Implementing the 2017 Mcdonald Criteria for the Diagnosis of Multiple

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are needed to identify those lesions. The good news is that the lack of access to MRI Implementing the 2017 McDonald sequences that allow detection of cortical lesions is not a limiting factor for the use of criteria for the diagnosis of multiple the 2017 McDonald criteria. In addition to these two parameters, the sclerosis diagnostic criteria have not changed for patients with primary progressive MS.

Frauke Zipp , Jiwon Oh , Yara Dadalti Fragoso and Emmanuelle Waubant Have the new criteria affected the speed Abstract | The latest revision of the McDonald criteria for the diagnosis of multiple and accuracy of diagnosis? sclerosis (MS) was published online in 2017. New features of the criteria, which J.O. By far the most important impact were designed to facilitate earlier diagnosis of MS, include the recognition of of the 2017 revisions to the McDonald oligoclonal bands in the cerebrospinal fluid as a possible marker of dissemination criteria is that they allow earlier diagnosis of MS pathology in time, the introduction of symptomatic lesions as a parameter of relapsing–remitting MS (RRMS) when to demonstrate spatial or temporal pathology dissemination, and the use of an individual presents with a characteristic cortical lesions to demonstrate dissemination in space. In this Viewpoint, a panel clinical syndrome and suggestive MRI findings6. The ability to reach a more rapid of world-renowned MS specialists share their personal experiences of the new diagnosis of RRMS is mainly attributable to criteria to date. two changes: the presence of CSF-specific OCBs can demonstrate dissemination in How do the 2017 McDonald criteria defined in the 2017 revision. However, time, and there is no longer a distinction compare with the 2010 criteria? these parameters require specific protocols between symptomatic and asymptomatic for MRI and cerebrospinal fluid (CSF) lesions. As a result of these changes, the Frauke Zipp. The previous McDonald analyses. Specialized MS units may use these vast majority of patients with characteristic criteria for the diagnosis of multiple sclerosis protocols regularly, but this is not the reality clinical syndromes will receive a diagnosis (MS)1 included simplified criteria for for general neurologists in some countries. of RRMS after the first clinical presentation. MRI lesion assessment. The 2017 criteria2 The main challenge is to keep the With respect to primary progressive MS, on have further improved on the ease of physician working on differential diagnoses the other hand, the 2017 revisions do not implementation by including symptomatic rather than concluding, perhaps too soon, substantially affect the speed of diagnosis. lesions. This inclusion means that lesions that the patient has full-blown MS. The The benefit of more rapid diagnosis of can simply be counted without having first implications of a rushed diagnosis go far RRMS is countered by a small decrease to determine whether they are associated beyond giving a name to a disease. The in specificity in comparison to the 2010 with clinical symptoms. therapeutic options for MS are not harmless revisions7. However, the incremental as they directly affect the patient’s immune decrease in specificity is unlikely to be Jiwon Oh. Another noteworthy change in system. Once a patient receives the diagnosis a major issue as these clinical criteria the 2017 McDonald criteria is the inclusion of MS, it will be very complicated to should be applied only to individuals with of cortical lesions to demonstrate ‘undiagnose’ it and to tell the patient that, in suggestive clinical syndromes, and clinical dissemination of MS pathology in space. fact, he or she has another disease. In daily judgement is always key to making any Although this change is reflective of medical practice, it is unusual to recheck the diagnostic or treatment decisions. accumulating scientific evidence of the diagnosis unless something serious happens. clinical relevance of cortical lesions in MS3, Y.D.F. In order to increase the speed of it does not materially change the practical Emmanuelle Waubant. The 2017 McDonald diagnosis, one might have to accept a utility of the revised criteria, as cortical criteria may be a little easier for neurologists decrease in accuracy. Although this balanced lesions are not easily detected with the to use than previous criteria. For example, equation may seem strange to neurologists routine MRI sequences and magnet strengths an enhancing lesion on the first MRI scan, with extensive experience in MS, those who that are typically used in clinical practice4,5. regardless of whether it is a symptomatic see fewer patients might find the decreased lesion, counts towards dissemination in sensitivity challenging. Yara Dadalti Fragoso. The new criteria are time. Of note, another change to the criteria In countries where the prevalence of not particularly difficult to implement. The in 2017, the presence of cortical lesions, is CNS infections far outweighs that of MS, inclusion of cortical lesions, symptomatic not yet within the reach of routine clinical the 2017 McDonald criteria could pose an lesions (except for the optic nerve) and practice. Cortical lesions are often not extra problem. The presence of OCBs in oligoclonal bands (OCBs) as parameters for detectable with conventional MRI, even the CSF is now considered to be a marker dissemination in space and time is clearly with a 3T scanner, as specific sequences of dissemination of MS pathology in time.

