ACQUIRED METABOLIC

AND TOXIC DISTURBANCES

Dr. Yonas A. (M.D.)
PATHOLOGY, DBU

Nutritional Diseases
Thiamine Deficiency
In addition to the systemic effects of thiamine

deficiency (beriberi), there may also be abrupt

development of confusion, abnormalities in eye
movement and ataxia, a syndrome termed
Wernicke encephalopathy. The acute stages, if
unrecognized and untreated, may be followed by a
prolonged and largely irreversible condition,
Korsakoff syndrome, associated with profound
memory disturbances. Because the two syndromes
are closely linked, the term Wernicke-Korsakoff
syndrome is often applied.

The syndrome is particularly common in the

setting of chronic alcoholism but may also be

encountered in patients with thiamine
deficiency resulting from gastric disorders,
including carcinoma, chronic gastritis, or
persistent vomiting. Treatment with thiamine
can reverse the manifestations of Wernicke
syndrome.

Morphology
Wernicke encephalopathy is characterized by foci of

hemorrhage and necrosis, particularly in the mammillary

bodies but also adjacent to the ventricle, especially the third
and fourth ventricles. Despite the presence of necrosis, there
is relative preservation of many of the neurons in these
structures. Early lesions show dilated capillaries with
prominent endothelial cells. Subsequently, the capillaries leak
red cells into the interstitium, producing hemorrhage.
As the lesions resolve, there is infiltration of macrophages and

development of a cystic space with hemosiderin-laden

macrophages as a permanent sign of the process. Lesions in
the medial dorsal nucleus of the thalamus seem to be the best
correlate of the memory disturbance in Korsakoff syndrome.

Vitamin B12 Deficiency

In addition to pernicious anemia, deficiency of vitamin B 12

may lead to devastating neurologic deficits associated

with changes in the spinal cord. This disorder involves
both ascending and descending fiber bundles in the spinal
cord and is responsible for its name, subacute combined
degeneration of the spinal cord. Symptoms develop over
weeks, initially with slight ataxia and numbness and
tingling in the lower extremities, but can progress rapidly
to include spastic weakness of the lower extremities.
Complete paraplegia can also occur. With prompt vitamin
replacement therapy, clinical improvement occurs;
however, if complete paraplegia has developed, recovery
is poor.

Acquired Metabolic Disorders

Hypoglycemia

Since the brain requires glucose as a substrate for

its energy production, the cellular effects of

diminished glucose resemble those of oxygen
deprivation (hypoxia). The pattern of injury
resembles global hypoxia, with injury particularly
evident in the CA1 area of the hippocampus. One
important difference, however, is that the Purkinje
cells of the cerebellum are relatively spared in
hypoglycemia. As with anoxia, if the level and
duration of hypoglycemia are of sufficient severity,
there may be widespread injury to many areas of

Hyperglycemia
Hyperglycemia is most commonly found in the

setting of inadequately controlled diabetes mellitus

and can be associated with either ketoacidosis or
hyperosmolar coma. Systemically there is
dehydration; however, patients develop confusion,
stupor, and eventually coma because of the mass
action transport of glucose (insulin-independent)
into neurons associated with osmotic accumulation
of water. The hyperglycemia must be corrected
gradually; otherwise, severe cerebral edema may
follow.

Hepatic encephalopathy
Individuals with decreased hepatic function develop depressed

levels of consciousness leading to coma. In the early stages

patients have a characteristic "flapping" tremor (asterixis) when
extending their arms with palms facing the observer. Since the
liver fails to clear ammonia through the urea cycle, it is thought
that this metabolic product causes the changes in brain function,
although the absolute levels of ammonia in symptomatic patients
vary widely.
Potential mechanisms are diverse but include alterations in

synaptic transmission as well as metabolic alterations in

astrocytes as they attempt to detoxify the ammonia. The cellular
response in the CNS is predominantly glial, with astrocytes in the
cortex and basal ganglia developing swollen pale nuclei (called
Alzheimer type II cells).

Toxic Disorders
The list of toxins with effects on the brain is

extremely long. Among the major categories of

neurotoxic substances are metals, including lead
(often causing a diffuse encephalopathy), as well as
arsenic and mercury; industrial chemicals, including
organophosphates as in pesticides and methanol
(causing blindness from retinal damage); and
environmental pollutants such as carbon monoxide
(combining hypoxia with selective injury to the
globus pallidus).

