AMERICAN ACADEMY OF
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`NEUROLOGY
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`Special Article
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`This article is protected by copyright and is provided by .Wisconsin TechSearch
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`under license from Wolters Kluwer Health. All rights reserved.
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`mm—
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`NamezlpKLZOlg’H
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` The utility of MRI in suspected MS
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`Report of the Therapeutics and Technology Assessment
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`Subcommittee of the American Academy of Neurology
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`E.M. Frohman, MD, PhD; D.S. Goodin, MD; PA. Calabresi, MD; J.R. Corboy, MD; PK. Coyle, MD;
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`M; Filippi, MD; J.A. Frank, MD; S.L. Galetta, MD; R.I. Grossman, MD; K. Hawker, MD; NJ. Kachuck, MD;
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`M.C. Levin, MD, PhD; J.T. Phillips, MD, PhD; M.K. Racke, MD; V.M. Rivera, MD; and W.H. Stuart, MD
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`Abstract—Advancements in imaging technologies and newly evolving treatments offer the promise of more effective
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`management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstra-
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`tion of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques,
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`occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation.
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`Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS.
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`Indeed, in a young to middle-aged adult with a clinically isolated syndrome (ClS), once alternative diagnoses are excluded
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`at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions
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`is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS
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`within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and
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`the appearance of either new T2 lesions or new Gd enhancement on follow—up scans are also highly predictive of the
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`subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presenta-
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`tion makes the future development of CDMS considerably less likely.
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`NEUROLOGY 2003;61:602—611
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`Overview. Multiple sclerosis (MS) affects up to
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`350,000 individuals in the United States.1 Different
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`clinical courses of MS have been defined, including
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`relapsing/remitting (RR) MS, secondary progressive
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`(SP) MS, primary progressive (PP) MS, and progres-
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`sive relapsing (PR) MS.2 RRMS is‘ characterized by
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`self—limited attacks of neurologic dysfunction fol-
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`lowed by a variable degree of recovery. By contrast,
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`PPMS is characterized by a steady decline in neuro-
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`logic function from onset, without superimposed at-
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`tacks. MS often presents at a time when the clinical
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`tents for the September 9 issue to find the title link for this article.
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`Additional material related to this article can be found on the Neurology
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`Web site. Go to \vww.neurology.org and scroll down the Table of Con-
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`extent of disease is apparently limited, although,
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`even at this early stage of disease, substantial dam-
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`age may have already occurred?5 Thus, approxi-
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`mately 50 to 80% of individuals who present with a
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`clinically isolated syndrome (CIS) already have le-
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`sions on MRI, consistent with prior (occult) disease
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`activity.‘""13 Two randomized, controlled trials of in-
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`terferon beta (IFNB) have recently demonstrated a
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`treatment benefit in patients with a C18 and MRI
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`abnormalities suggestive of MS.‘“5
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`All existing diagnostic criteria for RRMS, includ-
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`ing those of Schumacher et al.‘6 and Poser et a1.17 as
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`well as a recent consensus statement,18 require two
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`or more distinct events separated in time (generally
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`by more than a month) in addition to involvement of
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`From the University ofTexas Southwestern Medical Center at Dallas (Drs. Frohman, Hawker, Phillips, and Racke); University of California at San Francisco
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`(Dr. Goodin); University of Maryland (Dr. Calabresi), Baltimore; University of Colorado (Dr. Carboy), Denver; State University of New York (Dr. Coyle),
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`Stony Brook; University of Milan (Dr. Filippi), Italy; National Institutes of Health (Dr. Frank), Bethesda, MD: University of Pennsylvania (Dr. Galetta),
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`Philadelphia; New York University (Dr. Grossman)‘, New York; University of Southern California (Dr. Kachuck), Los Angeles; University of Tennessee (Dr.
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`Levin); Baylor College of Medicine (Dr. Rivera), Houston, TX; and Peachtree Neurological Clinic (Dr. Stuart), Atlanta, GA.
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`Approved by the Therapeutics and Technology Assessment Subcommittee November 8, 2002. Approved by the AAN Board of Directors June 22, 2003.
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`Received December 12, 2002. Accepted in final form May 29, 2003.
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`Address correspondence and reprint requests to Dr. Elliot M. Frohman, University of Texas Southwestern Medical School. Department of Neurology, 5323
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`Harry Hines Boulevard, Dallas, TX 75235-9036; e-mail: elliot.frohman@utsouthwesternedu; or Wendy S. Edlund. Manager, Clinical Practice Guidelines,
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`American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116; e-mail: wedlund@aan.com
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`602 Copyright © 2003 by AAN Enterprises, Inc.