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However, OCBs can also be found in be considered to have MS if their MRI scan with MS at baseline using the 2017 criteria. patients with infections, brain tumours or shows T2-bright changes in the deep white OCB positivity dropped from 74% in the lymphoproliferative disorders and can be matter and one focus displays enhancement original CIS cohort to 52% in the CIS cohort absent in patients with a definite diagnosis or OCBs are reported in the CSF, although reclassified according to the 2017 criteria. of MS, particularly in some areas of the they actually have another disorder. For world. In Brazil, for example, irrespective this reason, it remains crucial to carefully What has been the impact of the new of the method used for detecting OCBs in consider the clinical presentation when criteria on clinical practice? the CSF, only 54.4% of patients with definite making a diagnosis of MS. MS are positive for OCBs8. Furthermore, J.O. As a neurologist, I have found that the the African ancestry in Brazilian patients F.Z. Under the new criteria, discussion with revised diagnostic criteria have substantial increases the odds of OCBs in patients patients about their diagnosis is clearer at benefits in clinical practice, as I can more with MS. One study reported that 73.9% of an earlier stage. Previously, we would have easily make a definitive diagnosis in patients patients of African descent with definite MS advised patients with CIS who are positive presenting with a first clinical attack. had OCBs in the CSF, whereas only 48.5% of for intrathecal OCBs that they have potential Having a definitive diagnosis of MS allows patients of white ancestry had these bands9. early-stage MS, but OCBs are now included me to counsel patients appropriately and The same group of researchers showed that in the criteria for MS. Certainly, we will have with less uncertainty. In addition, the lack OCBs were present in 17.9% of patients with to follow up to see whether more people may of distinction between symptomatic and other disorders of the CNS, such as syphilis, be misdiagnosed under the new criteria. asymptomatic lesions obviates the need to hepatitis, schistosomiasis or human T- This is why diagnosing patients is an expert perform serial MRI scans in rapid succession, lymphotropic virus (HTLV) myelopathy8. activity, and neurologists should — as we which also has benefits with respect to If a patient with an infection is do — interpret original MRI scans as part of health-care resource utilization. Although misdiagnosed as having MS and is given the diagnostic process. the more frequent need for a lumbar immunosuppressive therapy, the 2017 puncture at diagnosis to demonstrate CSF- criteria will have done more harm than good Y.D.F. I am not particularly comfortable specific OCBs can utilize more resources for that person. Although it can be argued with the inclusion of OCBs as a marker of initially, the benefit of a more rapid diagnosis that clinical red flags should have been taken dissemination in time. From our point of of RRMS, and the ability to initiate DMT, if into consideration before prescribing MS view, many cases of ‘CIS’ have become MS appropriate, will result in substantial long- therapy, this expectation might not always be because the specialists who defined the term benefits that greatly outweigh the small realistic in the busy daily practice of general 2017 criteria voted for this, and there is no increase in resource use at diagnosis. neurologists. particular recommendation in the 2017 criteria to further investigate patients in E.W. The new criteria have had no impact E.W. The speed of MS diagnosis may whom dissemination in time is confirmed on my treatment decision-making as I treat be slightly increased for a few patients. exclusively through detection of OCBs. early (usually after the first clinical event) and However, confirming the diagnosis earlier Therapeutic decisions need to be accurate MS drugs are available in the USA for most is not necessarily meaningful in terms and not all drugs that are used to treat RRMS patients after a first demyelinating event, even of access to treatment in countries such have been evaluated for CIS. if they do not meet the McDonald criteria as the USA or Canada where patients for MS. Early treatment implementation is with clinically isolated syndrome (CIS) Is the distinction between CIS and MS especially important in patients