinal root lesions
Spinal root lesions (radiculopathy) are described above.
Clinical features include muscle weakness and wasting
and dermatomal sensory and reflex loss, which reflect
the pattern of the roots involved. Pain in the muscles
innervated by the affected roots may be prominent.
DISEASES OF THE NEUROMUSCULAR
JUNCTION
Myasthenia gravis
This is the most common cause of acutely evolving, fati-
gable weakness and preferentially affects ocular, facial
and bulbar muscles.
Pathophysiology
Myasthenia gravis is an autoimmune disease, most com-
monly caused by antibodies to acetylcholine receptors
in the post-junctional membrane of the neuromuscular
junction, which are found in around 80% of affected
patients. The resultant blockage of neuromuscular
transmission and complement-mediated inflammatory
response reduces the number of acetylcholine receptors
and damages the end plate (Fig. 26.47). Other antibodies
can produce a similar clinical picture, most notably
autoantibodies to muscle-specific kinase (MuSK), which
is involved in the regulation and maintenance of acetyl-
choline receptors.
About 15% of patients (mainly those with late onset)
have a thymoma, most of the remainder displaying
thymic follicular hyperplasia. Myasthenic patients are at
greater risk of associated organ-specific autoimmune
diseases. As with other autoimmune processes, triggers
are not always evident, but some drugs (e.g. penicilla-
1226 mine) can trigger an antibody-mediated myasthenic
syndrome that may persist after drug withdrawal. Other
drugs, especially aminoglycosides and quinolones, may
exacerbate the neuromuscular blockade and should be
avoided in patients with myasthenia.
Clinical features
Myasthenia gravis usually presents between the ages of
15 and 50 years and there is a female preponderance in
younger patients. In older patients, males are more com-
monly affected. It tends to run a relapsing and remitting
course.
The most evident symptom is fatigable muscle weak-
ness; movement is initially strong but rapidly weakens
as muscle use continues. Worsening of symptoms
towards the end of the day or following exercise is char-
acteristic. There are no sensory signs or signs of involve-
ment of the CNS, although weakness of the oculomotor
muscles may mimic a central eye movement disorder.
The first symptoms are usually intermittent ptosis or
diplopia, but weakness of chewing, swallowing, speak-
ing or limb movement also occurs. Any limb muscle
may be affected, most commonly those of the shoulder
girdle; the patient is unable to undertake tasks above
shoulder level, such as combing the hair, without fre-
quent rests. Respiratory muscles may be involved and
respiratory failure is an avoidable cause of death. Aspi-
ration may occur if the cough is ineffectual. Ventilatory
support is required where weakness is severe or of
abrupt onset.
Investigations
Intravenous injection of the short-acting anticholin-
esterase, edrophonium bromide (the Tensilon® test), is
less widely used than before. Improvement in muscle
function occurs within 30 seconds and usually persists
for 2–3 minutes, but the test is not universally specific
or sensitive. Cover with intravenous atropine is neces-
sary to avoid bradycardia. Planning the assessment
beforehand (e.g. speech or limb movements) allows
some objectivity in gauging the effect.
Repetitive stimulation during nerve conduction
studies may show a characteristic decremental response
(p. 1151) if the muscle has been clinically affected. Anti-
MuSK antibodies are more common in acetylcholine
receptor antibody-negative patients with prominent
bulbar involvement. All patients should have a thoracic
CT to exclude thymoma, especially those without anti-
acetylcholine receptor antibodies. Screening for associ-
ated autoimmune disorders, particularly thyroid disease,
is important.
Management
The goals of treatment are to maximise the activity of
acetylcholine at remaining receptors in the neuromuscu-
lar junctions and to limit or abolish the immunological
attack on motor end plates.
The duration of action of acetylcholine is prolonged
by inhibiting acetylcholinesterase. The most commonly
used anticholinesterase drug is pyridostigmine. Mus-
carinic side-effects, including diarrhoea and colic, may
be controlled by propantheline. Overdosage of anti-
cholinesterase drugs may cause a ‘cholinergic crisis’
due to depolarisation block of motor end plates, with
muscle fasciculation, paralysis, pallor, sweating, exces-
sive salivation and small pupils. This may be
 Diseases of the neuromuscular junction

Motor Lambert–Eaton syndrome

neuron Antibodies to pre-synaptic
calcium channels

Acetylcholinesterase
removes acetylcholine
from neuromuscular Voltage-gated
junction Ca++ calcium channel
Acetylcholine
packets released
by calcium influx

Acetylcholine Acetylcholine
receptor
Myasthenia gravis
Antibodies to
acetylcholine
receptors

In myasthenia
end plate is subject
to cell-mediated
immune assault
(end plate simplified)
Depolarisation Sodium channels
of muscle
membrane
in clefts amplify
potential change 26
Fig. 26.47 Myasthenia gravis and Lambert–Eaton myasthenic syndrome (LEMS). In myasthenia there are antibodies to the acetylcholine
receptors on the post-synaptic membrane, which block conduction across the neuromuscular junction (NMJ). Myasthenic symptoms can be transiently
improved by inhibition of acetylcholinesterase (e.g. with Tensilon® – edrophonium bromide), which normally removes the acetylcholine. A cell-mediated
immune response produces simplification of the post-synaptic membrane, further impairing the ‘safety factor’ of neuromuscular conduction. In LEMS,
antibodies to the pre-synaptic voltage calcium channels impair release of acetylcholine from the motor nerve ending; calcium is required for the
acetylcholine-containing vesicle to fuse with the pre-synaptic membrane for release into the NMJ.

distinguished from severe weakness due to exacerbation

26.106 Immunological treatment of myasthenia
Acute treatments
Intravenous immunoglobulin
• Reduces production of antibodies and rapidly reduces
weakness
Plasma exchange
• Removing antibody from the blood may produce marked
improvement; this is usually brief, so is normally reserved for
myasthenic crisis or for pre-operative preparation
Long-term treatments
Corticosteroid treatment
• Improvement is commonly preceded by marked exacerbation
of myasthenic symptoms, so treatment should be initiated in
hospital
• Usually necessary to continue treatment for months or years,
risking adverse effects
Pharmacological immunosuppression treatment
• Azathioprine 2.5 mg/kg daily reduces the necessary dosage
of steroids and may allow their withdrawal. Effect on clinical
features may be delayed for months
• Mycophenolate: less commonly used
Thymectomy
• Should be considered in any antibody-positive patient under
45 yrs with symptoms not confined to extraocular muscles,
unless the disease has been established for more than 7 yrs
• May be required for thymoma
of myasthenia (‘myasthenic crisis’) by the clinical fea-
tures and, if necessary, by the injection of a small dose
of edrophonium.
The immunological treatment of myasthenia is out-
lined in Box 26.106. Thymectomy may improve overall
prognosis but awaits clinical trial confirmation. Progno-
sis is variable and remissions may occur spontaneously.
When myasthenia is entirely ocular, prognosis is excel-
lent and disability slight. Young female patients with
generalised disease may benefit from thymectomy,
whilst older patients are less likely to have a remission
despite treatment. Rapid progression of the disease
more than 5 years after onset is uncommon.
Other myasthenic syndromes
Other rarer conditions can present with muscle weak-
ness due to impaired transmission across the neuro-
muscular junction. The most common of these is the
Lambert–Eaton myasthenic syndrome (LEMS), which
can occur as an inflammatory or paraneoplastic phe-
nomenon. Antibodies to pre-synaptic voltage-gated
calcium channels (see Fig. 26.47) impair transmitter
release. Patients may have autonomic dysfunction (e.g.
dry mouth) in addition to muscle weakness, but the
cardinal clinical sign is absence of tendon reflexes,
which return after sustained contraction of the relevant 1227
 NEUROLOGICAL DISEASE

26 muscle. The condition is associated with underlying

malignancy in a high percentage of cases and investiga-
tion must be directed towards identifying any neoplasm.
The condition is diagnosed electrophysiologically by the
presence of post-tetanic potentiation of motor response
to nerve stimulation at a frequency of 20–50/s. Treat-
ment is with 3,4-diaminopyridine, or pyridostigmine
and immunosuppression.
Clinical features
The pattern of the clinical features is defined by the
specific syndromes. Onset is often in childhood, although
some patients, especially those with myotonic dystro-
phy, may present as adults. Wasting and weakness are
usually symmetrical, without fasciculation or sensory
loss, and tendon reflexes are usually preserved until a
late stage. Weakness is usually proximal, except in myo-
tonic dystrophy type 1, when it is distal.