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`Page 1 of 10
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`Biogen Exhibit 2056
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`IPR 2018-01403
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`Page 1 of 10
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`

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`Table 1 Poser's criteria” for the diagnosis of multiple
`Table 2 Diagnostic considerations in patients with suspected
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`sclerosis (MS)
`multiple sclerosis or MRI white matter abnormalities
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`Age-related white matter changes
`Clinically delinite MS
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`A]: ‘2 Attacksi: + 2 lesions on examination?
`Acute disseminated encephalomyelitis
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`A2: 2 Attacks + 1 lesion on examination + 1 paraclinical
`Beheet disease
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`lesioni
`Bacterial infections (syphilis, Lyme disease)
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`Cerebral autosomal dominant arteriopathy, subcortical infarcts,
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`and leukoencephalopathy
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`Cervical spondylosis or stenosis
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`HIV infection
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`Human T—lymphotrophic virus [/11
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`lschemic optic neuropathy (arteritic and nonarteritic)
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`Leukodystrophies (e.g., adrenoleukodystrophy, metachromatic
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`leukodystrophy)
`Neoplasms (cg, lymphoma, glioma, meningioma)
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`Migraine
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`Sjogren syndrome
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`Stroke and ischemic cerebrovascular disease
`Systemic lupus erythematosus, antiphospholipid antibody
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`syndromes, and related collagen vascular disorders
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`Unidentified bright objects
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`Vascular malformations
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`Vasculitis (primary CNS or other)
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`Vitamin B12 deficiency
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`lesions (presumably reflecting new disease activity)
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`are commonly seen on followup MRI of patients
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`with MS. Furthermore, these criteria have no provi-
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`sion for making a diagnosis of PPMS.
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`An international panel recently proposed new di-
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`agnostic criteria for both RRMS and PPMS.18 The
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`new MRI criteria (table 3),‘8 in some ways, are more
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`stringent than those of Poser et al.‘7 For example,
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`instead of a single lesion, these new criteria for spa-
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`tial dissemination (MRI [a] criteria; see table 3) can
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`be fulfilled based on a minimum of two lesions pro-
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`vided that one is located juxtacortically, the other is
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`located infratentorially, and, in addition, one of these
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`two enhances with gadolinium (Gd) administration
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`(see table 3). If no Gd-enhancing lesions are de-
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`tected, a minimum of five MRI lesions in specific
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`locations must be demonstrated (three periventricu-
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`lar, one juxtacortical, and one infratentorial) (see ta—
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`ble 3). By contrast, these new criteria“ are, in some
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`ways, more permissive than those of Poser et al.‘7
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`Thus, MRI criteria for establishing dissemination in
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`time and for diagnosing PPMS, topics not addressed
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`in the Poser scheme, are proposed (see table 1).]7
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`It is the purpose of this assessment to consider the
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`evidence for the use of baseline and follow—up MRI in
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`the diagnosis of patients with suspected MS. For the
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`purpose of this assessment, the subsequent develop-
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`ment of MS by purely clinical criteria was considered
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`as the gold standard for comparison. Before review-
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`ing the evidence, however, it is important to consider
`September (1 of 2) 2003 NEUROLOGY 61
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`Laborator_\_'-supported definite MS
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`B]: 2 Attacks + 1 lesion on examination or 1 paraclinical
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`lesion + abnormal CSF§
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`1 Attack + 2 lesions on examination + abnormal CSF§
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`BB: 1 Attack + 1 lesion on examination + 1 paraclinical
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`lesion: + abnormal CSF§
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`Clinically probable MS
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`C1: 2 Attacks + 1 lesion on examination
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`1 Attack + 2 lesions on examination
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`C3:
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`lesion?
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`B2:
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`C2:
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`Laboratory-supported probable MS
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`D]: 2 Attacks + abnormal CSF§
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`:5: Symptoms lasting more than 24 hours would constitute an at-
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`tack even if they were “completely subjective and anamnestic.”
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`i Evidence of two separate lesions found on neurologic examina-
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`tion. Bilateral optic neuritis would constitute only one lesion
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`provided that the episodes of optic neuritis were separated by
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`less than 15 days.
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`: Includes lesions detected by MRI or evoked potentials.