with poor are allowed to receive disease-modifying still meaningful? prognostic features at onset. therapy (DMT), regardless of whether they meet the McDonald criteria for MS. By J.O. Overall, the 2017 revisions make Y.D.F. Unfortunately, the new 2017 criteria contrast, earlier diagnosis is an improvement the distinction between CIS and RRMS do not help us when we are conducting the in countries where patients with CIS who much less meaningful. In fact, it would differential diagnosis work-up. Cortical did not meet the 2010 McDonald criteria not be far-fetched to state that CIS is lesions that are seen in some infectious but now meet the 2017 criteria can receive becoming an obsolete disease entity. In diseases that mimic MS now count towards DMT. It should be emphasized, however, recent years, evidence has accumulated the diagnosis of MS. For example, spastic that diagnosing a patient with MS should that MS is a disease continuum and that paraparesis caused by HTLV may be not be considered equivalent to starting our characterization of MS subtypes is mistakenly diagnosed as primary progressive DMT. A small group of patients meet the suboptimal. As a result, these revisions MS. In some countries, the weight assigned McDonald criteria for MS, but their disease reflect evolving knowledge in the field and to imaging and CSF tests is too high in the characteristics are such that they may not allow simplification of treatment approaches, context of busy medical practices where benefit from being on a treatment to prevent which I believe is highly beneficial. a typical consultation lasts 15–20 min. MS exacerbations. Starting treatment Without the best protocols for MRI, remains at the discretion of the treating F.Z. The change in the distinction between including techniques for proper evaluation neurologist after discussion with the patient. CIS and MS means that many patients of cortical lesions, reports from imaging It is hard to comment on the accuracy of previously classified as having CIS can now clinics may not lead the physician towards diagnosis using the new criteria; prospective be given a definitive diagnosis of MS and have further investigations. Likewise, CSF studies based on general neurology practice access to a wider range of immunomodulatory analyses that are positive for OCBs but lack rather than academic MS centres will have drugs. In a CIS cohort in our centre, where the full immunological tests for potential to be completed to answer this question. It patients were initially diagnosed according infections may not clarify the situation. is conceivable that some patients with vague to the 2010 McDonald criteria, half of I live and work in Brazil, and the recent nonspecific neurological complaints will these patients would have been diagnosed outbreak of mosquito-borne arboviruses in

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my country is perhaps a good illustration states that the threshold for additional CSF of developing a chronic course after a single of the need for caution in making MS testing should be low, particularly if long- episode of symptoms have not changed, diagnoses. We receive patients with optic term DMT is being considered. and treatment decisions still require us to neuritis, brain lesions, encephalitis and balance the positive effects and risks of myelitis who have been diagnosed as having E.W. In a few select patients with a first DMT. Previously, we openly discussed the MS or neuromyelitis optica spectrum demyelinating event, the new criteria mean possibility of MS with patients who had disorder (NMOSD) but in fact have dengue, that they do not need a second MRI scan to CIS and OCBs, or when one lesion was Zika or chikungunya virus infections show dissemination in time if their initial lacking but differential diagnoses had been affecting their CNS10. I believe that it is a scan shows enhancement restricted to a excluded, although formal diagnosis was not step backwards to diagnose MS so early and symptomatic lesion or if CSF analysis reveals yet possible according to the 2010 criteria. prescribe immunosuppressive drugs to such OCBs that are not present in the serum. patients. The recent outbreak of yellow fever Therefore, in this small group of patients, Y.D.F. I am concerned about the effect in Brazil further emphasizes the importance establishing a diagnosis of MS may be of the 2017 criteria on the lives of my of distinguishing between MS and CNS more cost-effective