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Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria RAPID COMMUNICATION Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria 1 2 3 Chris H. Polman, MD, PhD, Stephen C. Reingold, PhD, Brenda Banwell, MD, 4 5 6 7 Michel Clanet, MD, Jeffrey A. Cohen, MD, Massimo Filippi, MD, Kazuo Fujihara, MD, 8 9 10 Eva Havrdova, MD, PhD, Michael Hutchinson, MD, Ludwig Kappos, MD, 11 12 13 Fred D. Lublin, MD, Xavier Montalban, MD, Paul O’Connor, MD, 14 15 Magnhild Sandberg-Wollheim, MD, PhD, Alan J. Thompson, MD, 16 17 18 Emmanuelle Waubant, MD, PhD, Brian Weinshenker, MD, and Jerry S. Wolinsky, MD New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. ANN NEUROL 2011;69:292–302 iagnostic criteria for multiple sclerosis (MS) include for their simplification to improve their comprehension 1,2 Dclinical and paraclinical laboratory assessments and utility and for evaluating their appropriateness in pop- emphasizing the need to demonstrate dissemination of ulations that differ from the largely Western Caucasian lesions in space (DIS) and time (DIT) and to exclude alter- adult populations from which the Criteria were derived. native diagnoses. Although the diagnosis can be made on In May 2010 in Dublin, Ireland, the International Panel clinical grounds alone, magnetic resonance imaging (MRI) on Diagnosis of MS (the Panel) met for a third time to of the central nervous system (CNS) can support, supple- examine requirements for demonstrating DIS and DIT 3–9 ment, or even replace some clinical criteria, as most and to focus on application of the McDonald Criteria in recently emphasized by the so-called McDonald Criteria of pediatric, Asian, and Latin American populations. 8,9 the International Panel on Diagnosis of MS. The McDo- nald Criteria have resulted in earlier diagnosis of MS with a Considerations Related to Revisions to the 10–13 high degree of both specificity and sensitivity, allowing McDonald Criteria for better counseling of patients and earlier treatment. The Panel reviewed published research related to the di- Since the revision of the McDonald Criteria in agnosis of MS and to the original and revised McDonald 2005, new data and consensus have pointed to the need Criteria, gathered from literature searches of English View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22366 Received Nov 2, 2010, and in revised form Dec 23, 2010. Accepted for publication Dec 29, 2010. Address correspondence to Dr Polman, Department of Neurology, VU Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, the Netherlands. E-mail: ch.polman@vumc.nl 1 2 3 From the Department of Neurology, Free University, Amsterdam, the Netherlands; Scientific and Clinical Review Associates LLC, New York, NY; Division 4 5 of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Neurosciences, University Hospital Center, Toulouse, France; Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinical Foundation, Cleveland, OH; Neuroimaging Research Unit, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Milan, Italy; Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology, First Faculty of Medicine, Charles University, Prague, Czech Republic; 9 10 St Vincent’s University Hospital, Elm Park, Dublin, Ireland; Departments of Neurology and Biomedicine, University Hospital, Kantonsspital, Basel, Switzerland; Corrine Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY; 12 13 Clinical Neuroimmunology Unit, Multiple Sclerosis Center of Catalonia, University Hospital Vall d’Hebron, Barcelona, Spain; Division of Neurology, St. 14 15 Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Neurology, University Hospital, Lund, Sweden; University College 16 17 London Institute of Neurology, United Kingdom; Multiple Sclerosis Center, University of California, San Francisco, CA; Department of Neurology, Mayo Clinic, Rochester, MN; and Department of Neurology, University of Texas Health Sciences Center, Houston, TX. 292 V 2011 American Neurological Association Polman et al: 2010 Revisions to MS Diagnosis language publications containing the terms multiple sclerosis to help make a differential diagnosis between NMO and and diagnosis, and from specific recommendations of rele- MS to help avoid misdiagnosis and to guide treatment. vant papers by Panelmembers.The Panelconcludedthat Correct interpretation of symptoms and signs is a most recent research supports the utility of the McDonald fundamental prerequisite for diagnosis. The Panel con- Criteria in a typical adult Caucasian population seen in MS sidered again what constitutes an attack (relapse, exacer- centers, despite only limited research and practical experi- bation) and defined this as patient-reported symptoms or ence in general neurology practice populations. objectively observed signs typical of an acute inflamma- In its discussions, the Panel stressed that the McDo- tory demyelinating event in the CNS, current or histori- nald Criteria should only be applied in those patients cal, with duration of at least 24 hours, in the absence of who present with a typical clinically isolated syndrome fever or infection. Although a new attack should be (CIS) suggestive of MS or symptoms consistent with a documented by contemporaneous neurological examina- CNS inflammatory demyelinating disease, because the tion, in the appropriate context, some historical events development and validation of the Criteria have been with symptoms and evolution characteristic for MS, but limited to patients with such presentations. CIS presenta- for which no objective neurological findings are docu- tions can be monofocal or multifocal, and typically mented, can provide reasonable evidence of a prior involve the optic nerve, brainstem/cerebellum, spinal demyelinating event. Reports of paroxysmal symptoms cord, or cerebral hemispheres. (historical or current) should, however, consist of multi- In applying the McDonald Criteria, it remains im- ple episodes occurring over not less than 24 hours. There perative that alternative diagnoses are considered and was consensus among the Panel members that before a excluded. Differential diagnosis in MS has been the sub- definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological exami- ject of previous data- and consensus-driven recommenda- nation, visual evoked potential (VEP) response in tions that point to common and less common alternative patients reporting prior visual disturbance, or MRI con- diagnoses for MS and identify clinical and paraclinical sistent with demyelination in the area of the CNS impli- red flags that should signal particular diagnostic cau- 14,15 cated in the historical report of neurological symptoms. tion. In its current review, the Panel focused specifi- The Panel concluded that the underlying concepts cally on the often-problematic differential diagnosis for of the original (2001) and revised (2005) McDonald Cri- MS of neuromyelitis optica (NMO) and NMO spectrum 8,9 teria are still valid, including the possibility of estab- disorders. There is increasing evidence of relapsing CNS lishing a diagnosis of MS based on objective demonstra- demyelinating disease characterized by involvement of tion of dissemination of lesions in both space and time optic nerves (unilateral or bilateral optic neuritis), often on clinical grounds alone or by careful and standardized severe myelopathy with MRI evidence of longitudinally integration of clinical and MRI findings. However, the extensive spinal cord lesions, often normal brain MRI (or Panel now recommends key changes in the McDonald with abnormalities atypical for MS), and serum aqua- 16,17 Criteria related to the use and interpretation of imaging porin-4 (AQP4) autoantibodies. There was agree- criteria for DIS and DIT as articulated by the recently ment that this phenotype should be separated from typi- 22–24 published work from the MAGNIMS research group. cal MS because of different clinical course, prognosis, Such changes are likely to further increase diagnostic sensi- and underlying pathophysiology and poor response to tivity without compromising specificity, while simplifying some available MS disease-modifying therapies. The the requirements for demonstration of both DIS and Panel recommends that this disorder should be carefully DIT, with fewer required MRI examinations. The Panel considered in the differential diagnosis of all patients pre- also makes specific recommendations for application of senting clinical and MRI features that are strongly sug- the McDonald Criteria in pediatric and in Asian and gestive of NMO or NMO spectrum disorder, especially Latin American populations. if (1) myelopathy is associated with MRI-detected spinal cord lesions longer than 3 spinal segments and primarily Recommended Modifications to the McDonald involving the central part of the spinal cord on axial sec- Criteria: The 2010 Revisions tions; (2) optic neuritis is bilateral and severe or associ- ated with a swollen optic nerve or chiasm lesion or an MAGNETIC RESONANCE IMAGING CRITERIA FOR altitudinal scotoma; and (3) intractable hiccough or nau- DIS. In past versions of the McDonald Criteria, DIS sea/vomiting is present