DISEASES OF MUSCLE Investigations

Muscle disease, either hereditary or acquired, is rare.
Most typically, it presents with a proximal symmetrical
weakness. Diagnosis is dependent on recognition of
clinical clues, such as cardiorespiratory involvement,
evolution, family history, exposure to drugs, the pres-
ence of contractures, myotonia and other systemic fea-
tures, and on investigation findings, most importantly
EMG and muscle biopsy. Hereditary syndromes include
the muscular dystrophies, muscle channelopathies, met-
abolic myopathies (including mitochondrial diseases)
and congenital myopathies.
Muscular dystrophies
These are inherited disorders with progressive muscle
destruction, and may be associated with cardiac and/or
respiratory involvement and sometimes non-myopathic
features (Box 26.107). Myotonic dystrophy is the most
common, with a prevalence of about 12/100 000.
The diagnosis can be confirmed by specific molecular
genetic testing, supplemented with EMG and muscle
biopsy if necessary. Creatine kinase is markedly ele-
vated in the dystrophinopathies (Duchenne and Becker)
but is normal or moderately elevated in the other dys-
trophies. Screening for an associated cardiac abnormal-
ity (cardiomyopathy or dysrhythmia) is important.
Management
There is no specific therapy for most of these conditions
but physiotherapy and occupational therapy help
patients cope with their disability. Steroids are used
in Duchenne muscular dystrophy. Treatment of associ-
ated cardiac failure or arrhythmia (with pacemaker
insertion if necessary) may be required; similarly, man-
agement of respiratory complications (including noc-
turnal hypoventilation) can improve quality of life.
Improvements in non-invasive ventilation have led to
significant improvements in survival for patients with

26.107 The muscular dystrophies

Type Genetics Age of onset Muscles affected Other features
Myotonic dystrophy Autosomal dominant; Any Face (including ptosis), Myotonia, cognitive
(DM1) expanded triplet repeat sternomastoids, distal impairment, cardiac conduction
chromosome 19q limb, generalised later abnormalities, lens opacities,
frontal balding, hypogonadism
Proximal myotonic Autosomal dominant; 8–50 Proximal, especially thigh, As for DM1 but cognition not
myopathy (PROMM; quadruplet repeat sometimes muscle affected
DM2) expansion in Zn finger hypertrophy Muscle pain
protein 9 gene
chromosome 3q
Duchenne X-linked; deletions in < 5 yrs Proximal and limb girdle Cardiomyopathy and respiratory
dystrophin gene Xp21 failure
Becker X-linked; deletions in Childhood/ Proximal and limb girdle Cardiomyopathy, respiratory
dystrophin gene Xp21 early adult failure uncommon
Limb girdle Many mutations on Childhood/ Limb girdle Very variable depending on
different chromosomes early adult genetic subtype, some involve
cardiac and respiratory
systems
Facioscapulohumeral Autosomal dominant; 7–30 yrs Face and upper limb Pain in shoulder girdle
(FSH) tandem repeat deletion girdle, distal lower limb common, deafness
chromosome 4q35 weakness Cardiorespiratory involvement
rare
Oculopharyngeal Autosomal dominant and 30–60 yrs Ptosis, external Mild lower limb weakness
recessive; triplet repeat ophthalmoplegia,
expansion in PABP2 gene dysphagia, tongue
chromosome 14q weakness
Emery–Dreifuss X-linked recessive; 4–5 yrs Humero-peroneal, proximal Contractures develop early
mutations in emerin gene limb girdle later Cardiac involvement leads to
sudden death
1228

Duchenne muscular dystrophy. Genetic counselling is
important.
Inherited metabolic myopathies
There are a large number of rare inherited disorders that
interfere with the biochemical pathways that maintain
the energy supply (adenosine triphosphate, ATP) to
muscles. These are mostly recessively inherited deficien-
cies in the enzymes necessary for glycogen or fatty acid
(β-oxidation) metabolism (Box 26.108). They typically
present with muscle weakness and pain.
Mitochondrial disorders
Mitochondrial diseases are discussed on page 65. Mito-
chondria are present in all tissues and dysfunction
causes widespread effects, on vision (optic atrophy,
retinitis pigmentosa, cataracts), hearing (sensorineural
deafness), and the endocrine, cardiovascular, gastro-
intestinal and renal systems. Any combination of these
should raise the suspicion of a mitochondrial disorder,
especially if there is evidence of maternal transmission.
Mitochondrial dysfunction can be caused by altera-
tions in either mitochondrial DNA or genes encoding for
oxidative processes. Genetic abnormalities or mutations
in mitochondrial DNA may affect single individuals and
single tissues (most commonly muscle). Thus, patients
26.108 Inherited disorders of muscle metabolism
Disease
Carbohydrate Myophosphorylase deficiency
(glycogen) metabolism (McArdle’s disease):
autosomal recessive
Acid maltase deficiency
(Pompe’s disease): autosomal
recessive
Lipid metabolism Carnitine-palmitoyl
(β-oxidation) transferase (CPT) deficiency
26.109 Mitochondrial syndromes
Syndrome
Myoclonic epilepsy with ragged red fibres (MERRF)
Mitochondrial myopathy, encephalopathy, lactic acidosis
and stroke-like episodes (MELAS)
Chronic progressive external ophthalmoplegia (CPEO)
Kearns–Sayre syndrome
Mitochondrial neurogastrointestinal encephalomyopathy
(MNGIE)
Neuropathy, ataxia and retinitis pigmentosa (NARP)
Diseases of muscle
with exercise intolerance, myalgia and sometimes recur-
rent myoglobinuria may have isolated pathogenic muta-
tions in genes encoding for oxidation pathways.
Inherited disorders of the oxidative pathways of the
respiratory chain in mitochondria cause a group of dis-
orders, either restricted to the muscle or associated with
non-myopathic features (Box 26.109). Many of these
mitochondrial disorders are inherited via the mitochon-
drial genome, down the maternal line (p. 53). Diagnosis
is based on clinical appearances, supported by muscle
biopsy appearance (usually with ‘ragged red’ and/or
cytochrome oxidase negative fibres), and specific muta-
tions either on blood or, more reliably, muscle testing.
Mutations may be due either to point mutations or to
deletions of mitochondrial DNA.
A disorder called Leber hereditary optic neuropathy
(LHON) is characterised by acute or subacute loss of
vision, most frequently in males, due to bilateral optic
atrophy. Three point mutations account for more than
90% of LHON cases.
Channelopathies
Inherited abnormalities of the sodium, calcium and chlo-
ride ion channels in striated muscle produce various
syndromes of familial periodic paralysis, myotonia and
malignant hyperthermia, which may be recognised by
26
Clinical features Diagnosis
Exercise-induced myalgia, Creatine kinase (CK) elevated
stiffness, weakness (with ‘second Muscle biopsy
wind’ phenomenon), myoglobinuria Enzyme assay
Infantile form: death within 2 yrs CK elevated
Childhood: death in 20–30s Blood lymphocyte analysis for
Adult: progressive proximal glycogen granules
myopathy with respiratory failure Muscle biopsy
Enzyme assay
Myalgia after exercise, CK normal between attacks
myoglobinuria, weakness Urinary organic acids
Enzyme assays
Muscle biopsy
Clinical features
Myoclonic epilepsy, cerebellar ataxia, dementia, sensorineural
deafness ± peripheral neuropathy, optic atrophy and multiple lipomas
Episodic encephalopathy, stroke-like episodes often preceded by
migraine-like headache, nausea and vomiting
Progressive ptosis and external oculomotor palsy, proximal myopathy
± deafness, ataxia and cardiac conduction defects
Like CPEO but early age of onset (< 20 yrs), heart block, pigmentary
retinopathy
Progressive ptosis, external oculomotor palsy, gastrointestinal
dysmotility (often pseudo-obstruction), diffuse leucoencephalopathy,
thin body habitus, peripheral neuropathy and myopathy
Weakness, ataxia and progressive loss of vision, along with dementia,
seizures and proximal weakness
1229
 NEUROLOGICAL DISEASE

26 26.110 Muscle channelopathies

Channel Muscle disease Gene and inheritance Clinical features
Sodium Paramyotonia congenita SCN4A (17q35) Cold-evoked myotonia with episodic weakness
Autosomal dominant provoked by exercise and cold
Potassium-aggravated SCN4A Pure myotonia without weakness provoked by
myotonia potassium
Hyperkalaemic periodic SCN4A Brief (mins to hrs), frequent episodes of weakness
paralysis Autosomal dominant provoked by rest, cold, potassium, fasting, pregnancy,
stress
Less common than hypokalaemic periodic paralysis
Hypokalaemic periodic SCN4A Longer (hrs to days) episodic weakness triggered by
paralysis Autosomal dominant rest, carbohydrate loading, cold
(one-third new mutations)
Chloride Myotonia congenita
Thomsen’s disease CLCN1 Myotonia usually mild, little weakness
Autosomal dominant
Becker’s disease CLCN1 Myotonia often severe, transient weakness
Autosomal recessive
Calcium Hypokalaemic periodic CACNA1S Episodic weakness triggered by carbohydrate meal
paralysis Autosomal dominant
Malignant hyperthermia CACNA1S, CACNL2A Hyperpyrexia due to excess muscle activity, precipitated
Autosomal dominant by drugs, usually anaesthetic agents; most common
cause of death during general anaesthetic
Potassium Andersen–Tawil syndrome KCNJ2 Similar to hypokalaemic periodic paralysis, associated
Autosomal dominant with cardiac and non-myopathic features (skeletal and
facial)
Ryanodine Malignant hyperthermia RYR1 (19q13) As malignant hyperthermia above
receptor Central core and multicore RYR1 Present in infancy with mild progressive weakness
disease Mostly autosomal dominant