with the 2017 criteria. patients. Through the internet, they have infections: vaccination against yellow fever In some countries, lumbar puncture is not full access to all new developments in is not recommended for patients with systematically performed for typical first diseases and treatments. I have a patient MS because of the attenuated live virus demyelinating events if imaging shows classic with one demyelinating lesion in his corpus component11. Furthermore, in our practice, changes suggestive of MS. As such, the new callosum who had one short-lived episode we have a notable number of cases of criteria are unlikely to result in an increased of double vision 5 years ago. He is not under NMOSD. To misdiagnose these patients as demand for lumbar puncture overall as often medication and, through his own choice, having MS and to treat them with MS drugs patients will prefer to wait for a repeat brain has never undergone CSF analysis. Once that worsen NMOSD is unjustifiable. MRI scan than to undergo a spinal tap. a year, he comes back for a new MRI scan, Many countries, particularly in the tropics, which remains unaltered. Now, he has read face similar issues to Brazil. The current What has been the impact of the new about OCBs being part of the MS diagnosis scenario is worrisome because the 2017 criteria on your patients? and wants to have this tested. In the unlikely criteria facilitate the diagnosis of MS but do event that we find that he is positive for not account for the different characteristics of J.O. From a patient’s perspective, I believe OCBs in his CSF, what should we do? Should particular regions of the globe. the revised criteria are beneficial for the we start therapy for MS? most part. First, having a definitive diagnosis On the other hand, having a definitive F.Z. The change in the distinction between of RRMS eliminates the uncertainty that diagnosis of MS can be detrimental for CIS and early MS diagnosis has the potential comes with a diagnosis of CIS. Although patients in specific situations. Stigma exists to change clinical decisions in that it could receiving a diagnosis of MS can initially be to some extent with any chronic disease, and put pressure on decision-makers to initiate distressing for many patients, in the longer a disease that affects patients in the prime treatment without taking into account the term most appreciate having a definitive of their lives can have substantial negative quality of the disease episode, the level of diagnosis as it allows people living with MS personal and professional repercussions. remission and lesion burden. We know that to educate themselves and enables personal A diagnosis of MS can have other negative early treatment prevents disease progression. and professional planning. In addition, and practical implications, including obtaining However, we also know that the kinetics of the perhaps most importantly, the revised criteria life insurance and even securing a disease are highly variable and some patients enable patients to access appropriate DMT, if home mortgage. Despite these potential do not undergo secondary progression12. appropriate. Accumulating evidence supports detrimental effects, however, I believe that Therefore, it is important that treatment the benefits of earlier treatment to prevent the benefits of a definitive diagnosis of MS decisions should continue to be made on a longer-term accumulation of neurological substantially outweigh the risks. case-by-case basis. In this respect, it is also disability, which can substantially change the useful to consider the American Academy of trajectory of a patient’s life14–16. Have the new criteria changed any of Neurology practice guidelines, which state your patients’ diagnoses? that after discussing the risks and benefits, F.Z. Questions of how to accept the clinicians should prescribe DMT to people relevance of a disease and whether to E.W. In the past year in my relatively with a single clinical demyelinating event and receive therapy depend more on individual large clinic, only two of my patients were two or more brain lesions characteristic of MS circumstances than on the diagnostic reclassified from a CIS to an MS diagnosis who decide they want this therapy but also criteria. A whole spectrum of factors should on the basis of the new criteria. It is hard to mention that patients without recent disease be taken into account in the treatment give a precise proportion of such patients