Ethanol is a drug with several different types of effects on the

brain. While the acute intoxication effects of ethanol are

reversible, excessive intake can result in profound metabolic
disturbances, including brain swelling and death. Chronic
alcohol exposure leads to cerebellar dysfunction in about 1%
cases, with truncal ataxia, unsteady gait, and nystagmus. This
is associated with atrophy in the anterior vermis of the
cerebellum. The brain can also be affected by exposure to
alcohol during development.
Neurotoxic side effects have also been associated with the

administration of chemotherapeutic agents for the treatment

of tumors. Methotrexate, an important antineoplastic agent,
may cause CNS injury, particularly in persons receiving
intrathecal or high-dose systemic therapy in conjunction with
radiation therapy. The morphologic changes associated with
methotrexate toxicity are most prominent in white matter and
consist of necrosis, demyelination, gliosis, and calcification.

Ionizing radiation can cause rapidly evolving

symptoms of an intracranial mass, including

headaches, nausea, vomiting, and papilledema,
even after months to years after irradiation. The
pathologic findings consist of large areas of
coagulative necrosis in white matter with adjacent
edema. Adjacent to the area of coagulative
necrosis, blood vessels exhibit thickened walls with
intramural fibrin-like material.

DISEASES OF THE PERIPHERAL NERVOUS

SYSTEM
Patterns of Nerve Injury

A variety of disease processes can affect nerves. In

general, there are two main patterns of response of

peripheral nerve to injury based on the target of the
insult: either the Schwann cell or the axon. Diseases
that affect primarily the Schwann cell lead to a loss
of myelin, referred to as segmental demyelination. In
contrast, primary involvement of the neuron and its
axon leads to axonal degeneration. In some
diseases, axonal degeneration may be followed by
axonal regeneration.

Segmental Demyelination

Segmental demyelination occurs when there is

dysfunction or death of the Schwann cell or damage

to the myelin sheath; there is no primary abnormality
of the axon. The process affects some Schwann cells,
and their corresponding internodes, while sparing
others . The disintegrating myelin is engulfed initially
by Schwann cells and later by macrophages. The
denuded axon provides a stimulus for remyelination,
with a population of cells within the endoneurium
differentiating to replace injured Schwann cells.
These cells proliferate and encircle the axon and, in
time, remyelinate the denuded portion.

Remyelinated internodes, however, are

shorter than normal, and several are required

to bridge the demyelinated region. In addition
to being shortened, remyelinated internodes
have thinner myelin in proportion to the
diameter of the axon than normal internodes.

With repetitive cycles of demyelination and

remyelination, there is an accumulation of

tiers of Schwann cell processes that, on
transverse section, appear as concentric
layers of Schwann cell cytoplasm and
redundant basement membrane that
surround a thinly myelinated axon (onion
bulbs). In time, many chronic demyelinating
neuropathies give way to axonal injury.

Axonal Degeneration
Axonal degeneration is the result of primary destruction of the

axon, with secondary disintegration of its myelin sheath.

Damage to the axon may be due either to a focal event
occurring at some point along the length of the nerve (such as
trauma or ischemia) or to a more generalized abnormality
affecting the neuron cell body (neuronopathy) or its axon
(axonopathy).
When axonal injury occurs as the result of a focal lesion, such

as traumatic transection of a nerve, the distal portion of the

fiber undergoes Wallerian degeneration. Within a day, the
axon breaks down, and Schwann cells begin to degrade the
myelin and then engulf axon fragments, forming small oval
compartments (myelin ovoids).

Macrophages are recruited into the area and

participate in the phagocytosis of axonal and

myelin-derived debris. In the slowly evolving
neuronopathies or axonopathies, evidence of
myelin breakdown is scant because only a few
fibers are degenerating at any given time. The
stump of the proximal portion of the severed
nerve shows degenerative changes involving
only the most distal two or three internodes and
then undergoes regenerative activity.

