Clinical Evaluation and

Treatment of Transverse
Myelitis
Report of the Therapeutics and Technology
Assessment Subcommittee of
the American Academy of Neurology
Thomas F. Scott, MD; Elliot M. Frohman, MD, PhD;
Jerome De Seze, MD; Gary S. Gronseth, MD, FAAN;
Brian G. Weinshenker, MD

2011 AMERICAN ACADEMY OF NEUROLOGY

 The AAN develops these presentation slides as
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 Endorsed by the Consortium of MS
Centers

2011 AMERICAN ACADEMY OF NEUROLOGY

 Presentation Objectives
To present analysis of the evidence for diagnostic tests
and therapies for transverse myelitis (TM)
To present evidence-based recommendations

2011 AMERICAN ACADEMY OF NEUROLOGY

 Overview
Background
Gaps in care
American Academy of Neurology (AAN) guideline
process
Analysis of evidence, conclusions, recommendations
Recommendations for future research

2011 AMERICAN ACADEMY OF NEUROLOGY

 Background
TM, an inflammatory lesion of the spinal cord, occurs in 1
(severe) to 8 (mild) cases/million per year.15
TM is usually accompanied by MRI signal abnormality in the
spinal cord, CSF pleocytosis, or both.
Typical manifestations and inclusion/exclusion criteria were
outlined by the Transverse Myelitis Consortium Working Group
in 20026 (see table e-1 of the published guideline).
The lesion typically spans multiple vertebral segments and is
not radiologically or pathologically transverse; the term
transverse has been retained because of the importance of a
spinal sensory level in making the diagnosis. 7

2011 AMERICAN ACADEMY OF NEUROLOGY

 Gaps in Care
Because of the spareness of high-quality studies, physicians may
not know presently which diagnostic tests and therapies are
effective.
o TM (in isolation from multiple sclerosis [MS]) is a rare disease for which
research funding is lacking.
o There are no prospective or controlled trials dedicated to TM as an
isolated entity.
o A large trial will be under way in 2012 to look at children and adults (two
individual groups powered separately).
Because of the lack of information on efficacy, patient care is often
limited to a few therapies.

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 AAN Guideline Process

Clinical Question

Evidence

Conclusions

Recommendations

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Questions

For patients with myelopathy, which demographic,

clinical, and laboratory features are useful to distinguish
TM from other causes of acute and subacute
noncompressive myelopathy?
For patients with myelopathy, which demographic,
clinical, radiographic, and laboratory features are useful
to determine the cause of the myelitis?
For patients with myelopathy, which demographic,
clinical, radiographic, and laboratory features are useful
to identify patients at increased risk for recurrence?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Questions, cont.

For patients with TM, which therapies alleviate acute

attacks?
For patients with TM, which therapies prevent future
attacks?

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 Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete

Search

Review abstracts

Review full text

Select articles
Relevant
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 AAN Classification of
Evidence
All studies rated Class I, II, III, or IV
Five different classification systems:
o Therapeutic
Randomization, control, blinding
o Diagnostic
Comparison to gold standard
o Prognostic
o Screening
o Causation

2011 AMERICAN ACADEMY OF NEUROLOGY

 AAN Level of
Recommendations
A = Established as effective, ineffective or harmful (or
established as useful/predictive or not useful/predictive)
for the given condition in the specified population.
B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for the
given condition in the specified population.
C = Possibly effective, ineffective or harmful (or possibly
useful/predictive or not useful/predictive) for the given
condition in the specified population.
U = Data inadequate or conflicting; given current
knowledge, treatment (test, predictor) is unproven.

Note that recommendations can be positive or negative.

2011 AMERICAN ACADEMY OF NEUROLOGY
 Translating Class to Recommendations

A = Requires at least two consistent Class I

studies.*
B = Requires at least one Class I study or two
consistent Class II studies.
C = Requires at least one Class II study or two
consistent Class III studies.
U = Studies not meeting criteria for Class I
through Class III.

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Translating Class to Recommendations,
cont.
*In exceptional cases, one convincing Class I study
may suffice for an A recommendation if 1) all
criteria are met, 2) the magnitude of effect is large
(relative rate improved outcome >5 and the lower
limit of the confidence interval is >2).

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 Applying This Process
to the Issue

We will now turn our attention to the guidelines.