activity may be followed up annually instead decision-making process, including drug in general, but this is rather an uncommon of starting treatment immediately13. mechanisms and safety, evidence-based situation. I explain to patients who are The new criteria have not brought about insights, tolerability, comfort, monitoring, reclassified from CIS to MS that it does not changes in practical issues in our centre. All family planning, professional conditions change their management. In fact, both of my expert centres in Germany already perform (such as starting a new job or still being in patients whose diagnosis changed with the lumbar puncture for initial diagnosis, thus a qualifying period), patient preference, new criteria were already on DMT owing to a we are not faced with the need to catch up therapy response and, ultimately, costs. substantial initial lesion load or to the severity on performing CSF analysis in order to The way in which we counsel patients of their first event. Neither patient exhibited select MS cases according to the new criteria. has not been substantially affected by the dissemination in time as per the 2010 criteria, To avoid losing specificity in diagnosis, the changes to the criteria. In practice, our as they started on effective treatment right international panel who wrote the guidelines discussions with patients regarding the risk away and did not experience any new relapses

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or MRI lesions. I also explain to my patients diagnostic criteria change as scientific another (definite MS) suddenly became the that the new criteria just change what we knowledge evolves and that these recent other one because of the new diagnostic call their early disease and that the criteria modifications reflect accumulating evidence, criteria. Her second consultation took longer are revised every 5–10 years with the goal which is beneficial overall for patients as it than the first because we had to explain to of enabling earlier diagnosis. In addition, allows earlier diagnosis and treatment of her why her diagnosis had changed. This although the 2017 criteria have not yet been RRMS, when appropriate. example is just an anecdotal case of a real- tested in Hispanic and Asian populations, life patient, but I think that it provides a ample data support the use of the 2010 Y.D.F. I had a particularly interesting case of good example from daily practice of the criteria, and I anticipate that the new criteria a young attorney who presented with optic consequences of changing the criteria. will be relevant in those populations. neuritis, five brain lesions on MRI (with no An issue that is often underestimated dissemination in time) and positive OCBs What is your overall experience with with changes in disease criteria is the in her CSF. I gave her a detailed explanation the new criteria? impact of these changes on existing research about the diagnosis of CIS and the risk of databases and the outcome of related conversion to clinically definite MS. She was J.O. Overall, my experience with the research projects. Should the diagnoses be treated in accordance with the guidelines for revised criteria has been positive, mainly updated every time the diagnostic criteria CIS and was asked to return after 45 days. related to the practical benefits in clinical change? It is unclear how changes in the When she returned, I had to explain to her care discussed above. In addition, from a criteria should be handled in long-term why her diagnosis had now changed from philosophical standpoint, I am supportive of databases that encompass decades of clinical CIS to definite MS according to the 2017 these revisions as I believe it is appropriate follow-up. criteria. I believe that this case illustrates the for diagnostic criteria to evolve over time, in problem well. She is an intelligent woman, line with accumulating scientific knowledge. F.Z. From time to time, a patient’s and we think that she understood what we The field of MS has evolved substantially employment status may be affected by how explained to her regarding the new criteria. in the past 7 years, and the latest revisions their diagnosis is named. For example, Nevertheless, I felt that she was somewhat are a reflection of a number of studies that it might be easier to find permanent suspicious that one condition (CIS) that have demonstrated the prognostic value of employment if they have experienced a single we