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Rapid Responses: Rapid Responses published:
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The clinical value of magnetic resonance imaging for the diagnosis of multiple sclerosis
- Chris H Polman, Stephen C. Reingold, Gilles Edan, Massimo Filippi, Hans-Peter Hartung, Ludwig Kappos, Fred D. Lublin, Luanne M. Metz, Henry F. McFarland, Paul W. O'Connor, Magnhild Sandberg-Wollheim, Alan J. Thompson and Jerry S. Wolinsky (31 March 2006)
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MRI is valuable in the diagnosis of multiple sclerosis
- David H Miller, Frederik Barkhof, Franz Fazekas, Massimo Filippi, Ludwig D Kappos, Xavier Montalban, Jacqueline Palace, Chris H Polman, Marco Rovaris, Alex Rovira, Nicola de Stefano, Alan J Thompson, and Tarek Yousry. (5 April 2006)
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Early diagnosis using MRI and early treatment definitely delays conversion to clinically definite MS
- Bharani Padmanabhan (14 April 2006)
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"Overdiagnoses"
- David Carvel (16 April 2006)
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Magnetic resonance imaging for the diagnosis of multiple sclerosis
- Jonathan A.C. Sterne, Jonathan J. Deeks, Penny Whiting, Roger Harbord, and Graziella Filippini. (22 April 2006)
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Meta-analysis for the sake of meta-analysis?
- Gavin Giovannoni (22 April 2006)
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MRi in the diagnosis of MS
- Douglas S. Goodin, 505 Parnassus Ave, San Francisco, CA 94143-0114 (22 November 2006)
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Chris H Polman, Professor of Neurology 1007 MB Amsterdam, Netherlands, Stephen C. Reingold, Gilles Edan, Massimo Filippi, Hans-Peter Hartung, Ludwig Kappos, Fred D. Lublin, Luanne M. Metz, Henry F. McFarland, Paul W. O'Connor, Magnhild Sandberg-Wollheim, Alan J. Thompson and Jerry S. Wolinsky
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We have read the manuscript by Whiting et al, that attempts to provide a different view on the role of magnetic resonance imaging (MRI) in the diagnosis of multiple sclerosis (MS)1. In our opinion this paper, by combining studies of such different design and quality, and such different patient selections, reduces 20 years of research and clinical practice into statistics that have little clinical relevance. In a past review paper one of the senior authors of this manuscript addresses this issue, and states that ‘the evaluation of the diagnostic accuracy of a test is only one component of assessing whether it is of clinical value’2. The statement –in the current paper- that MRI is of limited utility for both ruling in and ruling out MS, indicates that the authors have a lack of knowledge on the clinical differential diagnosis of a patient who presents to a neurologist with recent onset neurological dysfunction. Thoroughly conducted research and clinical experience over the last 20 years have shown that a diagnostic algorithm, of which MRI is an important component (in relation to other clinical and laboratory tests), provides the soundest ground for an early and objective diagnosis of MS. Such an algorithm was not properly tested in this study and therefore any conclusions that relate to clinical practice are unsubstantiated. 1. Whiting P, Harbord R, Main C, Deeks JJ, Filippini G, Egger M, Sterne JAC. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ 2006, online 2. Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. BMJ 2001; 323: 157-162. Chris H. Polman, Amsterdam, the Netherlands
On behalf of the International Panel on the Diagnosis of Multiple Sclerosis. Competing interests: None declared |
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David H Miller, Professor of Clinical Neurology Institute of Neurology, University College London, London WC1N 3BG, UK, Frederik Barkhof, Franz Fazekas, Massimo Filippi, Ludwig D Kappos, Xavier Montalban, Jacqueline Palace, Chris H Polman, Marco Rovaris, Alex Rovira, Nicola de Stefano, Alan J Thompson, and Tarek Yousry.