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 Methods

MEDLINE
o 1996 to March 2009
o Relevant, fully published, peer-reviewed articles
o Search terms were myelitis, transverse myelitis, Devic
disease, neuromyelitis optica, diagnosis, prognosis,
outcomes, MRI, and treatments
o For full search strategy, see appendix e-1 of the
published guideline

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 Methods, cont.

At least two authors reviewed each article for inclusion.

Risk of bias was determined using the classification of
evidence for each study (Classes IIV).
Strength of practice recommendations were linked directly
to levels of evidence (Levels A, B, C, and U).
Conflicts of interest were disclosed.

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 Literature Review

136 abstracts Inclusion criteria:

- Articles dealing with TM
- Reports in humans,
abstracts available in
English
Exclusion criteria:
- Case reports, review
articles

65 articles

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 AAN Classification of Evidence
for Diagnostic Accuracy
Class I: A cohort study with prospective data collection of a broad spectrum
of persons with the suspected condition, using an acceptable reference
standard for case definition. The diagnostic test is objective or performed
and interpreted without knowledge of the patients clinical status. Study
results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the
condition established by an acceptable reference standard compared to a
broad spectrum of controls or a cohort study where a broad spectrum of
persons with the suspected condition where the data was collected
retrospectively. The diagnostic test is objective or performed and
interpreted without knowledge of disease status. Study results allow
calculation of measures of diagnostic accuracy.

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 AAN Classification of Evidence
for Diagnostic Accuracy, cont.
Class III: A case control study or cohort study where either persons
with the condition or controls are of a narrow spectrum. The condition
is established by an acceptable reference standard. The reference
standard and diagnostic test are objective or performed and
interpreted by different observers. Study results allow calculation of
measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II or III criteria including

consensus, expert opinion or a case report.

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 AAN Classification of Evidence
for Prognostic Accuracy
Class I: A cohort study of a broad spectrum of persons at risk for developing
the outcome (e.g. target disease, work status). The outcome is defined by an
acceptable reference standard for case definition. The outcome is objective or
measured by an observer who is masked to the presence of the risk factor.
Study results allow calculation of measures of prognostic accuracy.

Class II: A case control study of a broad spectrum of persons with the
condition compared to a broad spectrum of controls or a cohort study of a
broad spectrum of persons at risk for the outcome (e.g. target disease, work
status) where the data was collected retrospectively. The outcome is defined
by an acceptable reference standard for case definition. The outcome is
objective or measured by an observer who is masked to the presence of the
risk factor. Study results allow calculation of measures of prognostic accuracy.

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 AAN Classification of Evidence
for Prognostic Accuracy, cont.
Class III: A case control study or a cohort study where either the
persons with the condition or the controls are of a narrow spectrum
where the data was collected retrospectively. The outcome is defined
by an acceptable reference standard for case definition. The outcome
is objective or measured by an observer who did not determine the
presence of the risk factor. Study results allow calculation of measures
of a prognostic accuracy.

Class IV: Studies not meeting Class I, II or III criteria including

consensus, expert opinion or a case report.

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 AAN Classification of Evidence
for Therapeutic Intervention
Class I: A randomized, controlled clinical trial of the intervention of
interest with masked or objective outcome assessment, in a
representative population. Relevant baseline characteristics are
presented and substantially equivalent among treatment groups or
there is appropriate statistical adjustment for differences. The following
are also required:
o Concealed allocation
o Primary outcome(s) clearly defined
o Exclusion/inclusion criteria clearly defined

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 AAN Classification of Evidence
for Therapeutic Intervention, cont.
o Adequate accounting for dropouts (with at least 80% of enrolled subjects
completing the study) and crossovers with numbers sufficiently low to have
minimal potential for bias.
o For noninferiority or equivalence trials claiming to prove efficacy for one or
both drugs, the following are also required*:
The authors explicitly state the clinically meaningful difference to be excluded by
defining the threshold for equivalence or noninferiority.
The standard treatment used in the study is substantially similar to that used in
previous studies establishing efficacy of the standard treatment (e.g., for a drug, the
mode of administration, dose and dosage adjustments are similar to those
previously shown to be effective).
The inclusion and exclusion criteria for patient selection and the outcomes of
patients on the standard treatment are comparable to those of previous studies
establishing efficacy of the standard treatment.
The interpretation of the results of the study is based upon a per protocol analysis
that takes into account dropouts or crossovers.