their clinical characteristics and potassium abnormali-

26.111 Causes of acquired proximal myopathy ties (Box 26.110). Genetic testing is available.
Inflammatory (p. 1114) Acquired myopathies
• Polymyositis • Inclusion body myositis These include the inflammatory myopathies, or myopa-
• Dermatomyositis (additional distal effects) thy associated with a range of metabolic and endocrine
Endocrine and metabolic disorders, or drug and toxin exposure (Box 26.111).
• Hypothyroidism • Osteomalacia
• Hyperthyroidism • Hypokalaemia (liquorice,
•
•
Acromegaly
Cushing’s syndrome
diuretic and purgative
abuse)
Further information
(including iatrogenic) • Hypercalcaemia
• Addison’s disease (disseminated bony Websites
• Conn’s syndrome metastases) www.aneuroa.org/ American Neurological Association.
Toxic www.dizziness-and-balance.com/disorders/bppv/
bppv.html and www.brainandspine.org.uk/about_us/
• Alcohol (chronic and acute • Vitamin E index.html Diagnosing benign paroxysmal positional
syndromes) • Organophosphates vertigo.
• Amphetamines/cocaine/ • Snake venoms
www.ihs-classification.org/en/ International Headache
heroin
Society; full access to 2nd edition of International Classification
Drugs of Headache Disorders.
• Corticosteroids • Chloroquine www.ninds.nih.gov National Institute of Neurological
• Statins • Ciclosporin Disorders and Stroke.
• Amiodarone • Vincristine www.sign.ac.uk Relevant SIGN guidelines – all available for
• Beta-blockers • Clofibrate free download:
• Opiates • Zidovudine SIGN 70 Diagnosis and management of epilepsy in adults
Paraneoplastic SIGN 107 Diagnosis and management of headache
SIGN 113 Diagnosis and management of Parkinson’s
• Carcinomatous • Dermatomyositis
disease.
neuromyopathy
1230 www.wfneurology.org World Federation of Neurology.
 P. Langhorne

27
Stroke disease

Clinical examination in stroke disease 1232 Stroke 1237

Functional anatomy and physiology 1234 Pathophysiology 1237
Clinical features 1239
Investigations 1235 Investigations 1240
Presenting problems 1236 Management 1242
Weakness 1236 Subarachnoid haemorrhage 1246
Speech disturbance 1236 Clinical features 1246
Visual deficit 1237 Investigations 1246
Visuo-spatial dysfunction 1237 Management 1246
Ataxia 1237
Cerebral venous disease 1247
Headache 1237
Seizure 1237 Clinical features 1247
Coma 1237 Investigations and management 1247

1231
 STROKE DISEASE

CLINICAL EXAMINATION IN STROKE DISEASE

Cranial nerve function 5

Neck stiffness/pain 6 Motor system
Visual fields Muscle bulk
Nerve palsy, e.g. 3rd, 6th, Abnormal posture or movements
7th or 12th Tone
Strength, including pronator drift
Co-ordination
Tendon reflexes
Plantar reflexes

Higher cerebral function 4

Speech and language
Attention and neglect
Abbreviated mental test

Blood pressure 3 Left pronator drift

Pulse 2
Rate and rhythm 7 Sensory system
Touch sensation
Cortical sensory function: sensory
inattention or neglect
Joint position sense

8 Gait
General appearance 1 Able to weight-bear?
Conscious level Ataxic
Posture: leaning to one side? Hemiparetic gait pattern
Facial symmetry

Left facial (7th nerve) palsy Hemiparetic posture

1232
 Clinical examination in stroke disease

General examination Rapid assessment of suspected stroke

Skin Rosier scale
• Xanthelasma Can be used by emergency staff to indicate probability of a stroke in acute presentations:
• Rash (arteritis, splinter haemorrhages)
• Colour change (limb ischaemia, deep Unilateral facial weakness +1 Loss of consciousness −1
vein thrombosis) Unilateral grip weakness +1 Seizure −1
• Pressure injury Unilateral arm weakness +1
Eyes Unilateral leg weakness +1
• Arcus senilis Speech loss +1
• Diabetic retinopathy Visual field defect +1
• Hypertensive retinopathy Total (−2 to +6); score of > 0 indicates stroke is possible cause
• Retinal emboli
Exclude hypoglycaemia
Cardiovascular system
• Bedside blood glucose testing with BMstix
• Heart rhythm (?atrial fibrillation)
Language deficit
• Blood pressure (high or low)
• Carotid bruit • The history and examination may indicate a language deficit
• Jugular venous pulse (raised if • Check comprehension (‘lift your arms, close your eyes’) to identify a receptive
heart failure, low in dysphasia
hypovolaemia) • Ask patient to name people/objects (e.g. nurse, watch, pen) to identify a nominal
• Murmurs (source of embolism) dysphasia
• Peripheral pulses and bruits • Check articulation (ask patient to repeat phrases after you) for dysarthria
(?generalised arteriopathy) Motor deficit
Respiratory system Subtle pyramidal signs
• Signs of pulmonary oedema or • Check for pronator drift: ask patient to hold out arms and maintain their position with
infection eyes closed (see opposite)
• Oxygen saturation • Check for clumsiness of fine finger movements
Abdomen Sensory and visual inattention
• Palpable bladder (urinary • Establish that sensation/visual field is intact on testing one side at a time
retention) • Retest sensation/visual fields on simultaneous testing of both sides; the affected side
Locomotor will no longer be felt/seen
• Perform clock drawing test (see below)
• Injuries sustained during collapse
• Comorbidities that influence recovery Truncal ataxia
e.g. osteoarthritis • Check if patient can sit up or stand without support

Clock drawing test A Image drawn by doctor.

A B B Image drawn by patient with left-sided neglect.

1233
 STROKE DISEASE

27 Cerebrovascular disease is the third most common cause

of death in high-income countries after cancers and
management are distinct from those of stroke. Vascular
dementia is described in Chapters 10 and 26.
ischaemic heart disease, and the most common cause of
severe physical disability. It includes a range of dis-
orders of the central nervous system (Fig. 27.1). Stroke
is the most common clinical manifestation of cere- FUNCTIONAL ANATOMY
brovascular disease, and results in episodes of brain AND PHYSIOLOGY
dysfunction due to focal ischaemia or haemorrhage.
Subarachnoid haemorrhage (SAH) and cerebral venous The main arterial supply of the brain comes from the
thrombosis (CVT) will be discussed separately, since internal carotid arteries, which supply the anterior brain,
their pathophysiology, clinical manifestations and and the vertebral and basilar arteries (vertebrobasilar

Stroke
(acute, focal brain dysfunction due to vascular disease)

Vascular system Arterial Venous

(>99%) (<1%)

Pathology Infarct Haemorrhage Infarct

(85%) (15%) (often develops
secondary
haemorrhage)

Site of lesion Anterior (carotid) circulation Posterior Brain Subarachnoid Venous

(65%) (vertebrobasilar parenchyma space system
circulation) (10%) (5%)
(20%)

Clinical Total anterior Partial anterior Lacunar stroke Posterior Intracerebral Subarachnoid Central venous
classification circulation circulation (LACS) circulation haemorrhage haemorrhage thrombosis
stroke (TACS) stroke (PACS) (20%) stroke (POCS) (10%) (5%) (<1%)
(15%) (30%) (20%)

Common • Embolism • Thrombosis • Thrombosis • Vascular • Aneurysm • Thrombosis

pathophysiology (cardiac, major vessels) in situ • Embolism degeneration • Arteriovenous in situ
• Thrombosis in situ (cardiac) • Aneurysm malformation
• Arteriovenous • Vascular
malformation degeneration

Fig. 27.1 A classification of stroke disease.

Anterior
communicating Anterior cerebral
artery (ACoA) artery (ACA)
Small perforating Middle cerebral
vessels artery (MCA) Anterior (carotid)
circulation
Posterior
(vertebrobasilar)
circulation PCA

Internal carotid Posterior

arteries (ICA) communicating MCA ACA
artery (PCoA)
Basilar artery (BA)
Posterior cerebral BA PCoA
artery (PCA)

Vertebral B
A arteries (VA) VA ICA
1234 Fig. 27.2 Arterial circulation of the brain. A Horizontal view. B Lateral view.