The proximal stumps of degenerated axons can develop

new growth cones as the axon regrows. These growth

cones will use the Schwann cells vacated by the
degenerated axons to guide them, if properly aligned
with the distal nerve segment. The presence of multiple
closely aggregated thinly myelinated small-caliber axons
is evidence of regeneration (regenerating cluster).
Regrowth of axons is a slow process, on the order of 1 to

2 mm per day, apparently limited by the rate of the slow

component of axonal transport, the movement of tubulin,
actin, and intermediate filaments. Despite its slow pace,
axonal regeneration accounts for some of the potential
for functional recovery following peripheral axonal injury.

Guillain-Barr Syndrome
This is one of the most common life-threatening diseases of the

peripheral nervous system. It may develop spontaneously or after a

systemic infection (usually viral) or other stress. Patients with
Guillain-Barr syndrome present with rapidly progressive, ascending
motor weakness that may lead to death from failure of respiratory
muscles. Sensory involvement is usually much less striking than is
motor dysfunction. The dominant histopathologic findings are
segmental demyelination along with scant infiltration of peripheral
nerves by macrophages and reactive lymphocytes.
The CSF usually contains increased levels of protein but only a

minimal cellular reaction. Because of those cases with infectious

antecedents, an immunologic basis is considered most likely;
treatments include plasmapheresis or intravenous immunoglobulin,
which can shorten the course of the disease. With supportive care,
most affected individuals recover over time.

Neoplasms of the Peripheral Nervous

System
These tumors arise from cells of the peripheral nerve, including

Schwann cells, perineurial cells, and fibroblasts. Many express

Schwann cell characteristics, including the presence of S-100
antigen as well as the potential for melanocytic differentiation.
As nerves exit the brain and spinal cord, there is a transition
between myelination by oligodendrocytes and myelination by
Schwann cells.
This occurs within several millimeters of the substance of the

brain; thus, in addition to arising along the peripheral course of

nerve, these tumors can arise within the confines of the dura.
When they do this, they may cause changes in adjacent brain
or spinal cord.

Schwannoma
These are benign tumors arising from Schwann cells. Symptoms

are referable to local compression of the involved nerve, or to

compression of adjacent structures (such as brain stem or spinal
cord). They are often encountered within the cranial vault, in the
cerebellopontine angle, where they are attached to the vestibular
branch of the eighth nerve . These patients often present with
tinnitus and hearing loss, and the tumor is often referred to as an
acoustic neuroma, although it is more accurately called a
vestibular schwannoma.
Elsewhere within the dura, sensory nerves are preferentially

involved, including branches of the trigeminal nerve and dorsal

roots. When extradural, schwannomas are most commonly found
in association with large nerve trunks, where motor and sensory
modalities are intermixed. Sporadic schwannomas are associated
with mutations in the NF2 gene on chromosome 22

Morphology
Schwannomas are well-circumscribed encapsulated

masses that are attached to the nerve but can be

separated from it. Tumors form firm, gray masses
but may also have areas of cystic and xanthomatous
change. On microscopic examination, tumors show a
mixture of two growth patterns . In the Antoni A
pattern of growth, elongated cells with cytoplasmic
processes are arranged in fascicles in areas of
moderate to high cellularity with little stromal
matrix; the "nuclear-free zones" of processes that lie
between the regions of nuclear palisading are
termed Verocay bodies.

In the Antoni B pattern of growth, the tumor is less

densely cellular with a loose meshwork of cells

along with microcysts and myxoid changes. In both
areas, the cytology of the individual cells is similar,
with elongated cell cytoplasm and regular oval
nuclei. Because the lesion displaces the nerve of
origin as it grows, axons are largely excluded from
the tumor. These tumors are usually uniformly
immunoreactive for S-100 protein.

Neurofibroma
The most common form of neurofibroma occurs in the skin

(cutaneous neurofibroma) or in peripheral nerve (solitary

neurofibroma). These arise sporadically or in association with
type 1 neurofibromatosis (NF1; see below). The skin lesions are
evident as nodules, sometimes with overlying hyperpigmentation;
they may grow to be large and become pedunculated. The risk of
malignant transformation from these tumors is extremely small,
and cosmetic concerns are their major morbidity.
The second type is the plexiform neurofibroma, mostly arising in

individuals with NF1. Of major concern in the care of these

individuals is the difficulty in surgical removal of these plexiform
tumors when they involve major nerve trunks and their potential
for malignant transformation.