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In investigating the diagnostic utility of MRI in cases of suspected multiple sclerosis (MS), Whiting et al have evaluated imaging findings reported in many different studies – mainly whether or not there are any lesions present on a brain scan1. This approach does not reflect the real life situation where neurologists use a more detailed interpretation of MRI abnormalities in the context of the clinical findings to come up with a diagnosis. Clinicians deal with many different clinical settings that make the diagnosis of MS more or less likely and also have to consider the differential diagnosis. An early and reliable diagnosis facilitates best management and alleviates anxiety due to diagnostic uncertainty. While the diagnosis of MS is based primarily on clinical manifestations, it is often helpfully - and sometimes crucially - supported by laboratory investigations. When used appropriately, MRI – and sometimes CSF and neurophysiological (evoked potentials) examination - improves diagnostic accuracy and helps exclude or identify other important conditions2. Appropriate use of MRI in cases of suspected MS involves more than determining whether or not there is a lesion in the brain and if so how many. There are numerous causes of white matter lesions and the correct use of brain imaging to improve specificity in suspected MS will take in to account lesion location (Barkhof-Tintore criteria for dissemination in space3,4), lesion activity (gadolinium enhancement) and the appearance of new lesions (dissemination in time, a mandatory requirement in making the diagnosis of MS3). The currently accepted brain MRI criterion for dissemination in space3 has a higher specificity than 3 lesions per se for MS versus other neurological diseases5. Detection by MRI of the characteristic spinal cord lesions of MS is of particular diagnostic value6, and because a cord syndrome is the presenting feature of ~50% of MS patients, imaging of this region is often needed to exclude an alternative treatable disorder such as spinal cord compression. Whiting et al have underestimated the contribution that MRI makes in the diagnosis and differential diagnosis of MS, and might encourage some clinicians to avoid using this investigation when required. Failure to do so will generate errors of diagnosis and will also delay making the diagnosis of MS in people who have the disease. 1. Whiting P, Harbord R, Main C, et al (2006). Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ online 2. Miller DH, McDonald WI, Smith K (2005). The diagnosis of multiple sclerosis. In: McAlpine’s Multiple sclerosis 4th edition, Ed: A Compston, Elsevier, London, pp 347-388. 3. Polman CH, Reingold SC, Edan G, et al (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 58:840-6 4. Korteweg T, Tintore M, Uitdehaag B, et al (2006). MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study. Lancet Neurol 5:221-7 5. Nielsen JM, Korteweg T, Barkhof F, et al (2005). Overdiagnosis of multiple sclerosis and magnetic resonance imaging criteria. Ann Neurol 58:781-3. 6. Bot JC, Barkhof F, Lycklama G, et al (2002). Differentiation of multiple sclerosis from other inflammatory disorders and cerebrovascular disease: value of spinal MR imaging. Radiology 223:46-56. We are members of the Steering Committee of MAGNIMS, a European Network on Magnetic Resonance in Multiple Sclerosis Competing interests: None declared |
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Bharani Padmanabhan, Director - Angels MS Service Angels Neurological Centers, 536 Washington Street, Abington MA 02351, USA
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The authors of the meta-analysis "Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review, BMJ 2006; 332: 875-884" have done a grave disservice to MS patients worldwide. The statement in the Implications section --- Wrongly ruling out a diagnosis of multiple sclerosis after a first attack seems less dangerous: not all patients who experience a first attack will develop the disease and currently no treatment has been shown to delay conversion to clinically definite multiple sclerosis or impacts on long term disability --- is not only factually wrong, it is the most damaging of all. This statement ignores data collected pain-stakingly by numerous MS researchers and clinicians worldwide over the past 15 years that show repeatedly that early diagnosis is vital and early treatment leads to a far better outcome on numerous measures, immunological and clinical, than late treatment. For the past 2 years members of the MS community have been aware of data from Dr. R.P. Kinkel et al (the CHAMPIONS study) that in patients with just one MS attack, starting immune therapy with Interferon beta-1a can actually delay the patient meeting diagnostic criteria for clinically definite MS compared to untreated patients and that the untreated patients never quite catch-up when they eventually begin immune therapy. This data has been published [1]. MS is clearly a preventable diagnosis! In the recent conference of the American Academy of Neurology another study (BENEFIT) using Interferon beta-1b confirms this same point [2,3]. Delayed conversion to clinically definite multiple sclerosis with immune therapy is thus both widely known and published. The field of MS has slowly been moving towards early diagnosis and treatment because it is the best way yet known to avoid the accumulation of significant deficits in the daily life of patients and to afford them the best quality of life and health possible for the longest possible time. That is why so much effort has been put into MRI studies and early treatment trials. The efforts of Whiting et al run counter to this noble trend. Following the recommendations of the authors would take us back to the way things were 30 years ago. For the sake of MS patients worldwide I pray we do not return to those times! Bharani Padmanabhan MD PhD 1 Kinkel RP and the CHAMPIONS study group IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006 Mar 14;66(5):678-84. Epub 2006 Jan 25. 2 Early Treatment Delays Multiple Sclerosis Progression [S02.001] Betaseron® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Clinical Outcomes Authors: Mark S. Freedman et al for the BENEFIT Study Group Session Info: Scientific Sessions: Multiple Sclerosis: Clinical Trials I (2:00 PM - 3:00 PM) Presentation Time: Tuesday, April 4, 2006, 2:00 pm 3 [S02.002] Betaseron® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Subgroup Analyses Authors: Chris H. Polman et al for the BENEFIT Study Group Session Info: Scientific Sessions: Multiple Sclerosis: Clinical Trials I (2:00 PM - 3:00 PM) Presentation Time: Tuesday, April 4, 2006, 2:10 pm Competing interests: None declared |