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`§ CSF analysis demonstrates the presence of oligoclonal bands or
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`an increased CNS synthesis of immunoglobulin G.
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`at least two distinct areas of the CNS (the so—called
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`criteria of dissemination in time and space). Impor-
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`tantly, also, all of the existing diagnostic schemes
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`require the exclusion of alternative diagnoses by ap-
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`propriate laboratory and radiographic studies prior
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`to the application of the diagnostic algorithm. As a
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`result, the sensitivity, specificity, and diagnostic ac-
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`curacy of each scheme must be considered in the
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`context of a population of patients from which indi-
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`viduals with alternative diagnoses have been largely
`culled. The Poser criteria utilize both clinical and
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`paraclinical information (including MRI and evoked
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`potentials) to establish spatial dissemination (table
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`1).‘7 For example, a C18 coupled with a single white
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`matter MRI abnormality in an area unrelated to the
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`clinical presentation establishes dissemination in
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`space.‘7 Nevertheless, because the Poser scheme was
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`developed at a time when MRI was in its infancy,
`and because white matter abnormalities are now
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`known to be nonspecific (table 2), there is concern
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`that these criteria (at least insofar as they relate to
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`the distribution of MRI lesions) may permit a diag-
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`nosis of MS in circumstances where it is unjustified.
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`By contrast, certain other features of the Poser
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`scheme‘7 seem overly restrictive and may,
`in some
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`circumstances, prevent an appropriate diagnosis
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`from being made. For example, there is no provision
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`for the use of sequential paraclinical tests to estab-
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`lish dissemination in time, despite the fact that new
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`Table 3 Proposed McDonald criteria" for the diagnosis of
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`multiple sclerosis (MS)
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`Clinically definite MS“:
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`1: 2 Attacksi + 2 lesions on examinationif
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`2: 2 Attacks + 1 lesion on examination + [MRI (a)§ or 2 MRI
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`lesions + abnormal CSF‘fl]
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`3: 1 Attack + 2 lesions on examination + MRI (MN
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`4: 1 Attack + 1 lesion on examination + [MRI (a)§ or 2 MRI
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`lesions + abnormal CSF] + MRI (b)||
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`5: Progressive disease + abnormal CSF + MRI (b)|| +
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`a) [29 T2 MRI lesions or 22 spinal cord lesions or 4—8
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`brain MRI lesions + 1 spinal cord lesion]
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`OR
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`b) Abnormal VEP;L + [24 brain MRI lesions or <4 MRI
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`lesions + 1 spinal cord lesion]
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`* If the criteria are fulfilled and met, the diagnosis is MS. If the
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`criteria are not completely met, the diagnosis is possible MS. If
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`the criteria are fully explored and not met, the diagnosis is not
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`MS.
`T Symptoms lasting at least 24 hours would constitute an attack
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`provided that the episode was not a pseudoattack such as due
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`to fever or infection.
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`: Objective evidence of two lesions necessarily separated in space
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`found on neurologic examination. A typical subclinical lesion
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`detected by visual evoked potential testing (delayed response,
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`well preserved waveform) can substitute for one clinical lesion.
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`§ MRI (3): Criteria for dissemination in space: three of the four
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`following criteria need to be met:
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`1. 21 gadolinium (Och-enhancing lesion or 29 T2 lesions
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`2. 21 infratentorial MRI lesion
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`3. 21 juxtacortical lesion
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`4. 23 periventricular lesions
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`1 spinal cord lesion can substitute for 1 brain lesion
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`‘fl CSF analysis demonstrates the presence of oligoclonal bands
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`different from any such bands in the serum or an increased
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`immunoglobulin G index.
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`[I MRI (b): Criteria for dissemination in time:
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`1. If original MRI was performed <3 months after the clinical
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`attack, a follow-up MRI (>3 months after event) is neces-
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`sary. A new Gd-enhancing lesion on this follow-up MR1 pro«
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`vides evidence ofdissemination in time. Otherwise, another
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`follow-up MRI (>3 months after first MRI) is necessary. A
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`new Gd-enhancing or a new T2 lesion on this second
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`follow-up MRI provides evidence ofdissemination in time.
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`2. If the original MRI was performed 23 months after the clin-
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`ical attack, a Gd-enhancing lesion (at a site not implicated
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`by the clinical event) provides evidence of dissemination in
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`time. Otherwise, a follow-up MRI is necessary (suggested to
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`be 3 months after original MRI). A new Gd-enhancing or a
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`new T2 lesion on this MRI provides evidence of dissemina-
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`tion in time.