Morphology
Cutaneous neurofibroma. Present in the

dermis and subcutaneous fat, these welldelineated but unencapsulated masses are
composed of spindle cells. Although they are
not invasive, the adnexal structures are
sometimes enwrapped by the edges of the
lesion. The stroma of these tumors is highly
collagenized and contains little myxoid material.
Lesions within peripheral nerves are of identical
histologic appearance.

Plexiform neurofibroma. These tumors may arise anywhere

along a nerve, although large nerve trunks are the most

common site. They are frequently multiple. At the site of each
lesion, the host nerve is irregularly expanded, as each of its
fascicles is infiltrated by the neoplasm. Unlike the case with
schwannomas, it is not possible to separate the lesion from
the nerve. The proximal and distal extremes of the tumor may
have poorly defined margins, as fingers of tumor and
individual cells insert themselves between the nerve fibers.
On microscopic examination, the lesion has a loose, myxoid

background with a low cellularity. A number of cell types are

present, including Schwann cells with typical elongated nuclei
and extensions of pink cytoplasm, larger multipolar
fibroblastic cells, and a sprinkling of inflammatory cells, often
including mast cells.

Malignant Peripheral Nerve Sheath Tumor

These are highly malignant sarcomas that are

locally invasive, frequently leading to multiple

recurrences and eventual metastatic spread.
Despite their name, these tumors do not arise from
malignant transformation of schwannomas. Instead,
they arise de novo or from transformation of a
plexiform neurofibroma. These tumors can also
occur after radiation therapy.

Morphology
The lesions are poorly defined tumor masses with

frequent infiltration along the axis of the parent

nerve as well as invasion of adjacent soft tissues.
Necrosis is commonly present. A wide range of
histologic findings may be encountered; often, the
tumor cells resemble Schwann cells, with elongated
nuclei and prominent bipolar processes. Fascicle
formation may be present. Mitoses, necrosis, and
extreme nuclear anaplasia are common. Some but
not all malignant peripheral nerve sheath tumors
are immunoreactive for S-100 protein.

PRIMARY DISEASES OF MYELIN

Within the CNS, axons are tightly ensheathed by myelin, which

serves as an electrical insulator to allow rapid propagation of

impulses. Myelin consists of multiple layers of the specialized
plasma membrane of oligodendrocytes, with most of the
cytoplasm excluded. These portions of the oligodenrocyte
membrane contain specialized proteins and lipids that contribute
to the orderly packing of the layers. An oligodendrocyte extends
processes toward many different axons and wraps a segment of
roughly a few hundred microns of axon.
Each of these segments is called an internode, and the gaps

between internodes are known as nodes of Ranvier. Although

myelinated axons are present in all areas of the brain, they are
the dominant component in the white matter; therefore, most
diseases of myelin are primarily white matter disorders.

The myelin in peripheral nerves is similar to the

myelin in the CNS but has several important

differences: Peripheral myelin is made by
Schwann cells, not oligodendrocytes; each cell
in the peripheral nerve contributes to only one
internode, while in the CNS, many internodes
comes from a single oligodendrocyte; and the
specialized proteins and lipids are also different.
Therefore, most diseases of CNS myelin do not
significantly involve the peripheral nerves, and
vice versa.

If the myelin along a set of axons is disrupted,

there are changes in the ability of these axons to

transmit signals. The symptoms of diseases of
myelin are related to this disruption of neuronal
communication; the exact nature of the symptoms
depends on the site (or sites, since most disease of
myelin affect many regions of the brain at the same
time) where myelin disruption occurs. The natural
history of demyelinating diseases is determined, in
part, by the limited capacity of the CNS to
regenerate normal myelin and by the degree of
secondary damage to axons that occurs as the
disease runs its course.

In general, diseases involving myelin are separated

into two broad groups. Demyelinating diseases of

the CNS are acquired conditions characterized by
preferential damage to previously normal myelin.
The most common diseases in this group result
from immune-mediated injury, such as multiple
sclerosis (MS) and related disorders. Other
processes that can cause this type of disease
include viral infection of oligodendrocytes as in
progressive multifocal leukoencephalopathy (see
above), and injury caused by drugs and other toxic
agents.

