4 Demyelinating Disorders MULTIPLE SCLEROSIS Perhaps no neurological condition better illustrates the evolution of diagnostic criteria over time or has better known criteria than multiple sclerosis (MS). The criteria have evolved with technological advances in neuroimaging and diagnostic testing, so-called paraclinical data, as well as increased knowledge about the natural history of MS. However, despite the apparent increasing rate of diagnostic acumen and technical sophistication, we have had revisions 18 years, respectively, after each set of published criteria—Schumacher, 1965; Poser, 1983; and McDonald, 2001. Because of the increased reliance on magnetic resonance imaging (MRI) in the McDonald criteria, and the changes in terminology, many studies have looked at both the sensitivity and specificity of MRI in predicting MS after a single event, and comparisons with the Poser criteria. In light of the development of new therapies for MS and the realization that axonal loss may occur with demyelina- tion, even with a clinically isolated syndrome, there has been increased emphasis on early diagnosis by whatever criteria the clinician chooses. Tintore et al. examined individuals with a clinically isolated syndrome (that is, patients with a single episode) and MRI findings suggestive of MS. At a 1-year follow-up, 11% had clinically def- inite MS by Poser criteria and 37% by McDonald criteria. Eighty percent of those who fulfilled the McDonald criteria had a second event over the follow-up period (mean: 49 months). In another study, Fangerau et al. found that all patients with definite MS by Poser criteria met criteria by McDonald criteria. However, many of the patients labeled as laboratory-supported MS by Poser cri- teria would be classified as possible MS because of the inability to meet the additional data or sec- ond attack criteria. The MRI itself has been investigated in terms of interrater reliability. Even within this narrower field, there exist several criteria for what constitutes a positive MRI scan (for current criteria, see Tables 4 and 5). In general,there was poor agreement for the total number of lesions, and better agree- ment for the presence of a lesion. Interestingly, lesion location influenced agreement rates, and using a dichotomous lesion vs no lesion on T2-weighted images produced good agreement. NEUROMYELITIS OPTICA Also known as Devic’s disease, neuromyelitis optica (NMO) has been considered a syndrome in its own right or a variant of MS. It has generally been considered a rare disease, but it is unclear if this is because of true rarity vs poor ascertainment methods, or whether its incidence varies by population. It has been estimated to cause about 5% of demyelinating disorders in Japan and India. All of the criteria listed in Table 6 agree that NMO must present with optic neuritis and myelitis, but the relative timing is not always specified. The addition of neuroimaging criteria, especially the From: Current Clinical Neurology: Diagnostic Criteria in Neurology Edited by: A. J. Lerner © Humana Press Inc., Totowa, NJ 63 64 Diagnostic Criteria in Neurology Table 1 Schumacher Criteria for the Diagnosis of Multiple Sclerosis 1. Neurological examination reveals objective abnormalities of central nervous system (CNS) function. 2. History indicates involvement of two or more parts of the CNS. 3. CNS disease predominately reflects white matter involvement. 4. Involvement of CNS follows one of two patterns: a. Two or more episodes, each lasting at least 24 hours and at least 1 month apart. b. Slow or stepwise progression of signs and symptoms over at least 6 months. 5. Patient aged 10–50 years old at onset. 6.Signs and symptoms cannot be better explained by other disease process. Adapted from Schumacher FA, Beeve GW, Kibler RF, et al. Problems of experimental trials of multiple sclerosis. Ann NY Acad Sci 1965;122:552–568. Table 2 Poser Criteria for the Diagnosis of Multiple Sclerosis Clinically definite multiple sclerosis (MS) • Two attacks and clinical evidence of two separate lesions. • Two attacks, clinical evidence of one, and paraclinical evidencea of another separate lesion. Laboratory-supported definite MS • Two attacks, either clinical or paraclinical evidence of one lesion, and cerebrospinal fluid (CSF) immunological abnormalities. • One attack, clinical evidence of two separate lesions, and CSF abnormalities. • One attack, clinical evidence of one, and paraclinical evidence of another separate lesion, and CSF abnormalities. Clinically probable MS •Two attacks and clinical evidence of one lesion. • One attack and clinical evidence of two separate lesions. • One attack, clinical evidence of one lesion, and