system), which provide the posterior circulation. The
anterior and middle cerebral arteries supply the frontal
and parietal lobes, while the posterior cerebral artery
supplies the occipital lobe. The vertebral and basilar
arteries perfuse the brain stem, mid-brain and cerebel-
lum (Fig. 27.2). The functions of each of these areas of
the brain are described on page 1141. Communicating
arteries provide connections between the anterior and
posterior circulations and between left and right hemi-
spheres, creating protective anastomotic connections
that form the circle of Willis. In health, regulatory mech-
anisms maintain a constant cerebral blood flow across a
wide range of arterial blood pressures to meet the high
resting metabolic activity of brain tissue; cerebral blood
vessels dilate when systemic blood pressure is lowered
and constrict when it is raised. This autoregulatory
mechanism can be disrupted after stroke. The venous
collecting system is formed by a collection of sinuses
over the surface of the brain, which drain into the jugular
veins (Fig. 27.3).
Superior sagittal sinus
Posterior
Cavernous
sinus
Transverse sinus Jugular vein
Fig. 27.3 Venous circulation of the brain.
A B
Fig. 27.4 Acute stroke seen on CT scan with corresponding MRI appearance. A CT may show no evidence of early infarction.
B Corresponding image seen on MRI diffusion weighted imaging (DWI) with changes of infarction in middle cerebral artery (MCA) territory (arrows).
Investigations
INVESTIGATIONS
A range of investigations may be required to answer
specific questions about brain structure and function
and about the function of the vascular system.
Neuroimaging
Computed tomography (CT) scanning is the mainstay of
stroke imaging. It allows the rapid identification of
intracerebral bleeding and stroke ‘mimics’ (i.e. patholo-
gies other than stroke that have similar presentations),
such as tumours. Magnetic resonance imaging (MRI) is
used when there is diagnostic uncertainty or delayed
presentation, and when more information on brain
structure and function is required (Fig. 27.4). Contra-
indications to MRI include cardiac pacemakers and
claustrophobia on entering the scanner. These tech-
niques are described on page 1149.
Vascular imaging
Various techniques are used to obtain images of extra-
cranial and intracranial blood vessels (Fig. 27.5). The
least invasive is ultrasound (Doppler or duplex scan-
Anterior ning), which is used to image the carotid and the verte-
bral arteries in the neck. In skilled hands, reliable
information can be provided about the degree of arterial
stenosis and the presence of ulcerated plaques. Blood
27
flow in the intracerebral vessels can be examined using
transcranial Doppler. While the anatomical resolution is
limited, it is improving and many centres no longer
require formal angiography before proceeding to carotid
endarterectomy (see below). Blood flow can also be
detected by specialised sequences in MR angiography
(MRA) but the anatomical resolution is still not compa-
rable to that of intra-arterial angiography, which out-
lines blood vessels by the injection of radio-opaque
contrast intravenously or intra-arterially. The X-ray
images obtained can be enhanced by the use of computer-
assisted digital subtraction or spiral CT. Because of
the significant risk of complications, intra-arterial con-
trast angiography is reserved for patients in whom
1235
 STROKE DISEASE

27 A B

C D

Fig. 27.5 Different techniques of imaging blood vessels. A Doppler scan showing 80% stenosis of the internal carotid artery (arrow).
B Three-dimensional reconstruction of CT angiogram showing stenosis at the carotid bifurcation (arrow). C MR angiogram showing giant aneurysm at
the middle cerebral artery bifurcation (arrow). D Intra-arterial angiography showing arteriovenous malformation (arrow).

non-invasive methods have provided a contradictory

picture or incomplete information, or in whom it is nec-
essary to image the intracranial circulation in detail: for
example, to delineate a saccular aneurysm, an arterio-
venous malformation or vasculitis.
Blood tests
These help identify underlying causes of cerebrovascu-
lar disease: for example, blood glucose (diabetes melli-
tus), triglycerides and cholesterol (hyperlipidaemia) or
full blood count (polycythaemia) in stroke. Erythrocyte
sedimentation rate (ESR) and immunological tests, such
as measurement of antineutrophil cytoplasmic antibod-
ies (ANCA) (p. 1068), may be required when vascu-
litis is suspected. Genetic testing for rarer inherited
conditions, such as CADASIL (cerebral autosomal domi-
nant arteriopathy with subcortical infarcts and leuco-
encephalopathy), may be indicated.
PRESENTING PROBLEMS
Most vascular lesions develop suddenly within a matter
of minutes or hours, and so should be considered in the
differential diagnosis of patients with any acute neuro-
logical presentation.
Weakness
Unilateral weakness is the classical presentation of
stroke and, much more rarely, of cerebral venous throm-
bosis. The weakness is sudden, progresses rapidly and
follows a hemiplegic pattern (see Fig. 26.18, p. 1163).
There is rarely any associated abnormal movement.
Reflexes are initially reduced but then become increased
with a spastic pattern of increased tone (see Box 26.20,
p. 1162). Upper motor neuron weakness of the face (7th
cranial nerve) is often present.

Lumbar puncture
Lumbar puncture (p. 1153) is largely reserved for the Speech disturbance
investigation of SAH.
Dysphasia and dysarthria are the most common presen-
tations of disturbed speech in stroke (p. 1168). Dyspha-
Cardiovascular investigations sia indicates damage to the dominant frontal or parietal
Electrocardiography (ECG; p. 532) and echocardiogra- lobe (see Box 26.2, p. 1142), while dysarthria is a non-
phy (p. 537) may reveal abnormalities that may cause localising feature reflecting weakness or incoordination
cardiac embolism in stroke. of the face, pharynx, lips, tongue or palate.
1236

Visual deficit
Visual loss in stroke can be due to unilateral optic
ischaemia (called amaurosis fugax if transient), caused
by disturbance of blood flow in the internal carotid
artery and ophthalmic artery, which leads to monocular
blindness. Ischaemic damage to the occipital cortex or
post-chiasmic nerve tracts results in a contralateral
hemianopia (p. 1169).
Visuo-spatial dysfunction
Damage to the non-dominant cortex often results in con-
tralateral visuo-spatial dysfunction, such as sensory or
visual neglect and apraxia (inability to perform complex
tasks despite normal motor, sensory and cerebellar func-
tion; p. 1167). This is sometimes misdiagnosed as acute
confusion.
Ataxia
Stroke causing damage to the cerebellum and its connec-
tions can present as an acute ataxia (p. 1168) and there
may be associated brainstem features such as diplopia
(p. 1170) and vertigo (p. 1167). The differential diagnosis
includes vestibular disorders (p. 1186).
Headache
Sudden severe headache is the cardinal symptom of
SAH but also occurs in intracerebral haemorrhage.
Although some degree of headache is common in acute
ischaemic stroke, it is rarely a dominant feature (p. 1156).
Headache also occurs in cerebral venous disease.
Seizure
Seizure is unusual in acute stroke but may be general-
ised or focal in cerebral venous disease.
Coma
Coma is an uncommon feature of stroke, though it may
occur with a brainstem event. If it is present in the first
24 hours, it usually indicates a subarachnoid or intra-
cerebral haemorrhage (see Box 26.16, p. 1160).
STROKE
Stroke is a common medical emergency. The incidence
rises steeply with age, and in many lower- and middle-
income countries it is rising in association with less
healthy lifestyles. About one-fifth of patients with an
acute stroke die within a month of the event and at least
half of those who survive are left with physical
disability.
Stroke
Pathophysiology
Of the 180–300 patients per 100 000 population present-
ing annually with a stroke, 85% sustain a cerebral infarc-
tion due to inadequate blood flow to part of the brain,
and most of the remainder have an intracerebral haem-
orrhage (see Fig. 27.1).
Cerebral infarction
Cerebral infarction is mostly caused by thromboembolic
disease secondary to atherosclerosis in the major extra-
cranial arteries (carotid artery and aortic arch). About
20% of infarctions are due to embolism from the heart,
and a further 20% are due to thrombosis in situ caused
by intrinsic disease of small perforating vessels (lenti-
culostriate arteries), producing so-called lacunar infarc-
tions. The risk factors for ischaemic stroke reflect the risk
factors for the underlying vascular disease (Box 27.1).
About 5% are due to rare causes, including vasculitis
(p. 1115), endocarditis (p. 625) and cerebral venous
disease (see below). Cerebral infarction takes some
hours to complete, even though the patient’s deficit may
be maximal shortly after the vascular occlusion. After
the occlusion of a cerebral artery, infarction may be fore-
stalled by the opening of anastomotic channels from
other arterial territories that restore perfusion to its ter-
ritory. Similarly, reduction in perfusion pressure leads
to compensatory homeostatic changes to maintain tissue
27
oxygenation (Fig. 27.6). These compensatory changes
can sometimes prevent occlusion of even a carotid artery
from having any clinically apparent effect.
However, if and when these homeostatic mecha-
nisms fail, the process of ischaemia starts, and ultimately
leads to infarction unless the vascular supply is restored.
As the cerebral blood flow declines, different neuronal
functions fail at various thresholds (Fig. 27.7). Once
blood flow falls below the threshold for the maintenance
of electrical activity, neurological deficit develops. At
this level of blood flow, the neurons are still viable; if
27.1 Risk factors for stroke
Fixed risk factors
• Age
• Gender (male > female except at extremes of age)
• Race (Afro-Caribbean > Asian > European)
• Previous vascular event
Myocardial infarction
Stroke
Peripheral vascular disease
• Heredity
• High fibrinogen
Modifiable risk factors
• Blood pressure • Diabetes mellitus
• Cigarette smoking • Excessive alcohol intake
• Hyperlipidaemia • Oestrogen-containing drugs
• Heart disease Oral contraceptive pill
Atrial fibrillation Hormone replacement
Congestive cardiac therapy
failure • Polycythaemia
Infective endocarditis
1237
 STROKE DISEASE

27 Symptoms Infarction Cerebral blood flow

mL/100 g/min
50
Perfusion
pressure

n 40
Cerebral tatio
odila
blood Vas A
Increased oxygen
volume extraction

30
Blood
flow

20
Cerebral
oxygen Failure of
extraction B electrical function
Symptoms
Cerebral 10
oxygen Failure of ionic pumps
metabolism C
Potassium efflux
Sodium influx
Time (mins/hrs)
Cell death
0
Fig. 27.6 Homeostatic responses to falling perfusion pressure in
the brain following arterial occlusion. Vasodilatation initially maintains Fig. 27.7 Thresholds of cerebral ischaemia. Symptoms of cerebral
cerebral blood flow (A), but after maximal vasodilatation further falls in ischaemia appear when the blood flow has fallen to less than half of
perfusion pressure lead to a decline in blood flow. An increase in tissue normal and energy supply is insufficient to sustain neuronal electrical
oxygen extraction, however, maintains the cerebral metabolic rate for function. Full recovery can occur if this level of flow is returned to normal
oxygen (B). Still further falls in perfusion, and therefore blood flow, cannot but not if it is sustained. Further blood flow reduction below the next
be compensated; cerebral oxygen availability falls and symptoms appear, threshold causes failure of cell ionic pumps and starts the ischaemic
then infarction (C). cascade, leading to cell death.