In contrast, when myelin is not formed properly

or has abnormal turnover kinetics, the resulting

diseases are referred to as dysmyelinating. As
would be expected, dysmyelinating diseases are
associated with mutations affecting the proteins
required for formation of normal myelin or in
mutations that affect the synthesis or
degradation of myelin lipids. The other general
term for these diseases is leukodystrophy.

Multiple Sclerosis
MS is an autoimmune demyelinating disorder

characterized by distinct episodes of neurologic

deficits, separated in time, attributable to white
matter lesions that are separated in space. The
disease becomes clinically apparent at any age,
although onset in childhood or after age 50 years is
relatively rare. Women are affected twice as often as
men. In most individuals with MS the illness shows
relapsing and remitting episodes of neurologic
deficits. The frequency of relapses tends to decrease
during the course of the illness, but there is a steady
neurologic deterioration in a subset of patients.

It is believed that MS, like other autoimmune

diseases, is caused by a combination of environmental

and genetic factors that result in a loss of tolerance to
self proteins (in this case, myelin antigens). A
transmissible agent has been proposed, but none has
ever been conclusively identified. The risk of
developing MS is 15-fold higher when the disease is
present in a first-degree relative. The concordance
rate for monozygotic twins is approximately 25%, with
a much lower rate for dizygotic twins; this indicates a
strong, but not causative, role for genes. Genetic
linkage of MS susceptibility to the HLA-DR2 extended
haplotype is also well established.

Given the prominence of chronic inflammatory cells

within and around MS plaques, immune

mechanisms that may cause myelin destruction
have been the focus of much investigation.
Experimental allergic encephalomyelitis is an
animal model of MS in which demyelination and
inflammation occur after immunization with myelin,
myelin proteins, or certain peptides from myelin
proteins. In this model, the lesions are caused by a
T cell-mediated delayed type hypersensitivity
reaction to myelin proteins, and the same immune
mechanism is thought to be central to the
pathogenesis of MS.

While MS is characterized by the presence of

demyelination out of proportion to axonal

loss, some injury to axons does occur. Toxic
effects of lymphocytes, macrophages, and
their secreted molecules have been
implicated in initiating the process of axonal
injury, sometimes even leading to neuronal
death.

Morphology
MS is a white matter disease; abnormalities on the

surface of the brain are usually restricted to those

regions where myelinated fiber tracts course
superficially (brain stem and spinal cord). Affected
areas show multiple, well-circumscribed, slightly
depressed, glassy, gray-tan, irregularly shaped
lesions, termed plaques. These commonly occur
beside the ventricles. They are also frequent in the
optic nerves and chiasm, brain stem, ascending and
descending fiber tracts, cerebellum, and spinal
cord. The lesions have sharply defined borders at

In an active plaque there is evidence of ongoing

myelin breakdown with abundant macrophages

containing myelin debris. Lymphocytes and
monocytes are present, mostly as perivascular
cuffs. Small active lesions are often centered on
small veins. Axons are relatively preserved,
although they may be reduced in number. When
plaques become quiescent (inactive plaques), the
inflammation mostly disappears, leaving behind
little to no myelin. Instead, astrocytic proliferation
and gliosis are prominent.

There can also be shadow plaques, where the

border between normal and affected white

matter is not sharply circumscribed. Here,
thinned-out myelin sheaths can be
demonstrated, especially at the outer edges,
suggesting that this border region represents
either incomplete myelin loss or partial
remyelination.

Clinical Features
The course of MS is variable, but commonly there are multiple

episodes of new symptoms (relapses) followed by episodes of

recovery (remissions); typically, the recovery is not complete.
The consequence of this pattern of relapsing-remitting disease
is the gradual, often stepwise, accumulation of increasing
neurologic deficits.
Although MS lesions can occur anywhere in the CNS and, as a

consequence, may induce a wide range of clinical

manifestations, certain patterns of neurologic symptoms and
signs are commonly observed. Unilateral visual impairment
occurring over the course of a few days is a frequent initial
manifestation of MS; it is due to involvement of the optic nerve
(optic neuritis, retrobulbar neuritis).