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`certain inherent limitations of the literature in this
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`area. For example, consider a study looking at the
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`predictive diagnostic validity of certain MRI features
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`in patients with symptoms suggestive of MS. Often
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`the design of such a study (as in this assessment)
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`seeks to identify specific MRI features (present on
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`the initial scan) and then to assess the ability of
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`these features to predict the future development of
`MS. If the defined MRI features are both sensitive
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`and specific for this outcome,
`then these baseline
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`features are held to be useful
`in establishing the
`604 NEUROLOGY 61 September (1 of 2) 2003
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`Page 3 0f 10
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`I“
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`diagnosis of MS. Nevertheless, MRI features identi-
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`fied in this fashion (regardless of how strongly they
`are associated with future MS) do not constitute cri-
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`teria for dissemination in space. Rather, they repre-
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`sent MRI features that help establish the diagnosis
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`of MS at baseline (i.e., using these features to diag-
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`nose MS, there would be no need to await further
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`developments). Moreover, any study of the predictive
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`validity of MRI is dependent upon the gold standard
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`used to establish the diagnosis of MS. Generally, this
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`standard is the development of clinically definite MS
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`(CDMS) by some criteria, after some period of follow-
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`up. Nevertheless, in a disease like MS (where the
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`development of CDMS can be delayed by decades
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`from the onset of clinical symptoms) such a design
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`serious
`limitations,
`especially when
`the
`has
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`follow-up is either too short or too variable. Most
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`studies of the predictive validity of MRI in MS are
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`confounded by this limitation. For example, in a pro-
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`spective study of patients with CIS followed for only
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`2 years, many of the patients classified as non-MS
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`(because they have not yet developed CDMS) would
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`still be expected to develop CDMS in the future.
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`Moreover, if the period of follow-up is variable, each
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`patient will not have had an equal chance to develop
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`CDMS. In such circumstances, any calculated value
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`for sensitivity, specificity, positive predictive value,
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`or diagnostic accuracy will be invalid. The use of
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`survival analysis methods might resolve, at least in
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`part, some of these difficulties but, for some reason,
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`these methods have not been widely employed in the
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`clinical literature to date. In addition, it is not clear
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`how best to measure specificity or predictive validity
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`in these circumstances. Thus,
`it would be useful
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`(from a therapeutic standpoint) to be able to distin-
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`guish a recurrent demyelinating disease (i.e., CDMS)
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`from a nonrecurrent demyelinating disease (i.e., a
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`monophasic syndrome). Just as crucial, however, is
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`the important process of ascertaining which patients
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`have another disease entirely (e.g., vitamin B12 defi—
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`ciency, systemic lupus erythematosus, vasculitis,
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`sarcoidosis).' Therefore, it is the specificity, sensitiv-
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`ity, positive predictive value, and diagnostic accu-
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`racy of MRI
`in differentiating against
`these
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`possibilities that is especially relevant clinically. In
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`addition, essentially all of the MRI data relating to
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`this topic are derived from young to middle-aged
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`adults, so that the predictive value of MRI in chil-
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`dren or elderly individuals in these contexts is not
`known.
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`Methods.
`In this assessment, we consider the evi-
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`dence that MRI can prospectively predict future con-
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`version to CDMS in patients presenting with a
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`syndrome consistent with inflammatory demyelina—
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`tion (e.g., table 4). A large panel of physicians includ-
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`ing MS investigators, MS clinicians, and MS
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`neuroradiologists was assembled to analyze the evi-
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`dence. A search was undertaken using the following
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`terms: clinically isolated syndromes, multiple sclero-
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`sis, andmagnetic resonance imaging.
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`Page 3 of 10
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`

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`Table 4 Clinically isolated syndromes cliaraclerislic of MS
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`Syndrome Features
`
`Optic neuritis
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`Typically unilateral
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`Retrobulbar
`
`f‘P‘P‘PP’Nh‘T’g’QFWNE
`.Nr-‘NHFI‘FPJN Paroxysmal dysarthria/a taxia
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`V
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`Typically painful
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`Some recovery expected
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`N0 retinal exudates
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`No macular star
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`Disc hemorrhages infrequent
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`Partial sensory or motor
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`Sensory more common
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`Lhermitte sign
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`Bowel and bladder dysfunction is common
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`“Band-like” abdominal or chest pressure
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`Acute dystonias
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`Ocular motor syndromes (cg,
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`internuclear ophthalmoparesis/
`
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`nystagmus)
`Hemisensory, crossed sensory syndromes
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`Hemiparesis
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`Trigeminal neuralgia
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`Hemifacial spasm
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`Cerebellar outflow tremor
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`. Acute ataxic syndrome
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`Tonic spasms
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`Myelitis
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`Brainstem/
`cerebrum
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`Cerebellum
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`Paroxysmal
`symptoms
`
`We used the Medline database from 1966 to 2003.
