CONFIDENTIAL: Not for publication, citation or dissemination 26

Elliott M. Frohman, MD PhD

MS#200202641

DRAFT April 3 2003

The Utility of MRI in Suspected MS

Report of the Therapeutics and Technology Assessment Subcommittee

of the American Academy of Neurology

Frohman EM, MD, University of Texas Southwestern Medical Center at Dallas; Goodin DS, MD, University of California at San Francisco; Calabresi PA, MD, University of Maryland; Corboy JR, MD, University of Colorado; Coyle PK, MD, State University of New York; Filippi M, MD, University of Milan; Frank JA, MD, National Institutes of Health; Galetta SL, MD, University of Pennsylvania; Grossman RI, MD, New York University; Hawker K, MD, University of Texas Southwestern Medical Center at Dallas; Kachuck NJ, MD, University of Southern California; Levin MC, MD, PhD, University of Tennessee; Phillips JT, MD, PhD, University of Texas Southwestern Medical Center at Dallas; Racke MK, MD, University of Texas Southwestern Medical Center at Dallas; Rivera VM, MD, Baylor College of Medicine; Stuart WH, MD, Peachtree Neurological Clinic

Correspondence:

Elliot M. Frohman, MD, PhD Wendy S. Edlund

University of Texas Manager, Clinical Practice Guidelines

Southwestern Medical School American Academy of Neurology

Department of Neurology 1080 Montreal Avenue

5323 Harry Hines Boulevard St. Paul, MN 55116

Dallas, TX 75235-9036 Tel: (651) 695-2716

Tel: (214) 648-9030 Fax: ((651) 361-4816

Fax: (214) 648-9129 Email:

Email:

Abstract

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both 'time and space'. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50-80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts the future conversion to clinically definite MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of clinically definite (CD) MS within the next 7-10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2-lesions or new Gd-enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, a normal MRI at the time of clinical presentation makes the future development of the CDMS considerably less likely.


Overview

MS affects up to 350,000 individuals in the United States.1 Different clinical courses of MS have been defined, including relapsing/remitting (RR) MS, secondary progressive (SP) MS, primary progressive (PP) MS, and progressive relapsing (PR) MS.2 RRMS is characterized by self-limited attacks of neurological dysfunction followed by a variable degree of recovery. By contrast, PPMS is characterized by a steady decline in neurologic function from onset, without superimposed attacks. MS often presents at a time when the clinical extent of disease is apparently limited, although, even at this early stage of disease, substantial damage may have already occurred.3-5 Thus, approximately 50-80% of individuals who present with a clinically isolated syndrome (CIS) already have lesions on MRI, consistent with prior (occult) disease activity.6-13 Two randomized, controlled trials of interferon beta (IFNb) have recently demonstrated a treatment benefit in patients with a CIS and MRI abnormalities suggestive of MS.14,15

All existing diagnostic criteria for RRMS, including those of Schumacher 16 and Poser 17 as well as a recent consensus statement 18, require two or more distinct events separated in time (generally by more than a month) in addition to involvement of at least two distinct areas of the central nervous system (the so-called criteria of dissemination in ‘time and space’). Importantly, also, all of the existing diagnostic schemes require the exclusion of alternative diagnoses by appropriate laboratory and radiographic studies prior to the application of the diagnostic algorithm. As a result, the sensitivity, specificity, and diagnostic accuracy of each scheme must be considered in the context of a population of patients from which individuals with alternative diagnoses have been largely culled. The Poser criteria utilize both clinical and paraclinical information (including MRI and evoked potentials) to establish spatial dissemination [Table 1].17 For example, a CIS coupled with a single white matter MRI abnormality in an area unrelated to the clinical presentation establishes dissemination in space17. Nevertheless, because the Poser scheme was developed at a time when MRI was in its infancy, and because white matter abnormalities are now known to be non-specific [Table 2], there is concern that these criteria (at least insofar as they relate to the distribution of MRI lesions) may permit a diagnosis of MS in circumstances where it is unjustified. By contrast, certain other features of the Poser scheme 17 seem overly restrictive and may, in some circumstances, prevent an appropriate diagnosis from being made. For example, there is no provision for the use of sequential paraclinical tests to establish dissemination in time, despite the fact that new lesions (presumably reflecting new disease activity) are commonly seen on follow-up MRIs of MS patients. Furthermore, these criteria have no provision for making a diagnosis of PPMS.