for >2 days with evidence of a ´ demonstrated by MRI was based on the Barkhof/Tintore 19,20 4,6 periaqueductal medullary lesion on MRI. In patients criteria. Despite having good sensitivity and specificity, with such features, AQP4 serum testing should be used these criteria have been difficult to apply consistently by February 2011 293 ANNALS of Neurology More recently, the MAGNIMS group confirmed TABLE 1: 2010 McDonald MRI Criteria for 29,30 earlier studies by showing that, in patients with typi- Demonstration of DIS cal CIS, a single brain MRI study that demonstrates DIS DIS Can Be Demonstrated by 1 T2 Lesion in at and both asymptomatic gadolinium-enhancing and non- Least 2 of 4 Areas of the CNS: enhancing lesions is highly specific for predicting early Periventricular development of clinically definite MS (CDMS) and reli- 23,24 ably substitutes for prior imaging criteria for DIT. Juxtacortical After review of these data, the Panel accepted that the Infratentorial presence of both gadolinium-enhancing and nonenhancing Spinal cord lesions on the baseline MRI can substitute for a follow-up 22,27 Based on Swanton et al 2006, 2007. scan to confirm DIT (Table 2), as long as it can be reli- Gadolinium enhancement of lesions is not required for ably determined that the gadolinium-enhancing lesion is DIS. not due to non-MS pathology. If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do By using the recommended simplified MAGNIMS not contribute to lesion count. criteria to demonstrate DIS and allowing DIT to be MRI ¼ magnetic resonance imaging; DIS ¼ lesion dissemi- demonstrated by a scan containing both enhancing and nation in space; CNS ¼ central nervous system. nonenhancing lesions in regions of the CNS typical for MS, a diagnosis of MS can be made in some CIS 25,26 patients based on a single MRI. The Panel felt this is nonimaging specialists. The European MAGNIMS justified because it simplifies the diagnostic process with- multicenter collaborative research network, which studies ´ out reducing accuracy. However, a new clinical event or MRI in MS, compared the Barkhof/Tintore criteria for 4,6 serial imaging to show a new enhancing or T2 lesion will DIS with simplified criteria developed by Swanton and 22,27 still be required to establish DIT in those patients who colleagues. In the MAGNIMS work, DIS can be do not have both gadolinium-enhancing and nonenhanc- demonstrated with at least 1 T2 lesion in at least 2 of 4 ing lesions on their baseline MRI. locations considered characteristic for MS and as speci- fied in the original McDonald Criteria (juxtacortical, THE VALUE OF CEREBROSPINAL FLUID FINDINGS IN periventricular, infratentorial, and spinal cord), with DIAGNOSIS. The Panel reaffirmed that positive cere- lesions within the symptomatic region excluded in brospinal fluid (CSF) findings (elevated immunoglobulin patients with brainstem or spinal cord syndromes. In 282 G [IgG] index or 2 or more oligoclonal bands) can be CIS patients, the Swanton-based DIS criteria were shown important to support the inflammatory demyelinating to be simpler and slightly more sensitive than the origi- nature of the underlying condition, to evaluate alternative nal McDonald Criteria for DIS, without compromising 15,31 diagnoses, and to predict CDMS. In the 2001 and specificity and accuracy. The Panel accepted these 2005 McDonald Criteria, a positive CSF finding could MAGNIMS DIS Criteria, which can simplify the diag- be used to reduce the MRI requirements for reaching nostic process for MS while preserving specificity and DIS criteria (requiring only 2 or more MRI-detected improving sensitivity (Table 1). 8,9 lesions consistent with MS if the CSF was positive). However, when applying the simplified MAGNIMS MAGNETIC RESONANCE IMAGING CRITERIA FOR DIT. The 2005 revision of the McDonald Criteria sim- TABLE 2: 2010 McDonald MRI Criteria for plified the MRI evidence required for DIT, basing it on Demonstration of DIT the appearance of a new T2 lesion on a scan compared to a reference or baseline scan performed at least 30 days DIT Can Be Demonstrated by: after the onset of the initial clinical event. In clinical 1. A new T2 and/or gadolinium-enhancing lesion(s) practice, however, there is reason not to postpone a first on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI MRI until after 30 days of clinical onset, which would result in an extra MRI scan to confirm a diagnosis. Aban- 2. Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing doning the requirement for an extra reference MRI after lesions at any time 30 days does not compromise specificity, and therefore Based on Montalban et al 2010. the Panel, in its current revision of the McDonald Crite- MRI ¼ magnetic resonance imaging; DIT ¼ lesion dissemi- ria, allows a new T2 lesion to establish DIT irrespective of nation in time. the timing of the baseline MRI. 294 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis imaging criteria for DIS and DIT, the Panel believes TABLE 3: 2010 McDonald Criteria for Diagnosis of that even further liberalizing MRI requirements in CSF- MS in Disease with Progression from Onset positive patients is not appropriate, as CSF status was not PPMS May Be Diagnosed in Subjects With: evaluated for its contribution to the MAGNIMS criteria 22,24 1. One year of disease progression (retrospectively for DIS and DIT. Prospective studies using widely or prospectively determined) available standardized techniques and the most sensitive methods of detection of oligoclonal bands in the CSF to- 2. Plus 2 of the 3 following criteria : gether with the new imaging requirements are needed to A. Evidence for DIS in the brain based on 1T2 32,33 confirm the additional diagnostic value of CSF. lesions in at least 1 area characteristic for MS (periventricular, juxtacortical, or infratentorial) MAKING A DIAGNOSIS OF PRIMARY PROGRESSIVE B. Evidence for DIS in the spinal cord based MULTIPLE SCLEROSIS. In 2005, the Panel recom- on 2T2 lesions in the cord mended revising the McDonald Criteria for diagnosis of C. Positive CSF (isoelectric focusing evidence of primary progressive multiple sclerosis (PPMS) to require, oligoclonal bands and/or elevated IgG index) in addition to 1 year of disease progression, 2 of the fol- If a subject has a brainstem or spinal cord syndrome, all lowing 3 findings: positive brain MRI (9 T2 lesions or 4 symptomatic lesions are excluded from the Criteria. or more T2 lesions with positive VEP); positive spinal b Gadolinium enhancement of lesions is not required. cord MRI (2 focal T2 lesions); or positive CSF. These MS ¼ multiple sclerosis; PPMS ¼ primary progressive MS; DIS ¼ lesion dissemination in space; CSF ¼ cerebrospinal criteria reflected the special role of both CSF examina- fluid; IgG ¼ immunoglobulin G. tion and spinal cord MRI in PPMS, have been found to be practical and are generally well accepted by the neuro- logical community, and have been used as inclusion cri- tional in children and should prompt detailed considera- 42–45 teria for PPMS clinical trials. To harmonize MRI criteria tion of alternative diagnoses. About 80% of pediatric within the diagnostic criteria for all forms of MS, while cases, and nearly all adolescent onset cases, present with recognizing the special diagnostic needs for PPMS, the attacks typical for adult CIS, with a similar or greater total 46–48 Panel recommends that the McDonald Criteria require- T2 lesion burden. In children younger than 11 years, ment of fulfilling 2 of 3 MRI or CSF findings be main- lesions are larger and more ill-defined than in teenagers. tained for PPMS, with replacement of the previous brain Imaging criteria for demonstrating DIS in pediatric MS 38,50,51 imaging criterion with the new MAGNIMS brain imaging show high sensitivity and/or specificity. criterion for DIS (2 of 3 of the following: 1 T2 lesions The Panel’s consensus was that the proposed MAG- in at least 1 area characteristic for MS [periventricular, jux- NIMS-based MRI revisions for DIS will also serve well tacortical, or infratentorial]; 2 T2 lesions in the cord; or for most pediatric MS patients, especially those with acute positive CSF [isoelectric focusing evidence of oligoclonal demyelination presenting as CIS, because most pediatric bands and/or elevated IgG index]) (Table 3). This consen- patients will have >2 lesions and are very likely to have sus-based recommendation is justified by comparing diag- lesions in 2 of the 4 specified CNS locations (periventricu- nostic criteria for PPMS and by a subsequent reanalysis lar, brainstem-infratentorial, juxtacortical, or spinal cord). of these data (X. Montalban, personal communication). The frequency of spinal cord lesions in pediatric MS Use of MAGNIMS-based imaging criteria for PPMS with patients is currently unreported, but the appearance of or without associated CSF evaluation should be supported cord lesions in pediatric MS patients with spinal cord by additional data further documenting the sensitivity and symptoms appears generally similar to that of adults. specificity of the criteria in this population. However, approximately 15 to 20% of pediatric MS patients, most aged <11 years, present