were trying to avoid converting into CSF-specific OCBs17, the value of cortical episode of symptoms with full recovery than if they have received a diagnosis of a chronic The contributors disease, namely MS, that could lead to permanent disability. Under the old criteria, • Frauke Zipp’s research focuses on the crosstalk between the immune and nervous systems in a patient could have received a diagnosis of neuroimmunological diseases. Her research career started with a scholarship at the Max Planck CIS even if the possibility of chronicity was Institute Martinsried, Germany. She subsequently worked as a visiting scientist at the NIH, already suggested by OCB positivity. The Bethesda, MD, USA, before becoming a professor at Charité–Universitätsmedizin, Berlin, ‘red line’ is now drawn much earlier. Patients Germany. Here, she served as spokesperson of a Collaborative Research Centre (CRC) and Board Director of the Excellence Cluster NeuroCure. In 2009, she became Director of Neurology at the at these early stages of the disease, which University Medical Center, Mainz, Germany, and in 2012 she became a founding spokesperson of represent tremendously important decision a CRC on Multiple Sclerosis (MS). She is a member of the Competence Network MS Executive points in disease management, may stay Board, the European Committee for Treatment and Research in MS (ECTRIMS) Council, the MS away from medical professionals to avoid International Federation, the International Society of Neuroimmunology Board, Academia receiving such a diagnosis and therefore Europaea and Leopoldina. losing a relevant job opportunity. To take • Jiwon Oh is a neurologist and scientist at the University of Toronto, Ontario, Canada, specializing in some examples from our practice, after multiple sclerosis (MS). Her research programme focuses on developing advanced MRI techniques open and confidential discussion with the in the spinal cord and brain. She leads the MRI research programme at St Michael’s Hospital and has patients, one teacher was grateful for further established an MS clinic registry at her centre, which contributes to international registries. She is confidential advice although she was still also the Executive Secretary and a founding Steering Committee member of the North American in the qualifying period of her profession, Imaging in MS Cooperative (NAIMS), a multinational collaborative MRI research endeavour in MS whereas a police officer preferred to not that now includes 29 sites across the continent. She is leading the Canadian National Progression Cohort, a prospective cohort study that has been designed to better understand progression in MS. come to a neurologist again despite our recommendation that they should. • Yara Dadalti Fragoso is a Brazilian medical doctor who graduated in medicine in 1981 and in neurology in 1985. She moved to Trondheim, Norway, and then to Aberdeen, UK, where she J.O. obtained master’s and doctoral degrees in medicine. On her return to Brazil in 1995, she resumed I have encountered a few patients whose her work as a clinician and researcher, particularly in the fields of headache and demyelinating diagnoses have changed from CIS to RRMS diseases. With over 160 articles published, she works as a professor of medicine in the as a result of the new criteria. This change undergraduate and postgraduate programmes on Health and Environment at Universidade did not result in any material difference Metropolitana de Santos, Brazil. She has set up the MS & Headache Research Centre in Santos, with respect to my treatment approach, where she oversees the training of a specialized multidisciplinary team. because my general treatment approach • Emmanuelle Waubant received her medical degree from the University of Lille, France. She then with CIS is nearly identical to that with early trained in Toulouse, France, and at the University of California–San Francisco (UCSF), USA, in RRMS. However, I was able to formally adult neurology, neuroimmunology and multiple sclerosis (MS) clinical research. She is currently give my patients a diagnosis of RRMS. In Professor of Neurology and Pediatrics at UCSF and serves as Section Editor for Annals of Clinical each situation, I initiated a discussion with Translational Neurology and Co-Chief Editor for Multiple Sclerosis and Related Disorders. Her my patients about why it is necessary and specific research interests include the translation of promising agents from bench to bedside to beneficial for diagnostic criteria to change advance patient care and risk factors for MS susceptibility and disease modification in paediatric and adult MS. over time. Specifically, we discussed that