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David Carvel, GP Biggar ML12 6BE
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Call me pedantic but the headline "MRI overdiagnoses multiple sclerosis", on the front cover of BMJ April 15 was both incorrectly and inappropriately worded. Firstly, "overdiagnoses" is neither a verb or indeed a word. "Diagnoses" is the plural of "diagnosis" and is a noun. Secondly and more importantly MRI, as with any other diagnostic tool, may demonstrate but does not diagnose anything. Doctors may use MRI to help form a diagnosis but if MRI had the capability to diagnose we would all be well on our way to redundancy. Semantics aside, it is of concern that more people are being diagnosed as having MS than actually have it. I treat an unfortunate patient who had more than one attack of neurological dysfunction. The MRI demonstrated "a single lesion of 9mm in the peri-trigonal white matter. Possible demyelination." The neurologist wisely adopted a "wait and see" policy. Sadly the insurance companies, on learning the scan report, "took fright" and the patient became literally uninsurable. It seems much work remains to be done on many fronts. Competing interests: None declared |
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Jonathan A.C. Sterne, Reader MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol, Jonathan J. Deeks, Penny Whiting, Roger Harbord, and Graziella Filippini.
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The quality of health care has improved immeasurably in recent years because of the combined efforts of doctors and researchers to use the best available evidence to inform decisions about clinical practice for individual patients. In the context of medical interventions, a large body of research clearly shows that it is wise to execute caution when estimating intervention effects from personal clinical experience, and that undertaking systematic reviews may act more towards patients’ best interests.(1) We hope that our paper will promote collaborations between doctors and researchers in the context of the diagnosis of multiple sclerosis (MS), rather than dividing different groups into opposing camps. We agree with Miller et al., and emphasised in our paper, that there are multiple reasons that magnetic resonance imaging (MRI) may be required in the clinical workup of patients with suspected MS, in particular its contribution to differential diagnoses. Our paper focussed on the narrower question of the diagnostic accuracy of MRI for MS. We also agree with Polman et al. that pooling 20 years of research on this topic into a single analysis would be misleading. For this reason, our review did not “combine studies of different design and quality”, as Polman et al. assert. In a paper that presented eight figures displaying different aspects of the diagnostic accuracy of MRI for MS, we quoted only two summary statistics for diagnostic accuracy.(2) These demonstrated conclusively (1) that MRI is diagnostic for MS (diagnostic odds ratio for cohort studies 9, 95% CI 5 to 16) and (2) that its diagnostic accuracy has been seriously exaggerated in case-control type evaluations that compare results of MRI images in a group of patients with MS with a separate group known not to have MS (diagnostic odds ratio 213, 95% CI 85 to 535). Given that the most widely used diagnostic algorithm (3) and a number of rules developed for interpreting MRI (4-6) were based on evidence from case-control studies as well as cohort studies, we proceeded to evaluate their diagnostic accuracy using available evidence from cohort studies alone. We were able to present results of studies evaluating both the McDonald 2001 criteria and commonly used MRI criteria (Barkhof, Paty, Fazekas) in cohort studies with up to 3 years’ follow up (McDonald, Barkhof, Fazekas) or 6 years’ follow up (Paty). To our knowledge, we evaluated all available evidence. Therefore, we do not know why Polman et al. believe in the existence of an algorithm that “was not properly tested in this study”. Even if a decision rule that includes MRI has good diagnostic accuracy this does not tell us the value of including MRI in the rule – to assess this requires a comparison of the performance of rules with and without inclusion of MRI. We need research that examines the additional diagnostic accuracy that results from adding MRI to clinical history and examination. As the diagnosis of MS depends on long-term clinical follow up, the diagnostic accuracy of newer MRI technologies will by definition not yet have been evaluated in cohort studies. Further, we found only limited evidence as to the diagnostic accuracy of gadolinium enhancement, spinal cord imaging and repeat scanning and therefore were unable to evaluate these separately, although they form part of the Barkhof and McDonald criteria. There was also insufficient evidence to evaluate the accuracy of MRI in patients presenting with different clinical symptoms. We question the assertion of Miller et al. that “a cord syndrome is the presenting feature of ~50% of MS patients”: the frequency of spinal cord lesions ranged from 9% to 45% in the highly selected series included in the review cited. Therefore, in clinical practice the accuracy of brain MRI in patients with a first clinical event suggestive of MS remains an important issue. We hope that our paper will stimulate further research that will address this and other relevant questions including the diagnostic value of newer MRI technologies, and hence clarify the best use of MRI in the diagnosis of MS. 1. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA. 1992;268:240-248. 2. Whiting P, Harbord R, Main C, Deeks JJ, Filippini G, Egger M, Sterne JAC. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ online, 2006 3. McDonald WI, Compston 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. 4. Barkhof F, Filippi M, Miller DH et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997;120:2059-2069 5. Fazekas F, Offenbacher H, Fuchs S et al. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology. 1988;38:1822-1825. 6. Paty DW, Oger JJ, Kastrukoff LF et al. MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology. 1988;38:180-185. Competing interests: None declared |
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Gavin Giovannoni, Reader in Clinical Neuroimmunology Institute of Neurology, UCL, Queen Square, London WC1N 3BG
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The attempted meta-analysis by Whiting and colleagues [1] on the “accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis” fails to take into account the definition of multiple sclerosis (MS) as a disease and the evolution of the diagnostic criteria based on this definition. MS can be defined conventionally as an inflammatory demyelinating disease of the central nervous characterised by mulifocal areas of demyelination and variable degrees of axonal loss and gliosis [2]. As this conventional definition of MS is not practical clinically, clinicians therefore have to depend on a pretheoretical definition [2] consisting of a set of polythetic clinical and paraclinical criteria, which in themselves define the disease. The underlying principles of these criteria require one to demonstrate involvement of more than one central nervous system white matter structure (anatomical dissemination) separated in time (temporal dissemination) and to exclude other potential causes of the clinical presentation. Despite appearing non-specific these criteria are probably quite specific in identifying MS during life when compared to the current gold-standard of pathological confirmation; neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%) [3]. The first set of polythetic criteria were purely clinical and were formulated by Schumacher and colleagues in the 1960’s [4]. The Schumacher criteria were then modified in 1982 [5] to include evoked potentials and CSF examination, and subsequently in 2000 [6] and 2005 [7] to include and refine the use of magnetic resonance imaging (MRI) in making a diagnosis of MS. Apart from the single Danish study referred to above [3], I am not aware of any large studies validating these criteria against a pathological diagnosis. One should therefore view these various sets of criteria as simply representing an evolving definition of MS and it therefore makes little sense to talk about the accuracy of MRI in making a diagnosis of MS, when the original criteria to what MRI is being compared have not be appropriately validated. Until we know the cause of MS and can define it using a theoretical definition [2], to talk about “inflated estimates of test performance” and “use of magnetic resonance imaging to confirm multiple sclerosis on the basis of a single attack of neurological dysfunction” makes little sense. As devils advocate I see no reason why we can’t make a diagnosis of MS in the pre-symptomatic phase of the illness. For example, a never symptomatic identical twin, of a subject with MS, undergoes a series of investigations as part of a research study. The asymptomatic twin has a normal neurological examination, but is found to have multiple lesions on MRI compatible with demyelination, abnormal visual and somatosensory evoked potentials due to central conduction slowing and locally synthesized oligoclonal IgG bands in the cerebrospinal fluid. Is this never symptomatic twin normal or does this subject have asymptomatic MS? Gavin Giovannoni 1. Whiting P, Harbord R, Main C, Deeks JJ, Filippini G, Egger M, et al. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. Bmj 2006;332(7546):875-84. 2. Flier FJ, de Vries Robbe PF. Nosology and causal necessity; the relation between defining a disease and discovering its necessary cause. Theor Med Bioeth 1999;20(6):577-88. 3. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand 1988;78(1):39-44. 4. Schumacker GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68. 5. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13(3):227-31. 6. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121-7. 7. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58(6):840-6. Competing interests: None declared |
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Douglas S. Goodin, Professor of Neurology University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0114