An international panel recently proposed new diagnostic criteria for both RRMS and PPMS.18 The new MRI criteria [Table 3],18 in some ways, are more stringent than those of Poser et al.17 For example, instead of a single lesion, these new criteria for spatial dissemination (MRI (a) criteria; Table 3) can be fulfilled based on a minimum of two lesions provided that one is located juxta-cortically, the other is located infra-tentorially, and, in addition, one of these two enhances with Gadolinium (Gd) administration, [Table 3]. If no Gd-enhancing lesions are detected, a minimum of five MRI lesions in specific locations must be demonstrated (three periventricular, one juxta-cortical, and one infra-tentorial) [Table 3]. By contrast, these new criteria 18 are, in some ways more permissive than those of Poser et al. 17 Thus, MRI criteria for establishing dissemination in time and for diagnosing PPMS are proposed; topics not addressed in the Poser scheme [Table 1] 17.

It is the purpose of this assessment to consider the evidence for the use of baseline and follow-up MRI in the diagnosis of patients with suspected MS. For the purpose of this assessment, the subsequent development of MS by purely clinical criteria was considered as the gold standard for comparison. Before reviewing the evidence, however, it is important to consider certain inherent limitations of the literature in this area. For example, consider a study looking at the predictive diagnostic validity of certain MRI features in patients with symptoms suggestive of MS. Often the design of such a study (as in this assessment) seeks to identify specific MRI features (present on the initial scan) and then to assess the ability of these features to predict the future development of MS. If the defined MRI features are both sensitive and specific for this outcome, then these baseline features are held to be useful in establishing the diagnosis of MS. Nevertheless, MRI features identified in this fashion (regardless of how strongly they are associated with future MS) do not constitute criteria for dissemination in space. Rather, they represent MRI features that help establish the diagnosis of MS at baseline (i.e., using these features to diagnose MS, there would be no need to await further developments). Moreover, any study of the predictive validity of MRI is dependant upon the ‘gold standard’ used to establish the diagnosis of MS. Generally, this standard is the development of clinically definite MS (CDMS) by some criteria, after some period of follow-up. Nevertheless, in a disease like MS (where the development of CDMS can be delayed by decades from the onset of clinical symptoms) such a design has serious limitations, especially when the follow-up is either too short or too variable. Most studies of the predictive validity of MRI in MS are confounded by this limitation. For example, in a prospective study of CIS patients followed for only 2 years, many of the patients classified as non-MS (because they have not yet developed CDMS), would still be expected to develop CDMS in the future. Moreover, if the period of follow-up is variable, each patient will not have had an equal chance to develop CDMS. In such circumstances, any calculated value for sensitivity, specificity, positive predictive value, or diagnostic accuracy will be invalid. The use of survival analysis methods might resolve, at least in part, some of these difficulties but, for some reason, these methods have not been widely employed in the clinical literature to date. In addition, it is not clear how best to measure specificity or predictive validity in these circumstances. Thus, it would be useful (from a therapeutic standpoint) to be able to distinguish a recurrent demyelinating disease (i.e., CDMS) from a non-recurrent demyelinating disease (i.e., a mono-phasic syndrome). Just as crucial however, is the important process of ascertaining which patients have another disease entirely (e.g., vitamin B12 deficiency, systemic lupus erythematosus, vasculitis, sarcoidosis, etc). Therefore, it is the specificity, sensitivity, positive predictive value, and diagnostic accuracy of MRI in differentiating against these possibilities that is especially relevant clinically. In addition, essentially all of the MRI data relating to this topic is derived from young to middle-aged adults so that the predictive value of MRI in children or elderly individuals in these contexts is not known.