↓Oxygen
+glucose Thromboxane
Anaerobic Prostaglandins
metabolism
1
Free fatty
H+ ↓ATP Free acids
5 radicals

Ca2+
Fig. 27.8 The process of neuronal
ischaemia and infarction. (1) Reduction of
Glia Fe + H H+ 4 Oedema blood flow reduces supply of oxygen and hence
6
Lipid peroxidases Water ATP. H+ is produced by anaerobic metabolism of
K+ Proteases Na+
NO synthase available glucose. (2) Energy-dependent
Na+/K+ ATPase↓
membrane ionic pumps fail, leading to cytotoxic
2
oedema and membrane depolarisation, allowing
Depolarisation calcium entry and releasing glutamate.
Na+ 3 Ca2+
AMPA NMDA (3) Calcium enters cells via glutamate-gated
↓Glutamate channels and (4) activates destructive
uptake by glia
intracellular enzymes (5), destroying intracellular
organelles and cell membrane, with release of
Glutamate free radicals. Free fatty acid release activates
2
pro-coagulant pathways that exacerbate local
ischaemia. (6) Glial cells take up H+, can no
Ca2+ longer take up extracellular glutamate and also
suffer cell death, leading to liquefactive necrosis
of whole arterial territory.

the blood flow increases again, function returns and the
patient will have had a transient ischaemic attack (TIA).
However, if the blood flow falls further, a level is reached
at which irreversible cell death starts. Hypoxia leads
to an inadequate supply of adenosine triphosphate
(ATP), which leads to failure of membrane pumps,
1238 thereby allowing influx of sodium and water into the cell
(cytotoxic oedema) and the release of the excitatory
neurotransmitter glutamate into the extracellular fluid.
Glutamate opens membrane channels, allowing the
influx of calcium and more sodium into the neurons.
Calcium entering the neurons activates intracellular
enzymes that complete the destructive process. The
release of inflammatory mediators by microglia and
 Stroke

astrocytes causes death of all cell types in the area of 27.2 Causes of intracerebral haemorrhage and
maximum ischaemia. The infarction process is worsened associated risk factors
by the anaerobic production of lactic acid (Fig. 27.8) and
Disease Risk factors
consequent fall in tissue pH. There have been attempts
to develop neuroprotective drugs to slow down the Complex small-vessel Age
processes leading to irreversible cell death but so far disease with disruption of Hypertension
these have proved disappointing. vessel wall High cholesterol
The final outcome of the occlusion of a cerebral blood Amyloid angiopathy Familial (rare)
vessel therefore depends upon the competence of the Age
circulatory homeostatic mechanisms, the metabolic Impaired blood clotting Anticoagulant therapy
demand, and the severity and duration of the reduction Blood dyscrasia
in blood flow. Higher brain temperature, as occurs in Thrombolytic therapy
fever, and higher blood sugar have both been associated
Vascular anomaly Arteriovenous malformation
with a greater volume of infarction for a given reduction
Cavernous haemangioma
in cerebral blood flow. Subsequent restoration of blood
flow may cause haemorrhage into the infarcted area Substance misuse Alcohol
(‘haemorrhagic transformation’). This is particularly Amphetamines
likely in patients given antithrombotic or thrombolytic Cocaine
drugs, and in patients with larger infarcts.
Radiologically, a cerebral infarct can be seen as a
lesion that comprises a mixture of dead brain tissue white-matter fibre tracts are split apart. The haemor-
that is already undergoing autolysis, and tissue that is rhage itself may expand over the first minutes or hours,
ischaemic and swollen but recoverable (the ‘ischaemic or it may be associated with a rim of cerebral oedema,
penumbra’). The infarct swells with time and is at its which, along with the haematoma, acts like a mass lesion
maximal size a couple of days after stroke onset. At this to cause progression of the neurological deficit. If big
stage, it may be big enough to exert mass effect both enough, this can cause shift of the intracranial contents,
clinically and radiologically; sometimes, decompressive producing transtentorial coning and sometimes rapid
craniectomy is required (see below). After a few weeks,
the oedema subsides and the infarcted area is replaced
death (p. 1212). If the patient survives, the haematoma
is gradually absorbed, leaving a haemosiderin-lined slit 27
by a sharply defined fluid-filled cavity. in the brain parenchyma.

Intracerebral haemorrhage
Intracerebral haemorrhage causes about 10% of acute
stroke events but is more common in low-income
countries. It usually results from rupture of a blood
vessel within the brain parenchyma but may also occur
in a patient with an SAH (see below) if the artery rup-
tures into the brain substance as well as into the
subarachnoid space. Haemorrhage frequently occurs
into an area of brain infarction and, if the volume of
haemorrhage is large, it may be difficult to distinguish
from primary intracerebral haemorrhage both clinically
and radiologically (Fig. 27.9). The risk factors and under-
lying causes of intracerebral haemorrhage are listed in
Box 27.2. The explosive entry of blood into the brain
parenchyma causes immediate cessation of function in
that area as neurons are structurally disrupted and
Clinical features
Acute stroke and TIA are characterised by a rapid-onset,
focal deficit of brain function. The typical presentation
occurs over minutes, affects an identifiable area of the
brain and is ‘negative’ in character (i.e. abrupt loss of
function without positive features such as abnormal
movement). Provided that there is a clear history of this,
the chance of a brain lesion being anything other than
vascular is 5% or less (Box 27.3). If symptoms progress
over hours or days, other diagnoses must be excluded.
Confusion and memory or balance disturbance are
more often due to stroke mimics. Transient symptoms,
such as syncope, amnesia, confusion and dizziness,
do not reflect focal cerebral dysfunction, but are often

A B

Fig. 27.9 CT scans showing

intracerebral haemorrhage. A Basal
ganglia haemorrhage with intraventricular
extension. B Small cortical haemorrhage. 1239
 STROKE DISEASE

27 27.3 Differential diagnosis of stroke and TIA

Several terms have been used to classify strokes, often
based on the duration and evolution of symptoms.
• Transient ischaemic attack (TIA) describes a stroke in
‘Structural’ stroke mimics
which symptoms resolve within 24 hours – an
• Primary cerebral tumours • Cerebral abscess arbitrary cutoff that has little value in practice, apart
• Metastatic cerebral • Peripheral nerve lesions from perhaps indicating that underlying cerebral
tumours (vascular or compressive) haemorrhage or extensive cerebral infarction is
• Subdural haematoma • Demyelination
extremely unlikely. The term TIA traditionally also
‘Functional’ stroke mimics includes patients with amaurosis fugax, usually due
• Todd’s paresis (after • Focal seizures to a vascular occlusion in the retina.
epileptic seizure) • Ménière’s disease or other • Stroke describes those events in which symptoms
• Hypoglycaemia vestibular disorder last more than 24 hours. The differential diagnosis
• Migrainous aura (with or • Conversion disorder (p. 246) of patients with symptoms lasting a few minutes or
without headache) • Encephalitis hours is similar to those with persisting symptoms
(see Box 27.3).
• Progressing stroke (or stroke in evolution) describes a
stroke in which the focal neurological deficit
worsens after the patient first presents. Such
27.4 Characteristic features of stroke and
worsening may be due to increasing volume of
non-stroke syndromes (‘stroke mimics’)
infarction, haemorrhagic transformation or
Feature Stroke Stroke mimics increasing cerebral oedema.
Symptom onset Sudden (minutes) Often slower onset • Completed stroke describes a stroke in which the focal
Symptom Rapidly reaches Often gradual onset deficit persists and is not progressing.
progression maximum severity When assessing a patient within hours of symptom
Severity of Unequivocal May be variable/ onset, it is not possible to distinguish stroke from TIA
deficit uncertain unless symptoms have already resolved. In clinical prac-
tice, it is important to distinguish those patients with
Pattern of Hemispheric May be non-specific
strokes who have persisting focal neurological symptoms
deficit pattern with confusion,
when seen from those whose symptoms have resolved.
memory loss,
balance disturbance
Loss of Uncommon More common Investigations
consciousness
Investigation of acute stroke aims to confirm the vascu-
lar nature of the lesion, distinguish cerebral infarction
from haemorrhage and identify the underlying vascular
mistakenly attributed to TIA (see Fig. 26.17, p. 1158, and disease and risk factors (Box 27.5).
Box 27.4). Public health campaigns to raise awareness of
the emergency nature of stroke exploit the fact that
weakness of the face or arm, or disturbance of speech is
the commonest presentation.
The clinical presentation of stroke depends upon 27.5 Investigation of a patient with
which arterial territory is involved and the size of the an acute stroke
lesion (see Fig. 27.1). These will both have a bearing on Diagnostic question Investigation
management, such as suitability for carotid endarterec- Is it a vascular lesion? CT/MRI
tomy. The neurological deficit can be identified from the
Is it ischaemic or CT/MRI
patient’s history and (if it is persistent) the neurological haemorrhagic?
examination. The presence of a unilateral motor deficit,
a higher cerebral function deficit such as aphasia or Is it a subarachnoid CT/lumbar puncture
neglect, or a visual field defect usually places the lesion haemorrhage?
in the cerebral hemisphere. Ataxia, diplopia, vertigo Is there any cardiac Electrocardiogram (ECG)
and/or bilateral weakness usually indicate a lesion in source of embolism? 24-hour ECG
the brainstem or cerebellum. Different combinations of Echocardiogram
these deficits define several stroke syndromes (Fig. What is the underlying Duplex ultrasound of carotids
27.10), which reflect the site and size of the lesion and vascular disease? Magnetic resonance
may provide clues to underlying pathology. angiography (MRA)
Reduced conscious level usually indicates a large- CT angiography (CTA)
volume lesion in the cerebral hemisphere but may result Contrast angiography
from a lesion in the brainstem or complications such as What are the risk factors? Full blood count
obstructive hydrocephalus, hypoxia or severe systemic Cholesterol
infection. The combination of severe headache and vom- Blood glucose
iting at the onset of the focal deficit is suggestive of
Is there an unusual Erythrocyte sedimentation rate (ESR)
intracerebral haemorrhage. cause? Serum protein electrophoresis
General examination may provide clues to the cause, Clotting/thrombophilia screen
1240 and identify important comorbidities and complications.
 Stroke