with ence- APPLICABILITY OF THE MCDONALD CRITERIA IN phalopathy and multifocal neurological deficits difficult PEDIATRIC, ASIAN, AND LATIN AMERICAN POPULA- to distinguish from acute disseminated encephalomyelitis TIONS. The McDonald Criteria were developed with 43,50 (ADEM). Current operational international consen- data gathered largely from adult Caucasian European and sus criteria for MS diagnosis in children with an ADEM- North American populations, and their applicability has like first attack require confirmation by 2 or more non- been questioned for other populations, particularly pedi- 37,38 39,40 41 ADEM like attacks, or 1 non-ADEM attack followed by atric cases, Asians, and Latin Americans. accrual of clinically silent lesions. Although children with an ADEM-like first MS attack are more likely Pediatric MS Over 95% of pediatric MS patients have an initial relaps- than children with monophasic ADEM to have 1 or ing–remitting disease course, whereas PPMS is excep- more non-enhancing T1 hypointense lesions, 2 or more February 2011 295 ANNALS of Neurology periventricular lesions, and the absence of a diffuse lesion of having NMO or NMO spectrum disorders, especially in pattern, these features are not absolutely discriminatory. patients with Asian or Latin American genetic background Furthermore, MRI scans of children with monophasic because of the higher prevalence of the disease in these ADEM typically demonstrate multiple variably enhancing populations. Such testing may be less important in those lesions (often >2) typically located in the juxtacortical subjects presenting with conventional Western type MS. white matter, infratentorial space, and spinal cord. Thus, Although not all patients with an NMO-like presentation application of the revised MAGNIMS-based criteria for will be AQP4 antibody positive, the majority are, whereas DIS and DIT on initial MRI would be inappropriate for those with MS are more likely to be AQP4 antibody nega- 16,56,61 such patients, and serial clinical and MRI observations are tive. CurrentevidencesuggeststhatonceNMO and required to confirm a diagnosis of MS. In this young age NMO spectrum disorders have been excluded, Western group, there can be marked lesion resolution following an type MS in Asia or Latin America is not fundamentally dif- initial attack prior to emergence over time of new lesions ferent from typical MS in the Caucasian population, and and attacks leading to a diagnosis of MS. that the MAGNIMS MRI criteria would apply for such patients, although confirmatory studies should be done. MS in Asian and Latin American Populations Among Asian patients with CNS inflammatory demyeli- The McDonald Criteria: 2010 Revisions nating disease, a phenotype characterized by NMO, lon- APPLICATION OF THE CRITERIA. The Panel recom- gitudinally extensive spinal cord lesions, and positive mends revisions to the McDonald Criteria for diagnosis of AQP4 autoantibody seropositivity has been relatively 55–57 MS (Table 4) focusing specifically on requirements to dem- more common than in Western populations. The onstrate DIS, DIT, and on diagnosis of PPMS. These 2010 Panel solicited input on use of the McDonald Criteria in revisions to the McDonald Criteria are likely to be applica- Asia and Latin America, where there is evidence of a sim- ble in pediatric, Asian, and Latin American populations ilar phenotype distinction. Although the McDonald once careful evaluation for other potential explanations for Criteria are widely used in these parts of the world, there the clinical presentation is made. The predictive validity of is some uncertainty, especially in Asia, about whether MS DIS and DIT based on a single first scan in children with and NMO are distinct and if so, how they should be dis- CIS needs to be confirmed in prospective studies. The tinguished. As currently applied, the term opticospinal McDonald Criteria have not yet been validated in Asian MS appears to be an admixture of conventional MS and and Latin American populations, and studies need to be NMO. Confusion has arisen (1) because of the recognition done to confirm the sensitivity and specificity of the Criteria that most cases of NMO are relapsing; (2) because AQP4 in such patients. Care must be taken to exclude NMO as a autoantibody testing has facilitated the diagnosis of NMO differential diagnosis, which can be confounded by the and permitted inclusion of individuals with symptomatic imperfect sensitivity of AQP-4 autoantibody assays, the pres- brain lesions who would previously have been excluded; ence of brain lesions in NMO, and the difficulty of detect- and (3) because of the recognition that selective involve- ing long spinal cord lesions in immunosuppressed patients. ment of optic nerve and spinal cord alone does not differ- entiate NMO from MS. It is insufficient to make a diag- Future Directions nosis of NMO in the absence of the required specificity criteria of the revised Wingerchuk Criteria for ‘‘definite’’ POTENTIAL ADDED VALUE OF BIOMARKERS. Al- NMO, which recommend presence of optic neuritis, acute though increased IgG index or the presence of oligoclonal myelitis, and at least 2 of 3 supportive paraclinical assess- bands in the CSF support an MS diagnosis, and AQP4 ments (a contiguous spinal cord lesion at least 3 segments antibody assays can help in the differential diagnosis pro- in length, brain MRI at onset that is nondiagnostic for cess, there are still no specific biomarkers to confirm the di- MS, or NMO-IgG seropositivity). These criteria are suc- agnosis. Several blood and CSF biomarkers may be promis- cessful in most instances to distinguish NMO from MS in 62–65 ing, and high-resolution spectral domain optical patients with optic neuritis and myelitis, but the spectrum coherence tomography might be as good as VEP in assess- of NMO includes recurrent myelitis and optic neuritis, ing visual involvement. The diagnostic utility of such NMO syndromes with symptomatic brain lesions at pre- markers needs to be validated and tested prospectively. sentation, and NMO associated with systemic autoimmune diseases. Failure to make the correct diagnosis in patients REFINEMENTS IN IMAGING CRITERIA. The McDo- with NMO may impact treatment. nald Criteria were based on detection of lesions generally The Panel recommends testing for AQP4 autoanti- using 1.5T magnet strength in noncortical regions of the bodies with validated assays in patients who are suspected brain and spinal cord. However, a large proportion of 296 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis TABLE 4: The 2010 McDonald Criteria for Diagnosis of MS Clinical Presentation Additional Data Needed for MS Diagnosis a c 2 attacks ; objective clinical None evidence of 2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack 2 attacks ; objective clinical Dissemination in space, demonstrated by: evidence of 1 lesion 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ;or Await a further clinical attack implicating a different CNS site 1 attack ; objective clinical Dissemination in time, demonstrated by: evidence of 2 lesions Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack 1 attack ; objective clinical Dissemination in space and time, demonstrated by: evidence of 1 lesion For DIS: (clinically isolated syndrome) 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ;or Await a second clinical attack implicating a different CNS site; and For DIT: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack Insidious neurological progression 1 year of disease progression (retrospectively or prospectively suggestive of MS (PPMS) determined) plus 2 of 3 of the following criteria : 1. Evidence for DIS in the brain based on 1 T2 lesions in the MS-characteristic (periventricular, juxtacortical, or infratentorial) regions 2. Evidence for DIS in the spinal cord based on 2T2 lesions in the cord 3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ‘‘MS’’; if suspicious, but the Criteria are not completely met, the diagnosis is ‘‘possible MS’’; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is ‘‘not MS.’’ An attack (relapse; exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occur- ring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms. Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and evolution character- istics for a prior inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings. No additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these Criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical pre- sentation, and objective evidence must be present to support a diagnosis of MS. Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes. MS ¼ multiple sclerosis; CNS ¼ central nervous system; MRI ¼ magnetic resonance imaging; DIS ¼ dissemination in space; DIT ¼ dissemination in time; PPMS ¼ primary progressive multiple sclerosis; CSF ¼ cerebrospinal fluid; IgG ¼ immunoglobulin G. February 2011 297 ANNALS of Neurology 67,68 MS lesions are in the cortex and can be detected The Panel acknowledges that using these refined 69–74 using double inversion recovery imaging. The pres- diagnostic criteria may change some of the outcomes of ence of at least 1 intracortical lesion in subjects with CIS patients in natural history studies and clinical trials, may help identify subjects at high risk for developing when original expectations for outcomes may be based CDMS. Magnet strengths >1.5T with tailored acquisi- on subjects whose diagnosis was made using past, some- 76–79 91 tion protocols may also enhance diagnosis, with what different criteria. Most of the currently recom- improvements in image resolution, signal-to-noise ratio, mended revisions are based upon new data generated and chemical shift. Scans at 7.0T showed lesions in the since the 2005 revisions. However, there remains a need white and gray matter with enhanced in vivo detection for further testing in prospective and retrospective data- 80–83 of pathological hallmarks of MS lesions. Finally, sets of many of these criteria, especially in populations of MRI techniques such as magnetic transfer imaging allow patients typical of those seen in general neurology prac- the detection of damage outside focal lesions (for tices, both to further assess their value and utility and to instance, in normal-appearing brain tissues) not present provide suggestions for further refinements in the future. 15,84,85 in conditions such as ADEM and NMO. The utility of these scanning technologies for MS diagnosis in Acknowledgment patients with CIS remains a matter for future research The work of the Panel was supported by the US and validation. National Multiple Sclerosis Society (NMSS), the Euro- Many individuals with high lesion loads may have pean Committee for Treatment and Research in Multiple had a protracted subclinical disease course prior to their Sclerosis, the Multiple Sclerosis International Federation, first clinical event. As a consequence, occasional individu- and MS Ireland. als investigated by MRI for indications unrelated to MS The Panel thanks Drs T. Saida, M. Lana-Peixoto, have incidental findings of brain lesions with appearance D. Callegaro, and C. Oehninger for help in gaining per- and topography consistent with MS. Detection of this spective on the use of the McDonald Criteria in Asia presymptomatic phase, or radiologically isolated syn- and Latin America. drome, is increasingly common. Some of these individu- This work is dedicated to the memory of Dr W. als followed clinically and by serial imaging will develop Ian McDonald, who chaired the original Panel and DIT by MRI, and some have clinical disease-defining whose continuing inspiration has driven the work for the 86–89 events after several years. However, in the absence of second and third revisions to the Criteria that now bear supportive research findings, the Panel concluded that a his name. firm diagnosis of MS based on incidental findings on MRI alone, even with additional supportive findings on Potential Conflicts of Interest evoked potentials or typical CSF findings in the absence C.H.P.: consultancy, Actelion, Biogen Idec, Bayer Scher- of MS-relevant clinical symptoms, is problematic. A ing, Teva, Merck-Serono, Novartis, Glaxo SK, UCB, future definite diagnosis of MS, however, cannot be Roche, Antisense Ther; expert testimony, Biogen Idec; excluded and may be likely, depending on the evolution grants/grants pending, Biogen Idec, Bayer Schering, Teva, of neurologic symptoms and signs. Merck-Serono, Novartis, Glaxo SK, UCB. S.C.R.: travel support, US NMSS, ECTRIMS, Multiple Sclerosis Conclusions The 2010 revisions to the McDonald Criteria will in International Federation, MS Ireland; payment for writing some instances allow a more rapid diagnosis of MS, with or reviewing manuscript, US NMSS, ECTRIMS; con- equivalent or improved specificity and/or sensitivity com- sultancy, US NMSS, ECTRIMS, Sanofi-Aventis, Bayer pared with past Criteria and will in many instances clar- Schering Pharma, BioMarin, EMD Merck Serono, Mt ify and simplify the diagnostic process with fewer Sinai College of Medicine (New York, NY), European required MRI examinations. A proportion of patients with Committee for Treatment and Research in MS, Eisai, INC nonspecific symptoms (eg, fatigue, weakness, or dizziness) Research, Eli Lilly Inc, Isis Pharmaceuticals Inc, Medici- and nonspecific MRI findings are referred to secondary Nova, Cleveland Clinic Foundation, Free University and tertiary MS centers in the developed world for a sec- Amsterdam, Genentech/F. Hoffmann-LaRoche, Synthon ond opinion and do not in fact have MS. These revised BV, Antisense Therapeutics Ltd, BaroFold, Protein Design McDonald Criteria for MS diagnosis should therefore be Laboratories; royalties, Demos Medical Publishers (New applied only when patients have experienced a typical CIS York, NY). B.B.: travel support, US NMSS, ECTRIMS, (or progressive paraparesis/cerebellar/cognitive syndrome in MSIF, MS Ireland; consultancy, Biogen Idec, Genzyme; the case of suspected PPMS). grants/grants pending, Multiple Sclerosis Society of 298 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis Canada, Canadian Institutes of Health Research; paid Idec, EMD Serono, Genentech, Teva Neuroscience, educational presentations, honoraria for symposia at the Genmab, Medicinova, Actelion, Allozyne, Sanofi-Aventis, American Academy of Neurology. M.C.: board member- Acorda, Questcor, Avanir, Roche, Celgene, Abbott, Pfizer, ship, GENMAB; consultancy, Biogen, Genzyme; grants/ Morphosys; grants/grants pending, NIH, NMSS, Acorda, grants pending, Bayer Schering, Biogen Elan, Novartis, Biogen Idec, Teva, Novartis, Sanofi-Aventis; speaking fees, Merck Serono, Sanofi-Aventis, Teva. J.A.C.: travel ex- Genzyme, Teva, EMD Serono; paid educational presenta- penses, US NMSS; consultancy, Biogen Idec, Lilly, tions, various continuing medical education services; stock/ Novartis, Serono, Teva; grants/grants pending, Depart- stock options, cognition pharmaceuticals. X.M.: travel ment of Defense, NIH, US NMSS; speaking fees, Biogen expenses, US NMSS; consultancy, Bayer Schering Pharma, Idec, Novartis, Sanofi-Aventis, Waterfront Media. M.F.: Biogen Idec, EMD Merck Serono, Genentech, Genzyme, travel expenses, US NMSS, ECTRIMS, MSIF, MS Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; Ireland; board membership, Teva Pharmaceutical Indus- grants/grants pending, Bayer Schering Pharma, Biogen tries Ltd, Genmab A/S; consultancy, Bayer Schering Idec, EMD Merck Serono, Genentech, Genzyme, Novar- Pharma, Biogen-Dompe AG, Genmab A/S, Merck Serono, tis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; speak- Pepgen Corporation, Teva Pharmaceutical Industries Ltd; ing fees, Bayer Schering Pharma, Biogen Idec, EMD grants/grants pending, Bayer-Schering, Biogen-Dompe´ Merck Serono, Genentech, Genzyme, Novartis, Sanofi- AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Aventis, Teva Pharmaceuticals, Almirall. M.S.-W.: travel Industries Ltd, Fondazione Italiana Sclerosi Multipla, support, US NMSS, ECTRIMS, MSIF, MS Ireland; fees Fondazione Mariani; speaking fees, Bayer Schering for review activities, Genentech, Merck Serono, Roche; Pharma, Biogen-Dompe´ AG, Genmab A/S, Merck Serono, board membership, Board of Directors of Active Biotech, Teva Pharmaceutical Industries Ltd; travel expenses, Teva, Sweden; consultancy, Elan, Merck Serono; speaking fees, Biogen-Dompe AG, Merck-Serono, Sanofi-Aventis, Gen- Bayer Health Care, Merck Serono, Serono Symposia mab, Bayer Schering. K.F.: travel expenses, US NMSS, International Foundation, Sanofi-Aventis, Swedish Bank ECTRIMS, MSIF, MS Ireland; consultancy, Bayer Scher- SEB. A.J.T.: travel support, US NMSS, ECTRIMS, MSIF, ing Pharma, Biogen Idec, Merck Serono; grants/grants MS Ireland; board membership, National Hospital Devel- pending, Bayer Schering Pharma, Biogen Idec, Asahi Kasei opment Foundation, Patrick Berthoud Charitable Trust; Kuraray Medical Co Ltd, Chemo-Sero-Therapeutic Re- consultancy, Weleda AG/Society for Clinical Research, search Institute, Mitsubishi Tanabe Pharma, Teijin Phar- Medical Research Council, MS Society of Great Britain, ma, Theva Pharmaceutical, Eisai Inc, Kowa Pharmaceu- Merck Serono, Biogen Idec, DIGNA Biotech, Novartis, tical, Ministry of Education, Science, and Technology of Eisai London Research Laboratories, Teva Pharmaceuticals; Japan, Ministry of Health, Labor, and Welfare of Japan; grants/grants pending, National Institute for Health speaking fees, Bayer Schering Pharma, Biogen Idec, Eisai Research, MS Society of Great Britain; speaking fees, Inc, Mitsubishi Tanabe Pharma, Astellas Pharma, Takeda Serono Symposia, Sanofi-Aventis; travel expenses, MS Pharmaceutical Company Ltd, Asahi Kasei Kuraray International Federation, US NMSS, Biogen Idec; honor- Medical Co; paid manuscript preparation, Cosmic Cor- aria, Editor-in-Chief of Multiple Sclerosis. E.W.: con- poration; royalties, Bunkodo. E.H.: travel expenses, US sultancy, Roche, Actelion; grants/grants pending, US NMSS, ECTRIMS, MSIF, MS Ireland; consultancy, NMSS, NIH; speaking fees, Teva; received free drug for Biogen Idec, Genzyme, Merck Serono, Novartis, Grifols; a trial given by Sanofi-Aventis and Biogen Idec. B.W.: grants/grants pending, Biogen Idec; speaking fees, Biogen travel support, US NMSS; European Committee for Idec, Genzyme, Merck Serono, Novartis, Bayer Healthcare, Treatment of MS; MS International Foundation; MS Ireland; consultancy, Novartis, Biogen Idec; employment, Sanofi-Aventis; paid educational presentations, Novartis. M.H.: consultancy, Biogen Idec; grant/grants pending, Mayo Clinic; royalties, RSR Ltd. J.S.W.: travel support, Health Research Board Ireland; speaking fees, Biogen Idec. US NMSS, ECTRIMS, MSIF, MS Ireland; board L.K.: travel expenses, US NMSS; board membership, membership, Antisense Therapeutics Ltd, BCDecker, Editorial Board of Multiple Sclerosis; grants/grants pend- Novartis Pharmaceuticals, Sanofi-Aventis, Teva Pharma- ing, National Research Foundation Switzerland, Rubatto ceuticals, Eli Lilly, UCB; consultancy, Genentech, Novartis Foundation, Swiss MS society, European Union, Roche Pharmaceuticals, Sanofi-Aventis, Teva Neuroscience, Teva Foundation, Novartis Foundation; speaking fees, various Pharmaceuticals, Acorda, Acetilon, Bayer HealthCare, companies involved in development of MS therapeutics; Facet Biotech, Peptimmune; grants/grants pending, NIH, paid educational presentations, Neurostatus System for Sanofi-Aventis, Clayton Foundation for Research, US Standardized Neurological Assessment. 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Copyright © 2011 American Neurological Association