paraclinical evidence of another separate lesion. Laboratory-supported probable MS • Two attacks and CSF abnormalities. aParaclinical evidence includes the results of magnetic resonance imaging, evoked potentials, or other diagnostic tests of central nervous system dysfunction. (Adapted with permission from Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple scle- rosis: guidelines for research protocols Ann Neurol 1983;13:227–231, and from John Wiley and Sons.) requirement that the spinal lesion span several vertebral levels, has helped in excluding cases of MS that clinically present as NMO. The differential diagnosis must also include individuals with a his- tory of isolated optic neuritis who later develop a myelopathy. Care must be taken to ascertain that mass lesions, cervical spondylosis, or other pathological entities have been excluded. Conversely, there may be individuals with incomplete syndromes, such as recurrent optic neuritis or recurrent “transverse myelitis,” without other extensive disease who should be considered at-risk for develop- ing NMO. This is important, because the clinical course of NMO is often more virulent than typical MS. The current standard therapy for attack prevention combines oral corticosteroids with immuno- suppressive agents, such as azathioprine. Early initiation of therapy is recommended to prevent attack-related disability. TRANSVERSE MYELITIS An inflammatory disease of the spinal cord, transverse myelitis is a rare but often devastating syn- drome. Its incidence is about one to four individuals per million per year. It may be associated with Demyelinating Disorders 65 Table 3 McDonald Criteria for the Diagnosis of Multiple Sclerosis Clinical presentation Additional data needed for MS diagnosis Two or more attacks, objective clinical Nonea evidence of two or more lesions Two or more attacks, objective clinical Dissemination in space, demonstrated by: evidence of one lesion • MRI, or • Two or more MRI-detected lesions consistent with MS plus positive CSF, or • Further clinical attack, implicating a different site One attack; objective clinical evidence • Dissemination in time (demonstrated by MRI), or of two or more lesions • Second clinical attack One attack; objective clinical evidence Dissemination in space, demonstrated by: of one lesion (monosymptomatic • MRI, or presentation, clinically isolated • Two or more MRI-detected lesions consistent with syndrome) MS plus positive CSF, and Dissemination in time, demonstrated by: • MRI, or • Second clinical attack Insidious neurological progression Positive CSF, and suggestive of MS Dissemination in space, demonstrated by: •Nine or more T2 lesions in brain, or • Two or more lesions in spinal cord, or • Four to eight brain lesions plus one spinal cord lesion, or • Abnormal VEP associated with four to eight brain lesions, or • Abnormal VEP with fewer than four brain lesions plus one spinal cord lesion; and Dissemination in time, demonstrated by: • MRI, or • Continued progression for 1 year aCaution urged if all tests are negative. MS, multiple sclerosis; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid (oligoclonal bands or raised immunoglobulin G index); VEP, visually evoked potential. (Adapted with permission from McDonald WI, Compton A, Edan G, et al. Recommended diagnostic criteria for mul- tiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121–127, and from John Wiley and Sons.) Table 4 Guidelines for Magnetic Resonance Imaging Criteria or Brain Abnormality Three of the four following guidelines: 1. One gadolinium-enhancing lesion or nine T2-hyperintense lesions if there is no gadolinium-enhancing lesions. 2. At least one infratentorial lesion. 3. At least one juxtacortical lesion. 4. At least three periventricular lesions. Note: One spinal cord lesion can be substituted for one brain lesion. (Adapted with permission from McDonald WI, Compton A, Edan G, et al. Recommended diagnostic criteria for multi- ple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127.) numerous viral, bacterial, parasitic (e.g., schistosomiasis), or autoimmune collagen vascular diseases. Transverse myelitis may be the presenting symptom of MS, and is an integral part of NMO. 66 Diagnostic Criteria in Neurology Table 5 Magnetic Imaging Criteria for Dissemination of Lesions in Time 1. If a first scan occurs 3 months or more after the onset of the clinical event, the presence of a gadolinium- enhancing lesion is sufficient to demonstrate dissemination in time, provided that it is not at the site implicated in the original clinical event. If there is no enhancing lesion at this time, a follow-up scan is required. The timing of this scan is not crucial, but 3 months