Clinical syndrome Common symptoms Common cause CT scan features

Total anterior circulation Combination of: Middle cerebral artery
syndrome (TACS) occlusion
Hemiparesis
Leg
(Embolism from heart
Higher cerebral dysfunction or major vessels)
Arm Higher (e.g. aphasia)
cerebral
functions Hemisensory loss
Face
Homonymous hemianopia
Optic
radiations (damage to optic radiations)

Partial anterior circulation Isolated motor loss (e.g. leg only, Occlusion of a branch
syndrome (PACS) arm only, face) of the middle cerebral
artery or anterior
Leg
Isolated higher cerebral cerebral artery
dysfunction (e.g. aphasia,
Arm Higher neglect) (Embolism from heart
cerebral or major vessels)
functions Mixture of higher cerebral
Face dysfunction and motor loss
(e.g. aphasia with right
Optic
radiations hemiparesis)

Lacunar syndrome (LACS) Pure motor stroke – affects Thrombotic occlusion

two limbs of small perforating
arteries
Leg
Pure sensory stroke
Arm Higher Sensory-motor stroke
(Thrombosis in situ) 27
cerebral
functions No higher cerebral dysfunction
Face or hemianopia
Optic
radiations

Posterior circulation Homonymous hemianopia Occlusion in vertebral,

stroke (POCS) (damage to visual cortex) basilar or posterior
(lateral view) cerbral artery territory
Cerebellar syndrome
(Cardiac embolism or
Cranial nerve syndromes thrombosis in situ)

Visual cortex
Cerebellum

Cranial nerve
nuclei

Fig. 27.10 Clinical and radiological features of the stroke syndromes. The top three diagrams show coronal sections of the brain, and the
bottom one shows a sagittal section. The anatomical locations of cerebral functions are shown with the nerve tracts in green. A motor (or sensory) deficit
(shown by the red shaded areas) can occur with damage to the relevant cortex (PACS), nerve tracts (LACS) or both (TACS). The corresponding CT scans
show horizontal slices at the level of the lesion, highlighted by the arrows.

Risk factor analysis
Initial investigation includes a range of simple blood
tests to detect common vascular risk factors and markers
of rarer causes, an ECG and brain imaging. Where there
is uncertainty about the nature of the stroke, further
investigations are indicated. This especially applies to
younger patients, who are less likely to have athero-
sclerotic disease (Box 27.6).
Neuroimaging
Brain imaging with either CT or MRI should be per-
formed in all patients with acute stroke. Exceptions are
where results would not influence management, such as
in the advanced stage of a terminal illness. CT remains
the most practical and widely available method of
imaging the brain. It will usually exclude non-stroke
lesions, including subdural haematomas and brain
tumours, and will demonstrate intracerebral haemor-
rhage within minutes of stroke onset (see Fig. 27.9).
However, especially within the first few hours after
symptom onset, CT changes in cerebral infarction may
be completely absent or only very subtle. Changes often
develop over time (see Fig. 27.11, p. 1245), but small
cerebral infarcts may never show up on CT scans. For
most purposes, a CT scan performed within 24 hours is 1241
 STROKE DISEASE

27 27.6 Causes and investigation of acute stroke in

young patients
27.7 Indications for emergency CT/MRI in
acute stroke
Cause Investigation • Patient on anticoagulants or with abnormal coagulation
Cerebral infarct • Consideration of thrombolysis or immediate anticoagulation
Cardiac embolism Echocardiography (including • Deteriorating conscious level or rapidly progressing deficits
transoesophageal) • Suspected cerebellar haematoma, to exclude hydrocephalus
Premature atherosclerosis Serum lipids
Arterial dissection MRI
Angiography cerebellum, and unlike CT, can reliably distinguish
Thrombophilia Protein C, protein S haemorrhagic from ischaemic stroke even several weeks
Antithrombin III after the onset. CT and MRI may reveal clues as to the
Factor V Leiden, prothrombin nature of the arterial lesion. For example, there may be
a small, deep lacunar infarct indicating small-vessel
Homocystinuria (p. 449) Urinary amino acids
disease, or a more peripheral infarct suggesting an
Methionine loading test
extracranial source of embolism (see Fig. 27.10). In a
Antiphospholipid antibody Anticardiolipin antibodies/ haemorrhagic lesion, the location might indicate the
syndrome (p. 1055) lupus anticoagulant presence of an underlying vascular malformation, sac-
Systemic lupus erythematosus Antinuclear antibodies cular aneurysm or amyloid angiopathy.
Vasculitis ESR
C-reactive protein
Vascular imaging
Antineutrophil cytoplasmic Many ischaemic strokes are caused by atherosclerotic
antibody (ANCA) thromboembolic disease of the major extracranial
CADASIL (cerebral autosomal MRI brain vessels. Detection of extracranial vascular disease can
dominant arteriopathy with Genetic analysis help establish why the patient has had an ischaemic
subcortical infarcts and Skin biopsy stroke and, in highly selected patients, may lead on to
leucoencephalopathy) specific treatments, including carotid endarterectomy to
reduce the risk of further stroke (see below). The pres-
Mitochondrial cytopathy Serum lactate
ence or absence of a carotid bruit is not a reliable
White cell mitochondrial DNA
indicator of the degree of carotid stenosis. Extracranial
Muscle biopsy
Mitochondrial molecular arterial disease can be non-invasively identified with
genetics duplex ultrasound, MRA or CT angiography (see Fig.
27.5), or occasionally intra-arterial contrast radiography
Fabry’s disease Alpha-galactosidase levels as above.
Neurovascular syphilis Syphilis serology
Primary intracerebral haemorrhage Cardiac investigations
Arteriovenous malformation MRI/angiography Approximately 20% of ischaemic strokes are due to
(AVM) embolism from the heart. The most common causes are
Drug misuse Drug screen (amphetamine, atrial fibrillation, prosthetic heart valves, other valvular
cocaine) abnormalities and recent myocardial infarction. These
may be identified by clinical examination and ECG, but
Coagulopathy Prothrombin time (PT) and a transthoracic or transoesophageal echocardiogram is
activated partial
also required to confirm the presence of a clinically
thromboplastin time (APTT)
apparent cardiac source or to identify an unsuspected
Platelet count
source such as endocarditis, atrial myxoma, intracardiac
Subarachnoid haemorrhage thrombus or patent foramen ovale. Such findings may
Saccular (‘berry’) aneurysm MRI/angiography lead on to specific cardiac treatment.
AVM MRI/angiography
Vertebral dissection MRI/angiography
Management
Management is aimed at minimising the volume of brain
adequate but there are certain circumstances in which that is irreversibly damaged, preventing complications
an immediate CT scan is essential (Box 27.7). Even in (Box 27.8), reducing the patient’s disability and handi-
the absence of changes suggesting infarction, abnormal cap through rehabilitation, and reducing the risk of
perfusion of brain tissue can be imaged with CT after recurrent stroke or other vascular events. With TIA there
injection of contrast media (i.e. perfusion scanning). is no brain damage and disability, so the priority is to
This can be useful in guiding immediate treatment of reduce the risk of further vascular events.
ischaemic stroke.
MRI is not as widely available as CT and scanning Supportive care
times are longer. However, MRI diffusion weighted Early admission of patients to a specialised stroke unit
imaging (DWI) can detect ischaemia earlier than CT, and facilitates coordinated care from a specialised multidis-
other MRI sequences can also be used to demonstrate ciplinary team (Box 27.9), and has been shown to reduce
abnormal perfusion (see Fig. 27.4). MRI is more sensitive both mortality and residual disability amongst survi-
1242 than CT in detecting strokes affecting the brainstem and vors. Consideration of a patient’s rehabilitation needs
 Stroke