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lesions3–5 and an increasing recognition of McDonald criteria could consider taking 1. Polman, C. H. et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. the importance of earlier treatment in many damage of the neuronal compartment Ann. Neurol. 69, 292–302 (2011). patients with MS14–16. further into account, as this damage seems 2. Thompson, A. J. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. to have its own dynamic even in cases where 17, 162–173 (2018). E.W. The new criteria have not changed it has been initiated by inflammation22. 3. Nelson, F. et al. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive much of my practice in adult MS, although Neuronal compartment pathology is inversion recovery in combination with fast double they are simpler to use. It is important to not only interesting in explaining early inversion recovery MR imaging. AJNR Am. J. 21 Neuroradiol. 28, 1645–1649 (2007). keep in mind that these criteria are not only cognitive and behavioural dysfunction 4. Kilsdonk, I. D. et al. Increased cortical grey matter diagnostic but also have some prognostic but is also highly relevant for therapy23, lesion detection in multiple sclerosis with 7 T MRI: a post-mortem verification study. Brain 139, value. That is, patients in whom we can and it may soon be possible to monitor this 1472–1481 (2016). diagnose MS at the time of a first event are pathology with a surrogate marker other 5. van der Vuurst de Vries, R. M. et al. Application of the 2017 revised McDonald criteria for multiple sclerosis probably more likely to relapse promptly if than MRI, such as serum neurofilament to patients with a typical clinically isolated syndrome. untreated than are those who do not meet light chain24. JAMA Neurol. 75, 1392–1398 (2018). 6. Nielsen, A. S. et al. Contribution of cortical lesion the MS criteria at onset. For paediatric subtypes at 7T MRI to physical and cognitive demyelinating diseases, however, especially Y.D.F. I often feel that I am too conservative performance in MS. Neurology 81, 641–649 (2013). in patients aged ≤10 years, the McDonald regarding MS diagnoses and therapy. 7. Krieger, S. C. & Sumowski, J. New insights into multiple criteria must be used carefully at the time There is no doubt that early diagnosis and sclerosis clinical course from the topographical model and functional reserve. Neurol. Clin. 36, 13–25 of a presenting demyelinating event owing adequate treatment is ideal, but this rule (2018). to the possible clinical and MRI overlap is not exclusive to MS. All diseases are 8. Gama, P. D. et al. Study of oligoclonal bands restricted to the cerebrospinal fluid in multiple sclerosis patients with other diagnoses such as NMOSD and better controlled if diagnoses come early in the city of São Paulo. Arq. Neuropsiquiatr. 67, acute disseminated encephalomyelitis. In and treatment is given sooner. However, 1017–1022 (2009). 9. da Gama, P. D. et al. Oligoclonal bands in conclusion, the 2017 McDonald criteria the eagerness to diagnose the disease cerebrospinal fluid of black patients with multiple have simplified the diagnosis of MS, but they too soon and to treat it very aggressively sclerosis. Biomed. Res. Int. 2015, 217961 (2015). 10. Fragoso, Y. D. & Brooks, J. B. Encephalomyelitis should be tested in less highly selected adult requires further consideration. Differential associated with dengue fever. JAMA Neurol. 73, 1368 and paediatric cohorts to establish their diagnosis is a craft that physicians perform (2016). 11. Frederiksen, J. L. & Topsøe Mailand, M. Vaccines and sensitivity and specificity. under pressure and with limited financial multiple sclerosis. Acta Neurol. Scand. 136(Suppl. 201), resources. I worry about the ‘cancerization’ 49–51 (2017). F.Z. 12. Larochelle, C., Uphaus, T., Prat, A. & Zipp, F. The ease of MRI assessment and of of MS, whereby physicians are required Secondary progression in multiple sclerosis: neuronal diagnosing patients with MS on the basis of to ‘hit early and hit hard’. We cannot exhaustion or distinct pathology? Trends Neurosci. 39, 325–339 (2016). positivity for OCBs has highlighted the need sacrifice precision in order to hit early, 13. Bittner, S. & Zipp, F. AAN unveils new guidelines for to think critically, although we were already and we cannot hit hard with the therapy MS disease-modifying therapy. Nat. Rev. Neurol. 