Transcript Slide 1
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
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Endorsed by the Consortium of MS Centers
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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.
1 –5 • 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 2002 6 (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
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Recommendations
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? © 2011 AMERICAN ACADEMY OF NEUROLOGY
Literature Search/Review
Complete Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Select articles Relevant © 2011 AMERICAN ACADEMY OF NEUROLOGY
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 o Screening 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.
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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 © 2011 AMERICAN ACADEMY OF NEUROLOGY
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 I –IV).
• 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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136 abstracts
Literature Review
Inclusion criteria
: - Articles dealing with TM - Reports in humans, abstracts available in English
Exclusion criteria
: - Case reports, review articles 65 articles © 2011 AMERICAN ACADEMY OF NEUROLOGY
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 patient’s 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 © 2011 AMERICAN ACADEMY OF NEUROLOGY
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 a e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b e 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.** © 2011 AMERICAN ACADEMY OF NEUROLOGY
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 1 3 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 observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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/mm 3 ) 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/mm 3 ) 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
).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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 3 –5 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
).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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 © 2011 AMERICAN ACADEMY OF NEUROLOGY
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
).
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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-4 –specific 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.
10 –12
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.
© 2011 AMERICAN ACADEMY OF NEUROLOGY
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.
2.
3.
4.
5.
6.
7.
Bastian HC. Thrombotic softening of the spinal cord: a case of so called “acute myelitis.” Lancet 1910;ii:1531–1534. Rivers TM. Viruses. JAMA 1929;92:1147 –1152. 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. Paine RS, Byers RK. Transverse myelopathy in childhood. AMA Am J Dis Child 1953;85:151 –163. Berman M, Feldman S, Alter M, Zilber N, Kahana E. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1981;31:966 –971. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002;59:499 –505. Scott TF. Nosology of idiopathic transverse myelitis syndromes. Acta Neurol Scand 2007;115:371 –376.
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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;294 –300. 9. Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999;46:878 –886. 10. Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA. Idiopathic transverse myelitis corticosteroids, plasma exchange, or cyclophosphamide.
Neurology 2007;68:1614 –1617.
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;15:487 –492. 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;13:128 –132.
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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
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Thank you for your participation!
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