27.8 Complications of acute stroke 27.10 Management of acute stroke

Complication Prevention Treatment Airway
Chest Nurse semi-erect Antibiotics • Perform bedside swallow screen and keep patient nil by
infection Avoid aspiration (nil by Physiotherapy mouth if swallowing unsafe or aspiration occurs
mouth, nasogastric Breathing
tube, possible
gastrostomy) • Check respiratory rate and oxygen saturation and give
oxygen if saturation < 95%
Epileptic Maintain cerebral Anticonvulsants
seizures Circulation
oxygenation
Avoid metabolic • Check peripheral perfusion, pulse and blood pressure and
disturbance treat abnormalities with fluid replacement, anti-arrhythmics
and inotropic drugs as appropriate
Deep venous Maintain hydration Anticoagulation
thrombosis/ Early mobilisation (exclude Hydration
pulmonary Anti-embolism haemorrhagic • If signs of dehydration, give fluids parenterally or by
embolism stockings stroke first) nasogastric tube
Heparin (for high-risk
Nutrition
patients only)
• Assess nutritional status and provide nutritional supplements
Painful Avoid traction injury Physiotherapy if necessary
shoulder Shoulder/arm supports Local corticosteroid • If dysphagia persists for > 48 hrs, start feeding via a
Physiotherapy injections nasogastric tube
Pressure Frequent turning Nursing care Medication
sores Monitor pressure areas Pressure-relieving
Avoid urinary damage mattress • If patient is dysphagic, consider alternative routes for
to skin essential medications
Urinary Avoid catheterisation Antibiotics Blood pressure
infection if possible
Use penile sheath
• Unless there is heart or renal failure, evidence of
hypertensive encephalopathy or aortic dissection, do not
27
Constipation Appropriate aperients Appropriate lower blood pressure in first week as it may reduce cerebral
and diet aperients perfusion. Blood pressure often returns towards patient’s
normal level within first few days
Depression Maintain positive Antidepressants
and anxiety attitude and provide Blood glucose
information • Check blood glucose and treat when levels are
≥ 11.1 mmol/L (200 mg/dL) (by insulin infusion or glucose/
potassium/insulin (GKI)
• Monitor closely to avoid hypoglycaemia
Temperature
27.9 Specialist stroke units • If pyrexic, investigate and treat underlying cause
• Control with antipyretics, as raised brain temperature may
‘Admitting 1000 patients to a stroke unit prevents about 50
increase infarct volume
patients from being dead or dependent at 6 months.’
Pressure areas
• Stroke Unit Trialists’ Collaboration. Cochrane Database of Systematic Reviews
2007, issue 4. Art. no.: CD000197. • Reduce risk of skin breakdown:
Treat infection
For further information: www.cochrane.org/cochrane-reviews
Maintain nutrition
Provide pressure-relieving mattress
Turn immobile patients regularly
Incontinence
should commence at the same time as acute medical
management. Dysphagia is common and can be detected • Check for constipation and urinary retention; treat
by an early bedside test of swallowing. This allows appropriately
• Avoid urinary catheterisation unless patient is in acute
hydration, feeding and medication to be given safely, if
urinary retention or incontinence is threatening pressure
necessary by nasogastric tube or intravenously. In the
areas
acute phase, a checklist may be useful (Box 27.10) to
ensure that all the factors that might influence outcome Mobilisation
have been addressed. • Avoid bed rest
The patient’s neurological deficits may worsen during
the first few hours or days after their onset. This is most
common in those with lacunar infarcts but may occur in
other patients, due to extension of the area of infarction, sepsis, epileptic seizures or metabolic abnormalities that
haemorrhage transformation, or the development of may be reversed more easily. Patients with cerebellar
oedema with consequent mass effect. It is important haematomas or infarcts with mass effect may develop
to distinguish these patients from those who are deterio- obstructive hydrocephalus and some will benefit from
rating as a result of complications such as hypoxia, insertion of a ventricular drain and/or decompressive 1243
 STROKE DISEASE
27 27.11 Role of treatments in acute stroke
Treatment Target group
Aspirin1 Acute ischaemic stroke
Thrombolysis with rt-PA2 Acute ischaemic stroke
Treated within 3 hrs of onset
Treated within 3–4.5 hrs of onset
Decompressive Large cerebral infarction
hemicraniectomy3
Stroke unit care4 Acute stroke
1
• Sandercock P, et al. Cochrane Database of Systematic Reviews 2008, issue 3. Art. no.: CD000029.
2
• Lees KR, et al. Lancet 2010; 375:1695–1703.
3
• Vahedi K, et al. Lancet Neurol 2007; 6(3):215–222.
4
• Stroke Unit Trialists’ Collaboration. Cochrane Database of Systematic Reviews 2007, issue 4. Art. no.: CD000197.
For further information: www.cochrane.org/cochrane-reviews
(NNT = number needed to treat; rtPA = tissue plasminogen activator)
surgery (Box 27.11). Some patients with large haemato-
mas or infarction with massive oedema in the cerebral
hemispheres may benefit from anti-oedema agents, such
as mannitol or artificial ventilation. Surgical decompres-
sion to reduce intracranial pressure should be consid-
ered in appropriate patients.
Thrombolysis
Intravenous thrombolysis with recombinant tissue plas-
minogen activator (rt-PA) increases the risk of haem-
orrhagic transformation of the cerebral infarct with
potentially fatal results. However, if it is given within
4.5 hours of symptom onset to carefully selected patients,
the haemorrhagic risk is offset by an improvement in
overall outcome (see Box 27.11). The earlier treatment is
given, the greater the benefit.
Aspirin
In the absence of contraindications, aspirin (300 mg
daily) should be started immediately after an ischaemic
stroke unless rt-PA has been given, in which case it
should be withheld for at least 24 hours. Aspirin reduces
the risk of early recurrence and has a small but clinically
worthwhile effect on long-term outcome (see Box 27.11);
it may be given by rectal suppository or by nasogastric
tube in dysphagic patients.
Heparin
Anticoagulation with heparin has been widely used to
treat acute ischaemic stroke in the past. Whilst it reduces
the risk of early ischaemic recurrence and venous
thromboembolism, it increases the risk of both intracra-
nial and extracranial haemorrhage. Furthermore, routine
use of heparin does not result in better long-term out-
comes, and therefore it should not be used in the routine
management of acute stroke. It is unclear whether
heparin might provide benefit in selected patients, such
as those with recent myocardial infarction, arterial dis-
section or progressing strokes. Intracranial haemorrhage
must be excluded on brain imaging before considering
1244 anticoagulation.
Approximate proportion of NNT to prevent 1 death or
patients eligible for treatment disability in those treated
90% 80
10% 9
10% 20
< 1% 2
80% 20
Coagulation abnormalities
In those with intracerebral haemorrhage, coagulation
abnormalities should be reversed as quickly as possible
to reduce the likelihood of the haematoma enlarging.
This most commonly arises in those on warfarin therapy.
There is no evidence that clotting factors are useful in
the absence of a clotting defect.
Management of risk factors
The approaches used are summarised in Figure 27.11.
The average risk of a further stroke is 5–10% within the
first week of a stroke or TIA, perhaps 15% in the first
year and 5% per year thereafter. The risks are not
substantially different for intracerebral haemorrhage.
Patients with ischaemic events should be put on long-
term antiplatelet drugs and statins to lower cholesterol.
For patients in atrial fibrillation, the risk can be reduced
by about 60% by using oral anticoagulation to achieve
an INR of 2–3. The role of newer oral anticoagulants
(such as dabigatran) is currently being investigated. The
risk of recurrence after both ischaemic and haemor-
rhagic strokes can be reduced by blood pressure reduc-
tion, even for those with relatively normal blood
pressures (Box 27.12).
Carotid endarterectomy
and angioplasty
A small proportion of patients with a carotid territory
ischaemic stroke or TIA will have a greater than 50%
stenosis of the carotid artery on the side of the brain
lesion. Such patients have a greater than average risk
of stroke recurrence. For those without major residual
disability, removal of the stenosis has been shown
to reduce the overall risk of recurrence, although the
operation itself carries about a 5% risk of stroke (see
Box 27.12). Surgery is most effective in patients with
more severe stenoses (70–99%) and in those in whom
it is performed within the first couple of weeks after
the TIA or ischaemic stroke. Carotid angioplasty and
stenting are technically feasible but have not been
shown to be as effective as endarterectomy for the
 Stroke

Stroke CT brain scan within

or atypical or multiple 24 hours of onset;
cerebral TIAs MRI if later than 7 days

Single Ischaemic Haemorrhagic

typical TIA

ECG Sinus rhythm Carotid duplex

Refer if > 70%

Atrial fibrillation stenosis on
symptomatic side
Antiplatelet drugs4
• Aspirin 300 mg at once
then 75 mg daily
• Clopidogrel 75 mg daily Carotid Lower BP1
if aspirin-intolerant endarterectomy if BP > 130/70 mmHg
Thyroid function tests
and • Dipyridamole MR 1–2 weeks after onset
echocardiogram 200 mg twice daily if • Thiazide diuretic
event whilst on aspirin Lower cholesterol2 • ACE inhibitor
if total cholesterol (check U & Es)
> 3.5 mmol/L • Other agents
27
(135 mg/dL) with
If contraindications simvastatin 40 mg
Consider to warfarin, e.g. nocte, after checking
• Cardioversion bleeding, falls, liver function tests
• Anti-arrhythmic binge drinking,
poor compliance Lifestyle
• Smoking cessation
Warfarin3 • Lower salt intake
if no • Lower fat intake
contraindications • Lower excess
Target INR 2–3, or alcohol intake
3.5 if mechanical • Increase exercise
prosthetic valve • Lose excess weight

Fig. 27.11 Strategies for secondary prevention of stroke. (1) Lower BP with caution in patients with postural hypotension, renal impairment or
bilateral carotid stenosis. (2) Pravastatin 40 mg can be used as an alternative to simvastatin in patients on warfarin or digoxin. (3) Warfarin and aspirin can
be used in combination in patients with prosthetic heart valves. (4) The combination of aspirin and clopidogrel is only indicated in patients with unstable
angina who demonstrate ECG or enzyme changes.