Methods

In this assessment we consider the evidence that MRI can prospectively predict the future conversion to CDMS in patients presenting with a syndrome consistent with inflammatory demyelination (e.g., Table 4). A large panel of physicians including MS investigators, MS clinicians, and MS neuro-radiologists was assembled to analyze the evidence. A key-word search was undertaken using the following terms: clinically isolated syndromes, MS, and MRI.

We used the Medline database from 1966 to 2003. In addition, the reference lists of the articles identified were also reviewed to identify articles not found by the computer search. Using these methods we identified 46 articles. We reviewed the abstracts of these articles and further limited our assessment to English language studies that were prospective, and utilized a well-defined gold-standard for the development of CDMS. We only reviewed articles that studied at least 20 patients. There were 22 such studies identified.14, 15, 19-38 All of these articles considered the risk of developing CDMS in CIS patients, based on the presence or absence of MRI lesions within the brain or spinal cord. The studies differed with respect to the number of patients included, the length of follow up, and the definition of an abnormal scan [Table 5].14, 15, 19-39 The predictive validity of CSF and evoked potential recordings in MS has also been studied, 19, 28, 38, 40, 41 but is beyond the scope of the current assessment.

Analysis of the Evidence

Relationship of Non-enhancing Baseline MRI Features to the Risk of

Subsequently Developing MS

In 1988 the group from Queen Square 19 reported the initial findings from a prospective series of patients (Class II evidence because of the large number of patients lost to follow up) which initially included 135 individuals with clinically isolated syndromes (optic nerve, brainstem, and spinal cord) suggestive of MS who were first studied by MRI between 1984 and 1987. 19-24 By the time of the first reports,19, 20 only 109 patients remained in the cohort, apparently reflecting an early dropout of 26 patients. Also by the time of these initial reports, 19,20 an additional three patients had received alternative diagnoses to MS (established at baseline) and were excluded from further study. The MRI findings in these 3 patients are not reported. For the purpose of this study, an MRI was defined as abnormal if it contained a single asymptomatic lesion at baseline

In 1991, the experience in 89 of these 109 patients who had been followed for 5 years was reported. 21 This cohort included 45 patients of the original 61 patients with brainstem and spinal cord syndromes 20, plus an additional 44 patients with isolated optic neuritis derived from a cohort reported earlier 19. By the time of this report, an additional 20 patients had apparently been lost to follow-up 19-21. Three of the original 135 patients (2.2%) were found (by the time of this report 21) to have diseases other than MS (cerebrovascular disease, myasthenia gravis, and HIV). The MRI findings in these patients, however, are not reported and these patients were excluded from further analysis (leaving 132 patients in the study cohort). Forty six of these were apparently lost to follow-up by the time of this report .24 Of these 89 patients, 57 (64%) had abnormal MRIs at baseline. Of these, 72% developed CDMS at follow-up (Poser criteria 17) compared to only 6% in the group of patients without MRI abnormalities.

In 1994, a study of 89 of these CIS patients followed prospectively for 43 to 84 months after their initial MRI (Class II evidence) was reported.22 This cohort consisted of the same patients as that reported earlier by Morrissey et al. 21 These authors found that patients with T2-weighted lesion burdens in excess of 1.23 cm3 had a 90% risk of developing clinically definite MS during follow-up compared to only 6% in patients with a normal baseline MRI.

In 1998, a further report23 detailed their experience with 81 patients with CIS (these patients were derived from same initial cohort of 135 patients reported earlier. 19-22) who were followed for 10 years after their initial clinically isolated event (Class II evidence). Apparently, of the 89 patients reported earlier 21, eight had been lost to follow-up (two of whom apparently died from causes unrelated to MS). Fifty one of these patients (63%) had 2 or more T2-weighted white matter lesions on their baseline scans and, of these, 44 (86%) developed CDMS at follow-up compared to only 13% of patients without such MRI abnormalities. One additional patient was excluded from study because systemic lupus erythematosis (SLE) had been diagnosed rather than MS. As in the other patients with alternative diagnoses, the findings (if any) on the baseline MRI of this patient are not reported (making a total of four patients from the initial cohort with alternate diagnoses).