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 AAN Classification of Evidence
for Therapeutic Intervention, cont.
Class II: A randomized controlled clinical trial of the intervention of
interest in a representative population with masked or objective
outcome assessment that lacks one criteria ae above or a
prospective matched cohort study with masked or objective outcome
assessment in a representative population that meets be above.
Relevant baseline characteristics are presented and substantially
equivalent among treatment groups or there is appropriate statistical
adjustment for differences.
Class III: All other controlled trials (including well-defined natural
history controls or patients serving as own controls) in a representative
population, where outcome is independently assessed, or
independently derived by objective outcome measurement.**

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 AAN Classification of Evidence
for Therapeutic Intervention, cont.
Class IV: Studies not meeting Class I, II or III criteria including
consensus or expert opinion.
*Note that numbers 13 in Class I, item 5 are required for Class II in equivalence trials. If
any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by
an observers (patient, treating physician, investigator) expectation or bias (e.g., blood
tests, administrative outcome data).

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 Clinical Question 1
Question 1: For patients with myelopathy,
which demographic, clinical, and laboratory
features are useful to distinguish TM from
other causes of acute and subacute
noncompressive myelopathy?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Demographic Features
Conclusion:
In patients presenting with acute myelopathy, age is possibly useful in
identifying patients at higher risk for spinal cord infarcts, and female gender is
possibly useful in identifying patients at higher risk for inflammatory
myelopathies (2 Class III studies).
Recommendation:
Age and gender may be considered useful to determine etiology in a patient
presenting with TM syndrome, with spinal infarcts seen more often in older
patients and more female than male patients having TM due to MS (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Features
Conclusion:
There is insufficient evidence to determine whether clinical features of
the myelopathy are associated with myelitis vs. other myelopathies.
Recommendation:
There is insufficient evidence to determine whether clinical features of
the myelopathy are associated with myelitis vs. other myelopathies
(Level U).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Laboratory Features
Conclusion:
For patients with subacute myelopathies, an elevated CSF leukocyte count (greater than
10 cells/mm3) is possibly useful in identifying patients with inflammatory myelopathies
(including TM) as opposed to those with spinal cord infarcts (2 Class III studies).
Recommendation:
For patients with subacute myelopathies, an elevated CSF leukocyte count (greater than
10 cells/mm3) may be considered useful in identifying patients with inflammatory
myelopathies (including TM) as opposed to those with spinal cord infarcts (Level C).*
*Recommendation not formally made in published guideline

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Question 2
Question 2: For patients with myelopathy,
which demographic, clinical, radiographic,
and laboratory features are useful to
determine the cause of the myelitis?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Demographic Features

Conclusion:
For patients with myelopathy, demographic features are possibly not
useful in distinguishing causes of myelitis (multiple Class III studies).
Recommendation:
Due to considerable overlap between groups, patient demographic
characteristics are not definitive in establishing the cause of myelopathy
(Level U).
There is insufficient evidence to support or refute the usefulness of
ethnicity to determine the cause of a subacute myelopathy (Level U).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Features

Conclusion:
Patients with myelopathy who present as having acute partial TM
(APTM) possibly have a higher risk of transition to MS vs. those
presenting as having acute complete TM (ACTM) (multiple Class III
studies).
Recommendation:
In patients with suspected TM, distinction between ACTM or APTM may
be considered useful to determine the etiology of TM (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Radiographic Features

Conclusion:
The longitudinal extent of MRI lesions is possibly useful in determining
the cause of TM (multiple Class III studies), specifically in distinguishing
between neuromyelitis optica (NMO) spectrum disorders and MS in
patients with idiopathic TM.
Recommendation:
Longer spinal lesions extending over more than 3 vertebral segments
may be considered useful in determining NMO vs. MS (Level C).