27.12 Strategies for secondary prevention

Approximate proportion of NNT to prevent 1
Treatment Target group patients eligible for treatment recurrent stroke
Antiplatelet drugs (clopidogrel, Ischaemic stroke or TIA (in sinus rhythm) 90% 100
aspirin/dipyridamole1
Statins2 Ischaemic stroke or TIA 80% 60
Blood pressure-lowering3 All stroke (ischaemic or haemorrhagic) 60% 50
with blood pressure > 130/80 mmHg
Anticoagulation with warfarin Ischaemic stroke patients in atrial 20% 15
(or newer oral anticoagulant)4 fibrillation
Carotid endarterectomy5 Ischaemic stroke or TIA < 10% 15
Recently symptomatic severe carotid
stenosis

• 1Antithrombotic Trialists’ Collaboration. BMJ 2002; 324:71–86. • 3PROGRESS Collaborative Group. Lancet 2001; 358:1033–1041.
• 2Heart Protection Study Collaborative Group. Lancet 2002; 360:7–22 and SPARCL • 4Lip GYH, et al. Lancet 2012; 379:648–661.
investigators. N Engl J Med 2006; 355:549–559. • 5Rothwell PM, et al. Lancet 2003; 361:107–116.

For further information: www.cochrane.org/cochrane-reviews

1245
 STROKE DISEASE
27 majority of eligible patients. Endarterectomy of asymp-
tomatic carotid stenosis has been shown to reduce the
subsequent risk of stroke, but the small absolute benefit
does not justify its routine use.
SUBARACHNOID HAEMORRHAGE
Subarachnoid haemorrhage (SAH) is less common than
ischaemic stroke or intracerebral haemorrhage (see Fig.
27.1) and affects about 6/100 000 of the population.
Women are affected more commonly than men and the
condition usually presents before the age of 65. The
immediate mortality of aneurysmal SAH is about 30%;
survivors have a recurrence (or rebleed) rate of about
40% in the first 4 weeks and 3% annually thereafter.
Eighty-five percent of SAH are caused by saccular
or ‘berry’ aneurysms arising from the bifurcation
of cerebral arteries (see Fig. 27.2), particularly in the
region of the circle of Willis. The most common sites
are in the anterior communicating artery (30%), poste-
rior communicating artery (25%) or middle cerebral
artery (20%). There is an increased risk in first-degree
relatives of those with saccular aneurysms, and in
patients with polycystic kidney disease (p. 505) and
congenital connective tissue defects such as Ehlers–
Danlos syndrome (p. 1045). In about 10% of cases,
SAH are non-aneurysmal haemorrhages (so-called peri-
mesencephalic haemorrhages), which have a very char-
acteristic appearance on CT and a benign outcome
in terms of mortality and recurrence. Five percent of
SAH are due to arteriovenous malformations and verte-
bral artery dissection.
Clinical features
SAH typically presents with a sudden, severe, ‘thunder-
clap’ headache (often occipital), which lasts for hours or
even days, often accompanied by vomiting, raised blood
pressure and neck stiffness or pain. It commonly occurs
on physical exertion, straining and sexual excitement.
Emergency CT
Shows subarachnoid
haemorrhage Blood/xanthochromia
Traumatic lumbar punctures
do not cause xanthochromia
in that specimen
Refer to neurosurgeons
Resuscitate
Nimodipine 60 mg
1246 Fig. 27.12 Investigation of subarachnoid haemorrhage.
There may be loss of consciousness at the onset, so SAH
should be considered if a patient is found comatose.
About 1 patient in 8 with a sudden severe headache has
SAH and, in view of this, all who present in this way
require investigation to exclude it (Fig. 27.12).
On examination, the patient is usually distressed and
irritable, with photophobia. There may be neck stiffness
due to subarachnoid blood but this may take some hours
to develop. Focal hemisphere signs, such as hemiparesis
or aphasia, may be present at onset if there is an associ-
ated intracerebral haematoma. A third nerve palsy may
be present due to local pressure from an aneurysm of
the posterior communicating artery, but this is rare. Fun-
doscopy may reveal a subhyaloid haemorrhage, which
represents blood tracking along the subarachnoid space
around the optic nerve.
Investigations
CT brain scanning and lumbar puncture are required.
The diagnosis of SAH can be made by CT, but a negative
result does not exclude it, since small amounts of blood
in the subarachnoid space cannot be detected by CT (see
Fig. 27.12). Lumbar puncture should be performed 12
hours after symptom onset if possible, to allow detection
of xanthochromia (p. 1153). If either of these tests is posi-
tive, cerebral angiography (see Fig. 27.5) is required to
determine the optimal approach to prevent recurrent
bleeding.
Management
Nimodipine (30–60 mg IV for 5–14 days, followed by
360 mg orally for a further 7 days) is usually given
to prevent delayed ischaemia in the acute phase. Inser-
tion of platinum coils into an aneurysm (via an endovas-
cular procedure) or surgical clipping of the aneurysm
neck reduces the risk of both early and late recurrence.
Coiling is associated with fewer perioperative com-
plications and better outcomes than surgery; where
Negative
(15% of subarachnoid
haemorrhage)
CSF
(after 12 hours)
If CT and CSF at 12 hours are
negative the patient has not had
a subarachnoid haemorrhage
 Cerebral venous disease

feasible, it is now the procedure of first choice. Arterio-
venous malformations can be managed either by surgi-
cal removal, by ligation of the blood vessels that feed or
drain the lesion, or by injection of material to occlude
the fistula or draining veins. Treatment may also be
required for complications of SAH, which include
obstructive hydrocephalus (that may require drainage
via a shunt), delayed cerebral ischaemia due to vaso-
spasm (which may be treated with vasodilators),
hyponatraemia (best managed by fluid restriction) and
systemic complications associated with immobility,
such as chest infection and venous thrombosis.
CEREBRAL VENOUS DISEASE
27.14 Clinical features of cerebral venous
thrombosis
Cavernous sinus thrombosis
• Proptosis, ptosis, headache, external and internal
ophthalmoplegia, papilloedema, reduced sensation in
trigeminal first division
• Often bilateral, patient ill and febrile
Superior sagittal sinus thrombosis
• Headache, papilloedema, seizures
• Clinical features may resemble idiopathic intracranial
hypertension (p. 1217)
• May involve veins of both hemispheres, causing advancing
motor and sensory focal deficits
Transverse sinus thrombosis

Thrombosis of the cerebral veins and venous sinuses
(cerebral venous thrombosis) is much less common than
arterial thrombosis. However, it has been recognised
with increasing frequency in recent years, as access to
non-invasive imaging of the venous sinuses using MR
venography has increased. The main causes are listed in
Box 27.13.
Clinical features
Cerebral venous sinus thrombosis usually presents with
symptoms of raised intracranial pressure, seizures and
focal neurological symptoms. The clinical features vary
according to the sinus involved (Box 27.14 and see
Fig. 27.3, p. 1235). Cortical vein thrombosis presents
with focal cortical deficits such as aphasia and hemi-
paresis (depending on the area affected), and epilepsy
(focal or generalised). The deficit can increase if spread-
ing thrombophlebitis occurs.
• Hemiparesis, seizures, papilloedema
• May spread to jugular foramen and involve cranial nerves 9,
10 and 11
Investigations and management
MR venography demonstrates a filling defect in the
affected vessel.
Anticoagulation, initially with heparin followed by
27
warfarin, is usually beneficial, even in the presence of
venous haemorrhage. In selected patients, the use of
endovascular thrombolysis has been advocated. Man-
agement of underlying causes and complications, such
as persistently raised intracranial pressure, is also
important.
About 10% of cerebral venous sinus thrombosis, par-
ticularly cavernous sinus thrombosis, is associated with
infection (most commonly Staphylococcus aureus), which
necessitates antibiotic treatment. Otherwise, the treat-
ment of choice is anticoagulation.

27.13 Causes of cerebral venous thrombosis

Predisposing systemic causes
• Dehydration
• Pregnancy
• Behçet’s disease (p. 1119)
Local causes
• Paranasal sinusitis
• Meningitis, subdural
empyema
• Penetrating head and eye
wounds
• Thrombophilia (p. 1001)
• Hypotension
• Oral contraceptive use
• Facial skin infection
• Otitis media, mastoiditis
• Skull fracture
Further information
Websites
www.eso-stroke.org/pdf/ESO%20Guidelines_update_
Jan_2009.pdf European Stroke Organisation guidelines.
www.nhs.uk/actfast/pages/stroke.aspx Details of the FAST
(face, arms, speech, time) campaign to raise public awareness of
the emergency nature of stroke.
www.rcplondon.ac.uk/resources/stroke-guidelines Royal
College of Physicians of London stroke guideline.
www.stroketraining.org Stroke training awareness and
resources website.

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