When this occurs as the first event, only a minority (10%

to 50%) go on to develop full-blown MS. Involvement of

the brain stem produces cranial nerve signs and ataxia,
and can disrupt conjugate eye movements. Spinal cord
lesions give rise to motor and sensory impairment of
trunk and limbs, spasticity, and difficulties with the
voluntary control of bladder function.
Changes in cognitive function can be present, but are

often much milder than the other findings. In any

individual patient it is hard to predict when the next
relapse will occur; most current treatments aim at
decreasing the rate and severity of relapses rather than
recovering lost function.

The CSF in MS patients shows a mildly elevated

protein level with an increased proportion of globulin; in one-third of cases there is moderate
pleiocytosis. When the immunoglobulin is
examined further, most MS patients show
oligoclonal bands, representing antibodies
directed against a variety of antigenic targets.
Although these antibodies constitute a marker
for disease activity, it is not clear if they are a
critical part of the disease mechanism.

Magnetic resonance imaging has greatly

added to the understanding of MS, since it

can show the distribution of lesions across the
nervous system during active disease. From
this work it has become clear that there are
often more lesions in the brains of MS
patients than might be expected by clinical
examination, and that lesions can come and
go much more often than was previously
suspected.

Other Acquired Demyelinating Diseases

Immune-mediated demyelination can be found

after a number of systemic infectious illnesses,

including relatively mild viral diseases. These
are not thought to be related to direct spread of
the infectious agents to the nervous system. It
is believed that the immune response to
pathogen-associated antigens cross-reacts with
myelin antigens, and that this results in myelin
damage

There are two general patterns of post-infectious

pathology involving autoimmune reaction to

myelin; unlike MS, they are monophasic illnesses
with relatively abrupt onset. With acute
disseminated encephalomyelitis, symptoms
typically develop a week or two after the
antecedent infection and suggest diffuse brain
involvement with headache, lethargy, and coma
rather than the focal findings typical of MS.
Symptoms progress rapidly, with a fatal outcome in

as many as 20% of cases; in the remaining patients

there is complete recovery. Acute necrotizing

Central pontine myelinolysis is a nonimmune

process characterized by loss of myelin involving

the center of the pons, most often after rapid
correction of hyponatremia. It occurs in a variety of
clinical settings including alcoholism and severe
electrolyte or osmolar imbalance. Although the
most characteristic lesion occurs in the pons,
similar lesions can be found elsewhere in the brain.
Because of the involvement of fibers in the pons
carrying signals to motor neurons in the spinal cord,
patients often present with rapidly evolving
quadriplegia.

Leukodystrophies
Leukodystrophies are inherited

dysmyelinating diseases in which the clinical

symptoms derive from either abnormal
myelin synthesis or turnover. Some of these
disorders involve lysosomal enzymes, while
others involve peroxisomal enzymes; a few
are associated with mutations in myelin
proteins. Most are autosomal recessive,
although X-linked diseases occur

Morphology
Much of the pathology of leukodystrophies is

found in the white matter, which is diffusely

abnormal in color (gray and translucent) and
volume (decreased). Some diseases may
show patchy involvement early, while others
have a predilection for occipital lobe
involvement as they begin. In the end,
though, nearly all of the white matter is
usually affected.

With the loss of white matter, the brain

becomes atrophic, the ventricles enlarge,

and secondary changes can be found in
the gray matter. Myelin loss is common
across the leukodystrophies, often with
macrophages stuffed with lipid. Some of
the diseases also show specific inclusions,
related to the accumulation of particular
lipids.

Clinical Features
Each of the various leukodystrophies has a

characteristic clinical presentation, and most can be

diagnosed by genetic or biochemical methods.
Despite differences in underlying mechanisms, the
leukodystrophies share many features because of
the common myelin target. Affected children are
normal at birth but begin to miss developmental
milestones during infancy and childhood. Diffuse
involvement of white matter leads to deterioration
in motor skills, spasticity, hypotonia, or ataxia. In
general, the earlier the age at onset, the more
severe the deficiency and clinical course.

REFERENCES
Robbins basics of pathology 8th Ed.
General & systemic pathology 4th Ed.
Uptodate

Thank you!