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SPECIAL ARTICLES: E. M. Frohman, D. S. Goodin, P. A. Calabresi, J. R. Corboy, P. K. Coyle, M. Filippi, J. A. Frank, S. L. Galetta, R. I. Grossman, K. Hawker, N. J. Kachuck, M. C. Levin, J. T. Phillips, M. K. Racke, V. M. Rivera, and W. H. Stuart The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology 2003; 61: 602-611 [Abstract] [Full text] [PDF]

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The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subc.

B.M. J. Uitdehaag, J.J.G. Geuerts, F. Barkhof, C.H. Polman   (20 April 2004)

Reply to Uitdehaag et al

Douglas S. Goodin, MD, Elliot M. Frohman, MD, PhD   (20 April 2004)

The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte

Elliot M. Frohman   (13 October 2003)

The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte

James M Gordon   (13 October 2003)

The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subc. 20 April 2004
B.M. J. Uitdehaag, VU Medical Centre, Amsterdam , J.J.G. Geuerts, F. Barkhof, C.H. Polman Send Correspondence to journal: Re: The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subc. bmj.uitdehaag{at}vumc.nl B.M. J. Uitdehaag, et al.	We read with interest the Report of the Therapeutics and Technology Assessment Subcommittee of the AAN.[1] The Subcommittee concludes that in patients with a typical clinically isolated syndrome the finding of even a few (three, perhaps even one) white matter lesions on a T2-weighted MRI scan is a more sensitive predictor of the subsequent development of clinically definite MS (CDMS) than the fulfillment of more stringent criteria as recommended by the International Panel on the diagnosis of MS. [2] However, it is also suggested that this increased sensitivity can be achieved without sacrificing specificity, a statement that we consider incorrect. In the studies they reviewed, several biases can be identified [3] including those due to patient selection like referral bias, patient filtering bias and spectrum bias. Although these biases do not necessarily affect the internal validity of a study, they limit the clinical applicability which is crucial for the purpose of the recommendations. Another bias is induced by the large number of patients lost to follow up. Since the gold standard is the diagnosis of CDMS verified during follow up, loss to follow up is a source of verification bias. Since sensitivity and specificity estimates are not valid when verification bias is present, it has been advocated to perform a sensitivity analysis in these situations. [4] Even more bias occurs when patients are excluded because of another diagnosis made during follow up. The Report correctly states that in our Centre, 10 patients from our original cohort were excluded because they were subsequently diagnosed as having a disease other than MS. [5] We present further data on those patients. These patients were referred to our Centre when MRI was not yet widely available in the Netherlands and clinicians specifically ordered MRI in less typical cases. The diagnoses subsequently made in these 10 patients from a cohort of 59 (16.9%) were: ischemic vascular disease in three, neoplasms in two, Lyme disease in two, acute disseminated encephalomyelitis in one, cervical stenosis in one, and ocular disease in one patient. Of these patients, eight had at least one cerebral white matter lesion, two at least three cerebral white matter lesions, and one (subsequently diagnosed as Lyme disease) five white matter lesions including three in the periventricular region. By contrast, none of these patients fulfilled the criteria for dissemination in space as recommended by the International Panel. [2] We agree with the Subcommittee that alternative diagnoses should be excluded, but this can be difficult at first presentation (table 2) of the Report which lists diagnostic alternatives, including ‘unidentified bright objects’. Specificity will therefore always be an issue with respect to MRI criteria for MS, especially when early initiation of treatment is considered. It is important to realize that increasing sensitivity will always be accompanied by decreasing specificity. Future research on this topic is urgently needed. The additional data we present here strongly suggest that the conclusions of the AAN Report should be interpreted with great caution. References 1. Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS. Neurology 2003;61:602-611. 2. McDonald WI, Compson A., Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-127. 3. Kelly S, Berry E, Roderick P, et al. The identification of bias in studies of the diagnostic performance of imaging modalities. Br J Radiol 1997;70:1028-1024. 4. Kosinski A, Barnhart H. A global sensitivity analysis of performance of a medical diagnostic test when verification bias is present. Statist Med 2003;22:2711-2721. 5. Barkhof F, Filippi M, Miller DH, et al. Comparison of MR imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059-2069.