14, careful with our exclusion diagnostics in if a patient may have an infection. MS is 384–386 (2018). 14. Leray, E. et al. Evidence for a two-stage disability the past and revisited borderline cases over not a fatal disease, but MS therapy can progression in multiple sclerosis. Brain 133, time. OCBs are not specific for MS but may have a fatal outcome if administered 1900–1913 (2010). 15. PRISMS Study Group & The University of British also occur in infectious, paraneoplastic inappropriately. Columbia MS/MRI Analysis Group. PRISMS-4: long- or other autoimmune CNS disorders. term efficacy of interferon-β-1a in relapsing MS. Neurology 56, 1628–1636 (2001). Multicentre studies show that misdiagnosis J.O. An important caveat to note is that 16. University of California, San Francisco MS-EPIC is not uncommon in patients with MS. The when applying the 2017 McDonald criteria, Team. Long-term evolution of multiple sclerosis disability in the treatment era. Ann. Neurol. 80, most common misdiagnosis is migraine, a diagnosis of MS does not always imply 499–510 (2016). which is associated with occasional MRI that treatment is necessary. Ultimately, 17. Tintore, M. et al. Defining high, medium and low impact prognostic factors for developing multiple periventricular lesions in up to one-third of clinical judgement and consideration of an sclerosis. Brain 138, 1863–1874 (2015). cases18. individual patient’s specific circumstances 18. Solomon, A. J. et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. A problem with the new criteria is the are of paramount importance when making Neurology 87, 1393–1399 (2016). question of whether the new cohort of early- treatment decisions. 19. Preziosa, P. et al. Diagnosis of multiple sclerosis: a multicentre study to compare revised diagnosed patients — with CIS and no OCBs Frauke Zipp 1*, Jiwon Oh 2*, McDonald-2010 and Filippi-2010 criteria. — should be treated from the beginning. On Yara Dadalti Fragoso 3* and J. Neurol. Neurosurg. Psychiatry 89, 316–318 (2018). Emmanuelle Waubant4* the one hand, we know that non-repaired 20. Kolber, P. et al. Identification of cortical lesions using damage accumulates from the start of the 1Department of Neurology, Focus Program DIR and FLAIR in early stages of multiple sclerosis. Translational Neuroscience (FTN) and Immunotherapy J. Neurol. 262, 1473–1482 (2015). chronic disease. On the other hand, however, 21. Harrison, D. M. et al. Association of cortical lesion (FZI), Rhine Mein Neuroscience Network (rmn2), we have also followed up patients who have burden on 7-T magnetic resonance imaging with University Medical Center of the Johannes Gutenberg cognition and disability in multiple sclerosis. very rare relapses, full remission each time University Mainz, Mainz, Germany. JAMA Neurol. 72, 1004–1012 (2015). 22. Ellwardt, E. et al. Maladaptive cortical hyperactivity and no cognitive symptoms, as well as an 2 Division of Neurology, Department of Medicine, upon recovery from experimental autoimmune adverse response to all immunomodulatory St Michael’s Hospital, University of Toronto, Toronto, encephalomyelitis. Nat. Neurosci. 21, 1392–1403 treatments. The new CIS cohort of patients Ontario, Canada. (2018). 23. Zipp, F., Gold, R. & Wiendl, H. Identification of 3 has not yet been studied in trials, and Department of Neurology, Universidade inflammatory neuronal injury and prevention reanalysing the seminal CIS treatment trials Metropolitana de Santos, Santos, Sao Paulo, Brazil. of neuronal damage in multiple sclerosis: hope for novel therapies? JAMA Neurol. 70, 1569–1574 4Department of Neurology, University of California– to take into account the presence of OCBs (2013). would be worthwhile. San Francisco, San Francisco, CA, USA. 24. Siller, N. et al. Serum neurofilament light chain is a *e-mail: zipp@uni-mainz.de; [email protected]; biomarker of acute and chronic neuronal damage in The inclusion of the cortex as an early multiple sclerosis. Mult. Scler. 25, 678–686 [email protected]; [email protected] additional area where MS lesions can (2018). 19–21 https://doi.org/10.1038/s41582-019-0194-0 occur is a minor but relevant change Competing interests in the criteria. Future revisions of the Published online 13 May 2019 The authors declare no competing interests.

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