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10.1002/ana.22366
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Abstract

RAPID COMMUNICATION Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria 1 2 3 Chris H. Polman, MD, PhD, Stephen C. Reingold, PhD, Brenda Banwell, MD, 4 5 6 7 Michel Clanet, MD, Jeffrey A. Cohen, MD, Massimo Filippi, MD, Kazuo Fujihara, MD, 8 9 10 Eva Havrdova, MD, PhD, Michael Hutchinson, MD, Ludwig Kappos, MD, 11 12 13 Fred D. Lublin, MD, Xavier Montalban, MD, Paul O’Connor, MD, 14 15 Magnhild Sandberg-Wollheim, MD, PhD, Alan J. Thompson, MD, 16 17 18 Emmanuelle Waubant, MD, PhD, Brian Weinshenker, MD, and Jerry S. Wolinsky, MD New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. ANN NEUROL 2011;69:292–302 iagnostic criteria for multiple sclerosis (MS) include for their simplification to improve their comprehension 1,2 Dclinical and paraclinical laboratory assessments and utility and for evaluating their appropriateness in pop- emphasizing the need to demonstrate dissemination of ulations that differ from the largely Western Caucasian lesions in space (DIS) and time (DIT) and to exclude alter- adult populations from which the Criteria were derived. native diagnoses. Although the diagnosis can be made on In May 2010 in Dublin, Ireland, the International Panel clinical grounds alone, magnetic resonance imaging (MRI) on Diagnosis of MS (the Panel) met for a third time to of the central nervous system (CNS) can support, supple- examine requirements for demonstrating DIS and DIT 3–9 ment, or even replace some clinical criteria, as most and to focus on application of the McDonald Criteria in recently emphasized by the so-called McDonald Criteria of pediatric, Asian, and Latin American populations. 8,9 the International Panel on Diagnosis of MS. The McDo- nald Criteria have resulted in earlier diagnosis of MS with a Considerations Related to Revisions to the 10–13 high degree of both specificity and sensitivity, allowing McDonald Criteria for better counseling of patients and earlier treatment. The Panel reviewed published research related to the di- Since the revision of the McDonald Criteria in agnosis of MS and to the original and revised McDonald 2005, new data and consensus have pointed to the need Criteria, gathered from literature searches of English View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22366 Received Nov 2, 2010, and in revised form Dec 23, 2010. Accepted for publication Dec 29, 2010. Address correspondence to Dr Polman, Department of Neurology, VU Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, the Netherlands. E-mail: ch.polman@vumc.nl 1 2 3 From the Department of Neurology, Free University, Amsterdam, the Netherlands; Scientific and Clinical Review Associates LLC, New York, NY; Division 4 5 of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Neurosciences, University Hospital Center, Toulouse, France; Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinical Foundation, Cleveland, OH; Neuroimaging Research Unit, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Milan, Italy; Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology, First Faculty of Medicine, Charles University, Prague, Czech Republic; 9 10 St Vincent’s University Hospital, Elm Park, Dublin, Ireland; Departments of Neurology and Biomedicine, University Hospital, Kantonsspital, Basel, Switzerland; Corrine Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY; 12 13 Clinical Neuroimmunology Unit, Multiple Sclerosis Center of Catalonia, University Hospital Vall d’Hebron, Barcelona, Spain; Division of Neurology, St. 14 15 Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Neurology, University Hospital, Lund, Sweden; University College 16 17 London Institute of Neurology, United Kingdom; Multiple Sclerosis Center, University of California, San Francisco, CA; Department of Neurology, Mayo Clinic, Rochester, MN; and Department of Neurology, University of Texas Health Sciences Center, Houston, TX. 292 V 2011 American Neurological Association Polman et al: 2010 Revisions to MS Diagnosis language publications containing the terms multiple sclerosis to help make a differential diagnosis between NMO and and diagnosis, and from specific recommendations of rele- MS to help avoid misdiagnosis and to guide treatment. vant papers by Panelmembers.The Panelconcludedthat Correct interpretation of symptoms and signs is a most recent research supports the utility of the McDonald fundamental prerequisite for diagnosis. The Panel con- Criteria in a typical adult Caucasian population seen in MS sidered again what constitutes an attack (relapse, exacer- centers, despite only limited research and practical experi- bation) and defined this as patient-reported symptoms or ence in general neurology practice populations. objectively observed signs typical of an acute inflamma- In its discussions, the Panel stressed that the McDo- tory demyelinating event in the CNS, current or histori- nald Criteria should only be applied in those patients cal, with duration of at least 24 hours, in the absence of who present with a typical clinically isolated syndrome fever or infection. Although a new attack should be (CIS) suggestive of MS or symptoms consistent with a documented by contemporaneous neurological examina- CNS inflammatory demyelinating disease, because the tion, in the appropriate context, some historical events development and validation of the Criteria have been with symptoms and evolution characteristic for MS, but limited to patients with such presentations. CIS presenta- for which no objective neurological findings are docu- tions can be monofocal or multifocal, and typically mented, can provide reasonable evidence of a prior involve the optic nerve, brainstem/cerebellum, spinal demyelinating event. Reports of paroxysmal symptoms cord, or cerebral hemispheres. (historical or current) should, however, consist of multi- In applying the McDonald Criteria, it remains im- ple episodes occurring over not less than 24 hours. There perative that alternative diagnoses are considered and was consensus among the Panel members that before a excluded. Differential diagnosis in MS has been the sub- definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological exami- ject of previous data- and consensus-driven recommenda- nation, visual evoked potential (VEP) response in tions that point to common and less common alternative patients reporting prior visual disturbance, or MRI con- diagnoses for MS and identify clinical and paraclinical sistent with demyelination in the area of the CNS impli- red flags that should signal particular diagnostic cau- 14,15 cated in the historical report of neurological symptoms. tion. In its current review, the Panel focused specifi- The Panel concluded that the underlying concepts cally on the often-problematic differential diagnosis for of the original (2001) and revised (2005) McDonald Cri- MS of neuromyelitis optica (NMO) and NMO spectrum 8,9 teria are still valid, including the possibility of estab- disorders. There is increasing evidence of relapsing CNS lishing a diagnosis of MS based on objective demonstra- demyelinating disease characterized by involvement of tion of dissemination of lesions in both space and time optic nerves (unilateral or bilateral optic neuritis), often on clinical grounds alone or by careful and standardized severe myelopathy with MRI evidence of longitudinally integration of clinical and MRI findings. However, the extensive spinal cord lesions, often normal brain MRI (or Panel now recommends key changes in the McDonald with abnormalities atypical for MS), and serum aqua- 16,17 Criteria related to the use and interpretation of imaging porin-4 (AQP4) autoantibodies. There was agree- criteria for DIS and DIT as articulated by the recently ment that this phenotype should be separated from typi- 22–24 