Reply to Uitdehaag et al 20 April 2004
Douglas S. Goodin, MD, Chair, TTA Subcommittee , Elliot M. Frohman, MD, PhD Send Correspondence to journal: Re: Reply to Uitdehaag et al wedlund{at}aan.com Douglas S. Goodin, MD, et al.	Dr. Uitdehaag et al make the point that, for any diagnostic test, increasing sensitivity always occurs at the expense of decreasing specificity. We agree. However, the point that we tried to make in our assessment [1] was that even when the criteria for spatial dissemination are considerably more lenient (i.e., more sensitive) than those proposed by the International Committee [2], the specificity seems extremely good. We also agree that there are many sources of potential bias in the current literature and that, perhaps, the apparently low likelihood of developing any alternative diagnosis at follow-up is due to these biases. Nevertheless, the published literature seems remarkably consistent on this point. Perhaps, as these authors suggest, the criteria of a single lesion will turn out to be too lenient. However, even with the additional data now provided about their cohort [3], the International criteria still seem too stringent. Thus, in this cohort, the spatial dissemination criterion of three or more lesions has a specificity of 97% for either monophasic or recurrent demyelinating disease and a sensitivity of 65%. [3] By contrast, the International criteria have a specificity of 100% but a sensitivity of only 49%. [3] Considering that this multi-center cohort [3] included the highest percentage of patients diagnosed with alternative illnesses of any reported series (all of whom were from a single center), together with the high sensitivity and specificity for monophasic or recurrent demyelinating disease, suggests that the criterion of three or more lesions is more than adequate to establish dissemination in space. Importantly, criteria for spatial dissemination, unlike the criteria proposed by Barkhof et al [3], are not meant to predict the future development of MS or to diagnose MS at baseline. Clearly, such a diagnosis requires, in addition to spatial dissemination, the documentation of dissemination in time. In this regard, it is notable that our assessment essentially agreed with the International consensus panel that the occurrence of new T2 lesions or new Gd-enhancing lesions 3 or more months after the onset of a clinically isolated syndrome (CIS) is sufficient to establish such temporal dissemination and, thus, to make a diagnosis of MS once spatial criteria were satisfied. Moreover, in both of the published studies that have evaluated specifically the utility of the new International criteria [2], all of the added value from the new diagnostic scheme has come from the new MRI definition of temporal dissemination and not from the proposed spatial requirements. [1, 4, 5] Lastly, Dr.Uitdehaag et al bring up the important issue of early treatment. We acknowledge that there is evidence that early treatment of multiple sclerosis (MS) with disease modifying therapy may be advisable. However, whether patients with CIS (and who don’t yet meet any diagnostic criteria for MS) should be started on such therapy is still controversial. There is no current evidence regarding the effectiveness of treatment in patients who meet only International criteria for dissemination in space [2], although there is such evidence for patients who meet lesser MRI standards. [6,7] References 1. Frohman EM, Goodin DS, Phillips JT, et al. The utility of MRI in suspected MS. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003;61:602- 611. 2. McDonald, W.I., Compson, A., Edan, G., et al. Recommended diagnostic criteria for multiple sclerosis:Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-127. 3. Barkhof, F., Filippi, M., Miller, D.H., et al. Comparison of MR imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059-2069. 4. Dalton CM, Brex PA, Miszkiel KA, et al. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 2002;52:47-53. 5. Tintore M, Rovira A, Rio J, et al. New diagnostic criteria fro multiple sclerosis: Application in first demyelinating episode. Neurology 2003;60:27-30. 6. Jacobs, L.D., Beck, R.W., Simon, J.H., et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904. 7. Comi, G., Filippi, M., Barkhof, F., et al. Effect of early interferon treatment on conversion to definite multiple sclerosis:a randomized study. Lancet 2001;357:1576-1582.
The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte 13 October 2003