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I read with interest the paper by Whiting et al. (1) about the use of magnetic resonance imaging (MRI) in the diagnosis of multiple sclerosis (MS) that was recently published in the BMJ. These authors criticized the AAN position paper on this topic (2) as a "detailed (but not systematic)" review which “did not carry out any statistical synthesis”. I don't completely disagree with this assessment of our AAN effort. However, paradoxically, I believe that the more systematic and statistically rigorous methods used by Whiting and colleagues (1) have actually lead them to mischaracterize the evidence and, thus, to question inappropriately the value of getting an MRI in a patient with a clinically isolated syndrome (CIS). There are several reasons for this. First, contrary to the circumstances envisioned in the analysis of Whiting and colleagues (1), neither the Poser criteria (3) nor of the current International criteria (4) treat the MRI as the dichotomous variable for the diagnosis of MS. For example, in both schemes, MRI is used at baseline only to establish dissemination in space (and after laboratory investigations have been utilized to exclude certain alternative diagnoses). Even though the two schemes differ with regard to the amount of the MRI evidence needed (Poser requires only one non- symptomatic MRI lesion whereas the International MRI criteria are more stringent), it is clearly recognized by both schemes that there is no diagnostic test for MS at the CIS stage. Both agree that only a diagnosis of possible MS can be made until a subsequent event occurs. The International criteria allow that future event to be MRI based whereas the Poser criteria require that this second event be clinical. However, neither diagnostic scheme relies solely upon the MRI data. Rather, each of them incorporates historical, clinical, laboratory, and MRI evidence into a complex diagnostic algorithm. Second, contrary to the author’s assertion, the so-called false negative rate for MRI (i.e., ruling out MS) is not of concern to MS clinicians. In fact, there are no true false negatives. Regardless of whether or not patients meet the MRI spatial criteria, they are still considered only ‘possible MS’. In both cases, the patient will need to experience subsequent events, although the nature and number of those events will differ in different circumstances. Moreover, we never really give up on the diagnosis (i.e., declare that the patient does not have MS) unless we have a better explanation for their symptoms. For example, if a person has an idiopathic demyelinating optic neuritis, even if it occurred 25 years previously, we are still suspicious and would still make the diagnosis of MS at the time of a second event. Moreover, all CIS patients will be followed prospectively and the diagnosis revised as necessary unless the baseline MRI suggests an alternative diagnosis. Third, in analyzing the utility of MRI, Whiting and co-workers (1) derive their conclusions principally from two long-term studies that probably should have been discarded from their analysis (5, 6). Thus, the study by Brex and co-workers (5) had a drop-out rate (lost to follow-up) of almost 50% and is, therefore, unreliable. Similarly, the cohort from the optic neuritis treatment trial (ONTT) studied by Beck and colleagues (6) is also suspect (7). Thus, this cohort was assembled only after an undisclosed reclassification all of the baseline and follow-up diagnoses subsequent to their original publication (lowering the number of new MS cases at follow-up from 83 to 50 despite having one more year of data) and then by excluding from analysis some individuals (but not others) with probable MS or definite MS at baseline (7). The net result of these data manipulations is that the cohort from the ONTT is filled with patients who already had MS at baseline) and, although the direction of the resulting bias is unclear, any information derived from this cohort will be unreliable (7). Fourth, by contrast, the authors chose to ignore the most systematically collected prospective data available on the topic (8), even though its findings had been publicly presented (in detail) in the Fall of 2005, prior the acceptance of their paper by the BMJ. In this study, 487 well-characterized CIS patients were carefully screened for alternative diagnoses at baseline, were required to have two clinically silent MRI lesions, and were followed prospectively for two years with the a priori plan to following them prospectively for another 3 years. Follow-up was available for 93% of the cohort. In this study, the occurrence of International criteria MS was 85% and the occurrence of Poser criteria MS was 45% after 2 years in the placebo arm (8). Importantly, none of the patients in this cohort has developed an alternative diagnoses to either MS or continued CIS in the two years. In this clinical context, then, the accuracy of these criteria (including both clinical and MRI information at baseline) for diagnosing a demyelinating event (either a monophasic event [i.e., a continued CIS] or the recurrent condition we call MS) seem extraordinarily good over two years (an accuracy for subsequent International MS of 85% and a specificity for either MS or continued CIS of approximately 100%). We await the results of prospective 5-year study with interest. However, it seems likely that the clinical accuracy (Poser) will be considerable higher than the current 45% despite treatment, that the International criteria accuracy will be close to100%, and that the specificity will remain as it is now (approximately 100%). In short, the baseline MRI obtained in the setting of a CIS seems to provide an extremely important piece of information to any clinician taking care of patients with suspected MS. References 1. Whiting P, Harbord R, Main C, et al. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ 2006;332:875-84. 2. Frohman EM, Goodin DS, Calabresi PA, 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- 11. 3. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31. 4. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6. 5. Brex PA, Molyneux PD, Smiddy P, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346:158-64. 6. Beck RW, Smith CH, Gal RL, et al. Neurologic impairment 10 years after optic neuritis. Arch Neurol 2004;61:1386-9. 7. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: a reflection on the recent experience in multiple sclerosis. Neuroepidemiology 1999;18:53-63. 8. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006;67:1242- 9. Competing interests: None declared |
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