published work from the MAGNIMS research group. cal MS because of different clinical course, prognosis, Such changes are likely to further increase diagnostic sensi- and underlying pathophysiology and poor response to tivity without compromising specificity, while simplifying some available MS disease-modifying therapies. The the requirements for demonstration of both DIS and Panel recommends that this disorder should be carefully DIT, with fewer required MRI examinations. The Panel considered in the differential diagnosis of all patients pre- also makes specific recommendations for application of senting clinical and MRI features that are strongly sug- the McDonald Criteria in pediatric and in Asian and gestive of NMO or NMO spectrum disorder, especially Latin American populations. if (1) myelopathy is associated with MRI-detected spinal cord lesions longer than 3 spinal segments and primarily Recommended Modifications to the McDonald involving the central part of the spinal cord on axial sec- Criteria: The 2010 Revisions tions; (2) optic neuritis is bilateral and severe or associ- ated with a swollen optic nerve or chiasm lesion or an MAGNETIC RESONANCE IMAGING CRITERIA FOR altitudinal scotoma; and (3) intractable hiccough or nau- DIS. In past versions of the McDonald Criteria, DIS sea/vomiting is present for >2 days with evidence of a ´ demonstrated by MRI was based on the Barkhof/Tintore 19,20 4,6 periaqueductal medullary lesion on MRI. In patients criteria. Despite having good sensitivity and specificity, with such features, AQP4 serum testing should be used these criteria have been difficult to apply consistently by February 2011 293 ANNALS of Neurology More recently, the MAGNIMS group confirmed TABLE 1: 2010 McDonald MRI Criteria for 29,30 earlier studies by showing that, in patients with typi- Demonstration of DIS cal CIS, a single brain MRI study that demonstrates DIS DIS Can Be Demonstrated by 1 T2 Lesion in at and both asymptomatic gadolinium-enhancing and non- Least 2 of 4 Areas of the CNS: enhancing lesions is highly specific for predicting early Periventricular development of clinically definite MS (CDMS) and reli- 23,24 ably substitutes for prior imaging criteria for DIT. Juxtacortical After review of these data, the Panel accepted that the Infratentorial presence of both gadolinium-enhancing and nonenhancing Spinal cord lesions on the baseline MRI can substitute for a follow-up 22,27 Based on Swanton et al 2006, 2007. scan to confirm DIT (Table 2), as long as it can be reli- Gadolinium enhancement of lesions is not required for ably determined that the gadolinium-enhancing lesion is DIS. not due to non-MS pathology. If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do By using the recommended simplified MAGNIMS not contribute to lesion count. criteria to demonstrate DIS and allowing DIT to be MRI ¼ magnetic resonance imaging; DIS ¼ lesion dissemi- demonstrated by a scan containing both enhancing and nation in space; CNS ¼ central nervous system. nonenhancing lesions in regions of the CNS typical for MS, a diagnosis of MS can be made in some CIS 25,26 patients based on a single MRI. The Panel felt this is nonimaging specialists. The European MAGNIMS justified because it simplifies the diagnostic process with- multicenter collaborative research network, which studies ´ out reducing accuracy. However, a new clinical event or MRI in MS, compared the Barkhof/Tintore criteria for 4,6 serial imaging to show a new enhancing or T2 lesion will DIS with simplified criteria developed by Swanton and 22,27 still be required to establish DIT in those patients who colleagues. In the MAGNIMS work, DIS can be do not have both gadolinium-enhancing and nonenhanc- demonstrated with at least 1 T2 lesion in at least 2 of 4 ing lesions on their baseline MRI. locations considered characteristic for MS and as speci- fied in the original McDonald Criteria (juxtacortical, THE VALUE OF CEREBROSPINAL FLUID FINDINGS IN periventricular, infratentorial, and spinal cord), with DIAGNOSIS. The Panel reaffirmed that positive cere- lesions within the symptomatic region excluded in brospinal fluid (CSF) findings (elevated immunoglobulin patients with brainstem or spinal cord syndromes. In 282 G [IgG] index or 2 or more oligoclonal bands) can be CIS patients, the Swanton-based DIS criteria were shown important to support the inflammatory demyelinating to be simpler and slightly more sensitive than the origi- nature of the underlying condition, to evaluate alternative nal McDonald Criteria for DIS, without compromising 15,31 diagnoses, and to predict CDMS. In the 2001 and specificity and accuracy. The Panel accepted these 2005 McDonald Criteria, a positive CSF finding could MAGNIMS DIS Criteria, which can simplify the diag- be used to reduce the MRI requirements for reaching nostic process for MS while preserving specificity and DIS criteria (requiring only 2 or more MRI-detected improving sensitivity (Table 1). 8,9 lesions consistent with MS if the CSF was positive). However, when applying the simplified MAGNIMS MAGNETIC RESONANCE IMAGING CRITERIA FOR DIT. The 2005 revision of the McDonald Criteria sim- TABLE 2: 2010 McDonald MRI Criteria for plified the MRI evidence required for DIT, basing it on Demonstration of DIT the appearance of a new T2 lesion on a scan compared to a reference or baseline scan performed at least 30 days DIT Can Be Demonstrated by: after the onset of the initial clinical event. In clinical 1. A new T2 and/or gadolinium-enhancing lesion(s) practice, however, there is reason not to postpone a first on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI MRI until after 30 days of clinical onset, which would result in an extra MRI scan to confirm a diagnosis. Aban- 2. Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing doning the requirement for an extra reference MRI after lesions at any time 30 days does not compromise specificity, and therefore Based on Montalban et al 2010. the Panel, in its current revision of the McDonald Crite- MRI ¼ magnetic resonance imaging; DIT ¼ lesion dissemi- ria, allows a new T2 lesion to establish DIT irrespective of nation in time. the timing of the baseline MRI. 294 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis imaging criteria for DIS and DIT, the Panel believes TABLE 3: 2010 McDonald Criteria for Diagnosis of that even further liberalizing MRI requirements in CSF- MS in Disease with Progression from Onset positive patients is not appropriate, as CSF status was not PPMS May Be Diagnosed in Subjects With: evaluated for its contribution to the MAGNIMS criteria 22,24 1. One year of disease progression (retrospectively for DIS and DIT. Prospective studies using widely or prospectively determined) available standardized techniques and the most sensitive methods of detection of oligoclonal bands in the CSF to- 2. Plus 2 of the 3 following criteria : gether with the new imaging requirements are needed to A. Evidence for DIS in the brain based on 1T2 32,33 confirm the additional diagnostic value of CSF. lesions in at least 1 area characteristic for MS (periventricular, juxtacortical, or infratentorial) MAKING A DIAGNOSIS OF PRIMARY PROGRESSIVE B. Evidence for DIS in the spinal cord based MULTIPLE SCLEROSIS. In 2005, the Panel recom- on 2T2 lesions in the cord mended revising the McDonald Criteria for diagnosis of C. Positive CSF (isoelectric focusing evidence of primary progressive multiple sclerosis (PPMS) to require, oligoclonal bands and/or elevated IgG index) in addition to 1 year of disease progression, 2 of the fol- If a subject has a brainstem or spinal cord syndrome, all lowing 3 findings: positive brain MRI (9 T2 lesions or 4 symptomatic lesions are excluded from the Criteria. or more T2 lesions with positive VEP); positive spinal b Gadolinium enhancement of lesions is not required. cord MRI (2 focal T2 lesions); or positive CSF. These MS ¼ multiple sclerosis; PPMS ¼ primary progressive MS; DIS ¼ lesion dissemination in space; CSF ¼ cerebrospinal criteria reflected the special role of both CSF examina- fluid; IgG ¼ immunoglobulin G. tion and spinal cord MRI in PPMS, have been found to be practical and are generally well accepted by the neuro- logical community, and have been used as inclusion cri- tional in children and should prompt detailed considera- 42–45 teria for PPMS clinical trials. To harmonize MRI criteria tion of alternative diagnoses. About 80% of pediatric within the diagnostic criteria for all forms of MS, while cases, and nearly all adolescent onset cases, present with recognizing the special diagnostic needs for PPMS, the attacks typical for adult CIS, with a similar or greater total 46–48 Panel recommends that the McDonald Criteria require- T2 lesion burden. In children younger than 11 years, ment of fulfilling 2 of 3 MRI or CSF findings be main- lesions are larger and more ill-defined than in teenagers. tained for PPMS, with replacement of the previous brain Imaging criteria for demonstrating DIS in pediatric MS 38,50,51 imaging criterion with the new MAGNIMS brain imaging show high sensitivity and/or specificity. criterion for DIS (2 of 3 of the following: 1 T2 lesions The Panel’s