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`In addition, the reference lists of the articles identi-
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`fied were also reviewed to identify articles not found
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`by the computer search. Using these methods we
`identified 46 articles. We reviewed the abstracts of
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`these articles and further limited our assessment to
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`English language studies that were prospective and
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`utilized a well-defined gold standard for the develop-
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`ment of CDMS. We only reviewed articles that stud-
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`ied at least 20 patients. There were 22 such studies
`identified.”v‘5v“"38 All of these articles considered the
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`risk of developing CDMS in patients with CIS, based
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`on the presence or absence of MRI lesions within the
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`brain or spinal cord. The studies differed with respect
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`to the number of patients included,
`the length of
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`follow-up, and the definition of an abnormal scan (table
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`E-5, available online at www.neurology.org).“‘v'fiv‘g‘”
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`The predictive validity of CSF and evoked potential
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`recordings in MS has also been studied,‘9-23~33-“°-“ but is
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`beyond the scope of the current assessment.
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`Analysis of the evidence. Relationship of nonen-
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`harming baseline MRI features to the risk of subse-
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`quently developing MS.
`In 1988,
`the group from
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`Queen Square” reported the initial findings from a-
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`prospective series of patients (class II evidence be-
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`cause of the large number of patients lost to follow-
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`Page 4 of 10
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`up) that initially included 135 individuals with CIS
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`(optic nerve, brainstem, and spinal cord) suggestive
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`‘of MS who were first studied by MRI between 1984
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`and 1987.”?4 By the time of the first reports,”20 only
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`109 patients remained in the cohort, apparently re-
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`flecting an early dropout of 26 patients. Also by the
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`time of these initial reports,‘9vz° an additional three
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`patients had received alternative diagnoses to MS
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`(established at baseline) and were excluded from fur-
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`ther study. The MRI findings in these three patients
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`are not reported. For the purpose of this study, an
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`MRI was defined as abnormal ifit contained a single
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`asymptomatic lesion at baseline.
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`In 1991, the experience in 89 of these 109 patients
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`who had been followed for 5 years was reported.21
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`This cohort included 45 patients of the original 61
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`patients with brainstem and spinal cord syn-
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`dromes,20 plus an additional 44 patients with iso-
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`lated optic neuritis derived from a cohort reported
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`earlier.19 By the time of this report, an additional 20
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`patients had apparently been lost to follow-up.”21
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`Three of the original 135 patients (2.2%) were found
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`(by the time of this report“) to have diseases other
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`than MS (cerebrovascular disease, myasthenia gra-
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`vis, and HIV). The MRI findings in these patients,
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`however, are not reported and these patients were
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`excluded from further analysis (leaving 132 patients
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`in the study cohort). Forty-six of these were appar-
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`ently lost to follow-up by the time of this report.24 Of
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`these 89 patients, 57 (64%) had abnormal MRI at
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`baseline. Of
`these,
`72% developed CDMS at
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`follow-up (Poser criteria”) compared to only 6% in
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`the group of patients without MRI abnormalities.
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`In 1994, a study of 89 of these patients with C18
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`followed prospectively for 43 to 84 months after their
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`initial MRI (class II evidence) was reported.22 This
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`cohort consisted of the same patients as those re-
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`ported earlier by Morrissey et al.2‘ These authors
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`found that patients with T2-weighted lesion burdens
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`in excess of 1.23 cm3 had a 90% risk of developing
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`CDMS during follow-up compared to only 6% in pa-
`tients with a normal baseline MRI.