Elliot M. Frohman, University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., Dallas, TX 75390 Send Correspondence to journal: Re: The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte elliot.frohman{at}utsouthwestern.edu Elliot M. Frohman	We thank Dr. Gordon for his comments. Our paper was prinicipally focused on a very restricted question: What is the role of an MRI at the time of a clinically isolated syndrome (CIS) in predicting the future conversion to clinically definite MS? This leads to another contentious, yet very important question: After ruling out mimicking conditions, does the patient with a CIS and concomitant MRI abnormalities characteristic of MS already have the disease and are these patients appropriate candidates for disease modifying therapy? This question is particularly important in the context of two Class I clinical trials in patients with CIS that benefited from the clinical and radiologic surrogate markers of disease activity. [1,2] Gordon’s comments are central to the implications advanced by the guidelines-- Who should we treat? Our guidelines were not meant to be proscriptive with respect to the treatment of individual patients. The studies that we analyzed concerned statistical risks of conversion to definite MS not directly applicable to the assessment of individual patients. MS diagnosis and treatment intervention should be at the discretion of the responsible neurologist. As a clinician caring for many patients with MS, I advocate for starting disease-modifying therapy as soon as an MS diagnosis is confirmed. I agree that currently available therapies are expensive. MS-related disability is substantially more expensive in terms of physical and cognitive disability and it may result in the patient being incapable of achieving personal, educational, economic, and family goals. It is difficult to predict which patients at baseline are destined for a milder versus a more aggressive course of the disease. Natural history studies have been instructive in confirming that, over time, the majority of patients will have significant and limiting disability. As such, early diagnosis and treatment of MS should be considered as a prevention treatment strategy. References 1. Jacobs, L.D., Beck, R.W., Simon, J.H., et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating eventinmultiple sclerosis. N Engl J Med 2000;343:898-904. 2. Comi, G., Filippi, M., Barkhof, F., et al. Effect of earlyinterferon treatment on conversion to definite multiple sclerosis:a randomizedstudy.Lancet 2001;357:1576-1582.
The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte 13 October 2003
James M Gordon 1570 N 115th St., Suite 14, Seattle, WA 98133 Send Correspondence to journal: Re: The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommitte jgordon{at}nwhsea.org James M Gordon	In the review of MRI in the diagnosis of MS, the Academy's Therapeutics and Technology Assessment Subcommittee has produced an enlightening and scholarly review of available evidence on its limited topic, but ultimately fails to address the elephant in the room: Who should we treat? Available treatment for MS requires such enormous personal and social commitment that the issue of diagnostic certainty is especially acute in every single case. Does >80% likelihood of a second attack over 7 to 10 years sufficiently predict treatment for every patient with three MRI lesions and a clinically isolated syndrome with immunomodulatory therapy for the rest of his or her life? By saying that "selected cases" should be treated, selection criteria should be offered. Unfortunately, the technique of the diagnostic/therapeutic trial -- useful, for example, in diagnostically elusive rheumatological diseases-- makes no sense in MS (least of all, early MS) not merely because the cost is prohibitive, but because there exists no reliable short term response to judge their success, and therefore appropriateness. The success of immunomodulatory therapies does not depend upon their ability to relieve MS symptoms. So again: Who should we treat? In a society that already fails to provide a minimum of outpatient health care to all its citizens, we tread on thin ice when we threaten to make an already common, expensive and devastating disease still commoner and more costly. If MS affects one in one thousand in the population as a whole, what is the cost of treating 10 or even as few as 5% false positives? And how would this compare to other diseases where similar uncertainty exists? How would it affect our ability to treat persons afflicted with other neurological diseases? Perhaps a partial solution might begin with consensus criteria, created not by ad hoc working groups of interested experts, nor funded by highly motivated pharmaceutical manufacturers, but sponsored by representative organizations like the AAN or the WFN. The subcommittee’s report provides a challenging first step. Perhaps the next step might also be assigned to the subcommittee.