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 Radiographic Features, cont.
Conclusion:
In patients with TM, especially APTM, MS-like brain MRI abnormalities
possibly indicate a higher risk of conversion to clinically defined MS
(approximately 80% by 35 years after onset) (1 Class II study and multiple
Class III studies).
Recommendation:
Brain MRI characteristics consistent with those of MS may be considered
useful to predict conversion to MS after a first episode of partial TM (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Laboratory Features
Conclusion:
Aquaporin-4 specific autoantibodies (NMO-IgG) are probably useful to
establish the cause of TM (NMO or NMO spectrum disorder) in patients
with suspected TM (1 Class I study and several Class III studies).
Recommendation:
NMO immunoglobulin G (NMO-IgG) antibodies should be considered
useful to determine the cause of TM in patients presenting with clinical
features of ACTM (Level B).

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 Laboratory Features, cont.
Conclusions:
CSF analysis for OCBs is possibly useful in determining MS vs other causes of TM, specifically for
the diagnosis of MS vs NMO, spinal cord infarct, vasculitis, and parainfectious and idiopathic TM (1
Class II study and 8 Class III studies). Analysis of CSF for pleocytosis is possibly useful in
distinguishing NMO from MS (1 Class III study) and MS from all other causes of TM (1 Class III
study).
Recommendations:
CSF analysis for OCBs may be considered in determining MS vs. other causes of TM, specifically
for the diagnosis of MS vs. NMO, spinal cord infarct, vasculitis, and parainfectious and idiopathic TM
(Level C).* Analysis of CSF for pleocytosis may be considered in distinguishing NMO from MS and
MS from all other causes of TM (Level C).*
*Recommendation not formally made in published guideline

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 Clinical Question 3
Question 3: For patients with myelopathy,
which demographic, clinical, radiographic,
and laboratory features are useful to identify
patients at increased risk for recurrence ?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Demographic Features
Conclusion:
There is insufficient evidence to determine whether demographic
features are associated with relapsing TM.
Recommendation:
There is insufficient evidence to determine whether demographic
features are associated with relapsing TM (Level U).

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 Clinical Features
Conclusion:
Relapse rates possibly differ in patients with ACTM and patients with
APTM (Class III evidence from multiple studies), with relapse possibly
being more common in APTM.
Recommendation:
In patients with suspected TM, distinction between ACTM or APTM may
be considered useful to determine the risk for relapse (more common in
APTM) (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Radiographic Features
Conclusion:
Longer lesions on spinal MRI possibly predict a higher risk of developing NMO; therefore,
some risk of recurrent TM is suspected, but the risk relative to that from short lesions has
not yet been directly studied (Class III evidence from multiple studies). There is insufficient
evidence regarding the value of multiple short lesions in predicting relapse or transition to
MS (1 Class III study).
Recommendation:
Longer lesions on spinal MRI may be considered useful in predicting a higher risk of
developing NMO and therefore a higher risk of recurrent TM (Level C).*
*Recommendation not formally made in published guideline

2011 AMERICAN ACADEMY OF NEUROLOGY

 Laboratory Features
Conclusion:
The presence of NMO autoantibodies probably predicts relapse in patients
with TM (1 Class I study). There is insufficient evidence concerning whether
the presence of SSA antibodies predicts recurrence after a first episode of
TM (1 Class III study).
Recommendation:
The presence of NMO-IgG antibodies (aquaporin-4specific antibodies)
should be considered useful in determining an increased risk of TM
recurrence (Level B).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Question 4
Question 4: For patients with TM, which
therapies alleviate acute attacks?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Plasma Exchange
Conclusion:
The AAN recently published an evidence-based guideline on the efficacy of plasma exchange
for neurologic disorders, including TM.8 The guideline concluded: Based on a single Class II
study[9] plasmapheresis is possibly effective for acute fulminant CNS demyelinating diseases
(including . . . TM) that fail to respond to high-dose corticosteroid treatment. Because the
study included subgroups of patients with [different] demyelinating diseases, it is not possible
to determine if plasmapheresis is more or less effective in patients with [TM]. We found no
additional studies to warrant changing this conclusion.1012
Recommendation:
Plasma exchange may be considered in patients with TM who fail to improve after
corticosteroid treatment (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Rituximab

Conclusion:
Rituximab is possibly effective in reducing TM attacks in patients
with NMO (2 Class III studies).
Recommendation:
Rituximab may be considered in patients with TM due to NMO to
decrease the number of relapses (Level C).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Other Therapies
Conclusion:
In patients with TM, there is insufficient evidence to determine the utility of
corticosteroids in alleviating TM attacks (Class IV studies).
There is insufficient evidence to determine the efficacy of mitoxantrone in alleviating
TM attacks (single Class III studies).
There is insufficient evidence to determine the efficacy of azathioprine,
cyclophosphamide, and intravenous immunoglobulin in alleviating TM attacks (Class
IV studies).
Recommendation:
There is insufficient evidence to support or refute the efficacy of other therapies
(Level U).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Context

Despite the absence of evidence, administration of high-

dose intravenous methylprednisolone (1 g daily for 3 to 7
days) is typically the first treatment offered to hasten
recovery, reduce disease activity, and restore neurologic
function.