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`In 1998, a further report23 detailed their experi-
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`ence with 81 patients with CIS (these patients were
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`derived from the same initial cohort of 135 patients
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`reported earlierlg‘“) who were followed for 10 years
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`after their initial clinically isolated event (class II
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`evidence). Apparently, of the 89 patients reported
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`earlier,“ 8 had been lost to follow—up (2 of whom
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`apparently died from causes unrelated to MS). Fifty-
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`one of these patients (63%) had two or more T2-
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`weighted white matter lesions on their baseline
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`scans and, of these, 44 (86%) developed CDMS at
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`follow-up compared to only 13% of patients without
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`such MRI abnormalities. One additional patient was
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`excluded from study because systemic lupus ery-
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`thematosus had been diagnosed rather than MS. As
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`in the other patients with alternative diagnoses, the
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`findings (if any) on the baseline MRI of this patient
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`are not reported (making a total of four patients from
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`the initial cohort with alternate diagnoses).
`September (1 of 2) 2003 NEUROLOGY 61
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`In 2002, a 14-year follow-up study of 71 of these
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`patients with CIS (class II evidence) was published.‘-’“
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`This cohort represented the remaining group from
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`the initial Queen Square cohort of 135 patients re-
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`ported earlier.”23 Between this reportz'x and the pre-
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`vious one,23 an additional eight were lost to follow-
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`up, one refused to participate, and another was
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`diagnosed as having a cerebrovascular accident. Of
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`these 71 patients, 50 (70%) had an abnormal MRI at
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`baseline and, of these, 88% subsequently developed
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`CDMS. Moreover, 48 of these 50 patients (96%) had
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`developed either CDMS or probable MS using only
`the clinical criteria of Poser.‘7 Documentation of tem-
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`poral dissemination by either a new clinical exacer-
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`bation or the radiologic appearance of new lesions
`consistent with MS was observed in 98% of those
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`individuals with abnormal baseline MRI?“ In those
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`patients with CIS who had a normal MRI at base-
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`line, only 19% of 21 patients went on to develop
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`CDMS over the same period of follow-up. Neverthe-
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`less, over the 14-year period, 40% of those with a
`normal baseline MRI exhibited either new clinical
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`activity or evidence of new MRI lesions. Interest-
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`ingly, higher MRI lesion numbers and volumes at
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`baseline did not seem to predict higher conversion
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`rates to CDMS. Thus, the low MRI burden (1 to 3
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`lesions and mean lesion volume of 0.6 c1113), medium
`burden (4 to 10 lesions and mean lesion volume of
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`0.9 cm3), and high burden (>10 lesions and mean
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`lesion volume of 5.6 cma) were all associated with
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`similar rates of conversion to CDMS (89%, 87%, and
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`88%). This suggests that the presence of even a few
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`(perhaps even one) characteristic MRI abnormalities
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`in patients with a CIS is strongly predictive of the
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`ultimate development of CDMS.
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`Unfortunately, however, the authors of this Queen
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`Square cohort study did not utilize the statistical
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`method of survival analysis for their data and the
`actual survival function cannot be constructed for
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`the available reports. In addition, a large number of
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`patients have been lost to follow-up and the MRI
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`findings in those patients who developed alternative
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`diagnoses were omitted from consideration in the
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`available reports. These difficulties complicate inter-
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`pretation of this data set. Nevertheless, the reported
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`findings suggest that the presence of even a few MRI
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`abnormalities (one to three lesions at baseline) are
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`just as predictive for future MS as are larger lesion
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`loads. In addition, after excluding alternative diag—
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`noses at baseline, only a small number of patients5
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`from the original cohort were known to have received
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`alternative diagnoses to MS at follow-up.
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`In 1991, a study of 200 suspected MS patients
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`followed prospectively for a mean of 2.1 years (class I
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`evidence) was reported.25 MRI scans were classified
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`as strongly supportive of MS at baseline in 94 pa—
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`tients (47%) on the basis of having either four or
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`more T2—weighted lesions in the cerebral white mat-
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`ter or three lesions, one of which was situated
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`periventricularly. Of these patients, CDMS (Schu-
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`macher criteria) developed in 46 (49%) compared to
`606 NEUROLOGY 61
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`only 5% of patients who had normal baseline MRI.
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`Three patients (all over age 60 years at initial pre-
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`sentation) with MRI strongly supportive of MS had
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`received alternative diagnoses to MS at follow-up,
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`In 1991, the findings in 60 patients with a CIS
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`(class I evidence), 24 of whom had three or more
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`white matter lesions, at least one of which was
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`periventricular in location, were reported.26 Of these
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`24 patients, 71% progressed to CDMS after an aver-
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`age follow-up of 14.3 months compared to only 24%
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`in those without lesions. No alternative diagnosis to
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`MS or CIS was made or