2011 AMERICAN ACADEMY OF NEUROLOGY

 Clinical Question 5

Question 5: For patients with TM, which

therapies prevent future attacks ?

2011 AMERICAN ACADEMY OF NEUROLOGY

 Other Immunosuppressive Strategies
Conclusion:
There is insufficient evidence regarding the use of other
immunosuppressive strategies to reduce the risk of future TM attacks.
Recommendation:
There is insufficient evidence regarding the use of other
immunosuppressive strategies to reduce the risk of future TM attacks
(Level U).

2011 AMERICAN ACADEMY OF NEUROLOGY

 Future Research

The efficacy of acute therapies, aimed at rapid intervention in acutely

declining patients, should be examined prospectively and should be
distinguished from efficacy of long-term therapies aimed at prevention
of relapse. These cohort studies should prospectively examine, over at
least a 3-year period, the clinical features of partial and complete TM,
the longitudinal extent of MRI lesions, the presence of NMO antibodies
or other laboratory information, and the presence or absence of
cerebral lesions typical of MS to predict prognosis for recovery and
relapse risk. Discriminant function analysis should be used to
determine which clinical features of idiopathic TM clearly differentiate
that condition from MS with myelopathy.

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 Future Research, cont.

Randomized trials of therapeutic interventions for TM, such as plasma

exchange or immunosuppressants, should be performed using
corticosteroid therapy as the gold standard for comparison and both
recovery and relapse as outcomes to be analyzed.

2011 AMERICAN ACADEMY OF NEUROLOGY

 References
1. Bastian HC. Thrombotic softening of the spinal cord: a case of so-called acute
myelitis. Lancet 1910;ii:15311534.
2. Rivers TM. Viruses. JAMA 1929;92:11471152.
3. Ford FR. The nervous complications of measles: with a summary of literature and
Publications of 12 additional case reports. Bull Johns Hopkins Hosp 1928;43:140
184.
4. Paine RS, Byers RK. Transverse myelopathy in childhood. AMA Am J Dis Child
1953;85:151163.
5. Berman M, Feldman S, Alter M, Zilber N, Kahana E. Acute transverse myelitis:
incidence and etiologic considerations. Neurology 1981;31:966971.
6. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and
nosology of acute transverse myelitis. Neurology 2002;59:499505.
7. Scott TF. Nosology of idiopathic transverse myelitis syndromes. Acta Neurol Scand
2007;115:371376.

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 References, cont.
8. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update:
plasmapheresis in neurologic disorders. Neurology 2011;76;294300.
9. Weinshenker BG, OBrien PC, Petterson TM, et al. A randomized trial of plasma
exchange in acute central nervous system inflammatory demyelinating disease. Ann
Neurol 1999;46:878886.
10. Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA. Idiopathic

transverse myelitis corticosteroids, plasma exchange, or cyclophosphamide.

Neurology 2007;68:16141617.
11. Bonnan M, Valentino R, Olindo S, Mehdaoui H, Smadja D, Cabre P. Plasma
exchange in severe spinal attacks associated with neuromyelitis optica spectrum
disorder. Mult Scler 2009;15:487492.
12. Watanabe S, Nakashima I, Misu T, et al. Therapeutic efficacy of plasma exchange in
NMO-IgG-positive patients with neuromyelitis optica. Mult Scler 2007;13:128132.

2011 AMERICAN ACADEMY OF NEUROLOGY

 References, cont.

For a complete list of references, please access the full

guideline at www.aan.com/guidelines

2011 AMERICAN ACADEMY OF NEUROLOGY

 Questions/Comments

2011 AMERICAN ACADEMY OF NEUROLOGY

 Thank you for your participation!

2011 AMERICAN ACADEMY OF NEUROLOGY