consensus was that the proposed MAG- in at least 1 area characteristic for MS [periventricular, jux- NIMS-based MRI revisions for DIS will also serve well tacortical, or infratentorial]; 2 T2 lesions in the cord; or for most pediatric MS patients, especially those with acute positive CSF [isoelectric focusing evidence of oligoclonal demyelination presenting as CIS, because most pediatric bands and/or elevated IgG index]) (Table 3). This consen- patients will have >2 lesions and are very likely to have sus-based recommendation is justified by comparing diag- lesions in 2 of the 4 specified CNS locations (periventricu- nostic criteria for PPMS and by a subsequent reanalysis lar, brainstem-infratentorial, juxtacortical, or spinal cord). of these data (X. Montalban, personal communication). The frequency of spinal cord lesions in pediatric MS Use of MAGNIMS-based imaging criteria for PPMS with patients is currently unreported, but the appearance of or without associated CSF evaluation should be supported cord lesions in pediatric MS patients with spinal cord by additional data further documenting the sensitivity and symptoms appears generally similar to that of adults. specificity of the criteria in this population. However, approximately 15 to 20% of pediatric MS patients, most aged <11 years, present with ence- APPLICABILITY OF THE MCDONALD CRITERIA IN phalopathy and multifocal neurological deficits difficult PEDIATRIC, ASIAN, AND LATIN AMERICAN POPULA- to distinguish from acute disseminated encephalomyelitis TIONS. The McDonald Criteria were developed with 43,50 (ADEM). Current operational international consen- data gathered largely from adult Caucasian European and sus criteria for MS diagnosis in children with an ADEM- North American populations, and their applicability has like first attack require confirmation by 2 or more non- been questioned for other populations, particularly pedi- 37,38 39,40 41 ADEM like attacks, or 1 non-ADEM attack followed by atric cases, Asians, and Latin Americans. accrual of clinically silent lesions. Although children with an ADEM-like first MS attack are more likely Pediatric MS Over 95% of pediatric MS patients have an initial relaps- than children with monophasic ADEM to have 1 or ing–remitting disease course, whereas PPMS is excep- more non-enhancing T1 hypointense lesions, 2 or more February 2011 295 ANNALS of Neurology periventricular lesions, and the absence of a diffuse lesion of having NMO or NMO spectrum disorders, especially in pattern, these features are not absolutely discriminatory. patients with Asian or Latin American genetic background Furthermore, MRI scans of children with monophasic because of the higher prevalence of the disease in these ADEM typically demonstrate multiple variably enhancing populations. Such testing may be less important in those lesions (often >2) typically located in the juxtacortical subjects presenting with conventional Western type MS. white matter, infratentorial space, and spinal cord. Thus, Although not all patients with an NMO-like presentation application of the revised MAGNIMS-based criteria for will be AQP4 antibody positive, the majority are, whereas DIS and DIT on initial MRI would be inappropriate for those with MS are more likely to be AQP4 antibody nega- 16,56,61 such patients, and serial clinical and MRI observations are tive. CurrentevidencesuggeststhatonceNMO and required to confirm a diagnosis of MS. In this young age NMO spectrum disorders have been excluded, Western group, there can be marked lesion resolution following an type MS in Asia or Latin America is not fundamentally dif- initial attack prior to emergence over time of new lesions ferent from typical MS in the Caucasian population, and and attacks leading to a diagnosis of MS. that the MAGNIMS MRI criteria would apply for such patients, although confirmatory studies should be done. MS in Asian and Latin American Populations Among Asian patients with CNS inflammatory demyeli- The McDonald Criteria: 2010 Revisions nating disease, a phenotype characterized by NMO, lon- APPLICATION OF THE CRITERIA. The Panel recom- gitudinally extensive spinal cord lesions, and positive mends revisions to the McDonald Criteria for diagnosis of AQP4 autoantibody seropositivity has been relatively 55–57 MS (Table 4) focusing specifically on requirements to dem- more common than in Western populations. The onstrate DIS, DIT, and on diagnosis of PPMS. These 2010 Panel solicited input on use of the McDonald Criteria in revisions to the McDonald Criteria are likely to be applica- Asia and Latin America, where there is evidence of a sim- ble in pediatric, Asian, and Latin American populations ilar phenotype distinction. Although the McDonald once careful evaluation for other potential explanations for Criteria are widely used in these parts of the world, there the clinical presentation is made. The predictive validity of is some uncertainty, especially in Asia, about whether MS DIS and DIT based on a single first scan in children with and NMO are distinct and if so, how they should be dis- CIS needs to be confirmed in prospective studies. The tinguished. As currently applied, the term opticospinal McDonald Criteria have not yet been validated in Asian MS appears to be an admixture of conventional MS and and Latin American populations, and studies need to be NMO. Confusion has arisen (1) because of the recognition done to confirm the sensitivity and specificity of the Criteria that most cases of NMO are relapsing; (2) because AQP4 in such patients. Care must be taken to exclude NMO as a autoantibody testing has facilitated the diagnosis of NMO differential diagnosis, which can be confounded by the and permitted inclusion of individuals with symptomatic imperfect sensitivity of AQP-4 autoantibody assays, the pres- brain lesions who would previously have been excluded; ence of brain lesions in NMO, and the difficulty of detect- and (3) because of the recognition that selective involve- ing long spinal cord lesions in immunosuppressed patients. ment of optic nerve and spinal cord alone does not differ- entiate NMO from MS. It is insufficient to make a diag- Future Directions nosis of NMO in the absence of the required specificity criteria of the revised Wingerchuk Criteria for ‘‘definite’’ POTENTIAL ADDED VALUE OF BIOMARKERS. Al- NMO, which recommend presence of optic neuritis, acute though increased IgG index or the presence of oligoclonal myelitis, and at least 2 of 3 supportive paraclinical assess- bands in the CSF support an MS diagnosis, and AQP4 ments (a contiguous spinal cord lesion at least 3 segments antibody assays can help in the differential diagnosis pro- in length, brain MRI at onset that is nondiagnostic for cess, there are still no specific biomarkers to confirm the di- MS, or NMO-IgG seropositivity). These criteria are suc- agnosis. Several blood and CSF biomarkers may be promis- cessful in most instances to distinguish NMO from MS in 62–65 ing, and high-resolution spectral domain optical patients with optic neuritis and myelitis, but the spectrum coherence tomography might be as good as VEP in assess- of NMO includes recurrent myelitis and optic neuritis, ing visual involvement. The diagnostic utility of such NMO syndromes with symptomatic brain lesions at pre- markers needs to be validated and tested prospectively. sentation, and NMO associated with systemic autoimmune diseases. Failure to make the correct diagnosis in patients REFINEMENTS IN IMAGING CRITERIA. The McDo- with NMO may impact treatment. nald Criteria were based on detection of lesions generally The Panel recommends testing for AQP4 autoanti- using 1.5T magnet strength in noncortical regions of the bodies with validated assays in patients who are suspected brain and spinal cord. However, a large proportion of 296 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis TABLE 4: The 2010 McDonald Criteria for Diagnosis of MS Clinical Presentation Additional Data Needed for MS Diagnosis a c 2 attacks ; objective clinical None evidence of 2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack 2 attacks ; objective clinical Dissemination in space, demonstrated by: evidence of 1 lesion 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ;or Await a further clinical attack implicating a different CNS site 1 attack ; objective clinical Dissemination in time, demonstrated by: evidence of 2 lesions Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack 1 attack ; objective clinical Dissemination in space and time, demonstrated by: evidence of 1 lesion For DIS: (clinically isolated syndrome) 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) ;or Await a second clinical attack implicating a different CNS site; and For DIT: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack Insidious neurological progression 1 year of disease progression (retrospectively or prospectively suggestive of MS (PPMS) determined) plus 2 of 3 of the following criteria : 1. Evidence for DIS in the brain based on 1 T2 lesions in the MS-characteristic (periventricular, juxtacortical, or infratentorial) regions 2. Evidence for DIS in the spinal cord based on 2T2 lesions in the cord 3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ‘‘MS’’; if suspicious, but the Criteria are not completely met, the diagnosis is ‘‘possible MS’’; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is ‘‘not MS.’’ An attack (relapse; exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occur- ring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms. Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and evolution character- istics for a prior inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings. No additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these Criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical pre- sentation, and objective evidence must be present to support a diagnosis of MS. Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes. MS ¼ multiple sclerosis; CNS ¼ central nervous system; MRI ¼ magnetic resonance imaging; DIS ¼ dissemination in space; DIT ¼ dissemination in time; PPMS ¼ primary progressive multiple sclerosis; CSF ¼ cerebrospinal fluid; IgG ¼ immunoglobulin G. February 2011 297 ANNALS of Neurology 67,68 MS lesions are in the cortex and can be detected The Panel acknowledges that using these refined 69–74 using double inversion recovery imaging. The pres- diagnostic criteria may change some of the outcomes of ence of at least 1 intracortical lesion in subjects with CIS patients in natural history studies and clinical trials, may help identify subjects at high risk for developing when original expectations for outcomes may be based CDMS. Magnet strengths >1.5T with tailored acquisi- on subjects whose diagnosis was made using past, some- 76–79 91 tion protocols may also enhance diagnosis, with what different criteria. Most of the currently recom- improvements in image resolution, signal-to-noise ratio, mended revisions are based upon new data generated and chemical shift. Scans at 7.0T showed lesions in the since the 2005 revisions. However, there remains a need white and gray matter with enhanced in vivo detection for further testing in prospective and retrospective data- 80–83 of pathological hallmarks of MS lesions. Finally, sets of many of these criteria, especially in populations of MRI techniques such as magnetic transfer imaging allow patients typical of those seen in general neurology prac- the detection of damage outside focal lesions (for tices, both to further assess their value and utility and to instance, in normal-appearing brain tissues) not present provide suggestions for further refinements in the future. 15,84,85 in conditions such as ADEM and NMO. The utility of these scanning technologies for MS diagnosis in Acknowledgment patients with CIS remains a matter for future research The work of the Panel was supported by the US and validation. National Multiple Sclerosis Society (NMSS), the Euro- Many individuals with high lesion loads may have pean Committee for Treatment and Research in Multiple had a protracted subclinical disease course prior to their Sclerosis, the Multiple Sclerosis International Federation, first clinical event. As a consequence, occasional individu- and MS Ireland. als investigated by MRI for indications unrelated to MS The Panel thanks Drs T. Saida, M. Lana-Peixoto, have incidental findings of brain lesions with appearance D. Callegaro, and C. Oehninger for help in gaining per- and topography consistent with MS. Detection of this spective on the use of the McDonald Criteria in Asia presymptomatic phase, or radiologically isolated syn- and Latin America. drome, is increasingly common. Some of these individu- This work is dedicated to the memory of Dr W. als followed clinically and by serial imaging will develop Ian McDonald, who chaired the original Panel and DIT by MRI, and some have clinical disease-defining whose continuing inspiration has driven the work for the 86–89 events after several years. However, in the absence of second and third revisions to the Criteria that now bear supportive research findings, the Panel concluded that a his name. firm diagnosis of MS based on incidental findings on MRI alone, even with additional supportive findings on Potential Conflicts of Interest evoked potentials or typical CSF findings in the absence C.H.P.: consultancy, Actelion, Biogen Idec, Bayer Scher- of MS-relevant clinical symptoms, is problematic. A ing, Teva, Merck-Serono, Novartis, Glaxo SK, UCB, future definite diagnosis of MS, however, cannot be Roche, Antisense Ther; expert testimony, Biogen Idec; excluded and may be likely, depending on the evolution grants/grants pending, Biogen Idec, Bayer Schering, Teva, of neurologic symptoms and signs. Merck-Serono, Novartis, Glaxo SK, UCB. S.C.R.: travel support, US NMSS, ECTRIMS, Multiple Sclerosis Conclusions The 2010 revisions to the McDonald Criteria will in International Federation, MS Ireland; payment for writing some instances allow a more rapid diagnosis of MS, with or reviewing manuscript, US NMSS, ECTRIMS; con- equivalent or improved specificity and/or sensitivity com- sultancy, US NMSS, ECTRIMS, Sanofi-Aventis, Bayer pared with past Criteria and will in many instances clar- Schering Pharma, BioMarin, EMD Merck Serono, Mt ify and simplify the diagnostic process with fewer Sinai College of Medicine (New York, NY), European required MRI examinations. A proportion of patients with Committee for Treatment and Research in MS, Eisai, INC nonspecific symptoms (eg, fatigue, weakness, or dizziness) Research, Eli Lilly Inc, Isis Pharmaceuticals Inc, Medici- and nonspecific MRI findings are referred to secondary Nova, Cleveland Clinic Foundation, Free University and tertiary MS centers in the developed world for a sec- Amsterdam, Genentech/F. Hoffmann-LaRoche, Synthon ond opinion and do not in fact have MS. These revised BV, Antisense Therapeutics Ltd, BaroFold, Protein Design McDonald Criteria for MS diagnosis should therefore be Laboratories; royalties, Demos Medical Publishers (New applied only when patients have experienced a typical CIS York, NY). B.B.: travel support, US NMSS, ECTRIMS, (or progressive paraparesis/cerebellar/cognitive syndrome in MSIF, MS Ireland; consultancy, Biogen Idec, Genzyme; the case of suspected PPMS). grants/grants pending, Multiple Sclerosis Society of 298 Volume 69, No. 2 Polman et al: 2010 Revisions to MS Diagnosis Canada, Canadian Institutes of Health Research; paid Idec, EMD Serono, Genentech, Teva Neuroscience, educational presentations, honoraria for symposia at the Genmab, Medicinova, Actelion, Allozyne, Sanofi-Aventis, American Academy of Neurology. M.C.: board member- Acorda, Questcor, Avanir, Roche, Celgene, Abbott, Pfizer, ship, GENMAB; consultancy, Biogen, Genzyme; grants/ Morphosys; grants/grants pending, NIH, NMSS, Acorda, grants pending, Bayer Schering, Biogen Elan, Novartis, Biogen Idec, Teva, Novartis, Sanofi-Aventis; speaking fees, Merck Serono, Sanofi-Aventis, Teva. J.A.C.: travel ex- Genzyme, Teva, EMD Serono; paid educational presenta- penses, US NMSS; consultancy, Biogen Idec, Lilly, tions, various continuing medical education services; stock/ Novartis, Serono, Teva; grants/grants pending, Depart- stock options, cognition pharmaceuticals. X.M.: travel ment of Defense, NIH, US NMSS; speaking fees, Biogen expenses, US NMSS; consultancy, Bayer Schering Pharma, Idec, Novartis, Sanofi-Aventis, Waterfront Media. M.F.: Biogen Idec, EMD Merck Serono, Genentech, Genzyme, travel expenses, US NMSS, ECTRIMS, MSIF, MS Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; Ireland; board membership, Teva Pharmaceutical Indus- grants/grants pending, Bayer Schering Pharma, Biogen tries Ltd, Genmab A/S; consultancy, Bayer Schering Idec, EMD Merck Serono, Genentech, Genzyme, Novar- Pharma, Biogen-Dompe AG, Genmab A/S, Merck Serono, tis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; speak- Pepgen Corporation, Teva Pharmaceutical Industries Ltd; ing fees, Bayer Schering Pharma, Biogen Idec, EMD grants/grants pending, Bayer-Schering, Biogen-Dompe´ Merck Serono, Genentech, Genzyme, Novartis, Sanofi- AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Aventis, Teva Pharmaceuticals, Almirall. M.S.-W.: travel Industries Ltd, Fondazione Italiana Sclerosi Multipla, support, US NMSS, ECTRIMS, MSIF, MS Ireland; fees Fondazione Mariani; speaking fees, Bayer Schering for review activities, Genentech, Merck Serono, Roche; Pharma, Biogen-Dompe´ AG, Genmab A/S, Merck Serono, board membership, Board of Directors of Active Biotech, Teva Pharmaceutical Industries Ltd; travel expenses, Teva, Sweden; consultancy, Elan, Merck Serono; speaking fees, Biogen-Dompe AG, Merck-Serono, Sanofi-Aventis, Gen- Bayer Health Care, Merck Serono, Serono Symposia mab, Bayer Schering. K.F.: travel expenses, US NMSS, International Foundation, Sanofi-Aventis, Swedish Bank ECTRIMS, MSIF, MS Ireland; consultancy, Bayer Scher- SEB. A.J.T.: travel support, US NMSS, ECTRIMS, MSIF, ing Pharma, Biogen Idec, Merck Serono; grants/grants MS Ireland; board membership, National Hospital Devel- pending, Bayer Schering Pharma, Biogen Idec, Asahi Kasei opment Foundation, Patrick Berthoud Charitable Trust; Kuraray Medical Co Ltd, Chemo-Sero-Therapeutic Re- consultancy, Weleda AG/Society for Clinical Research, search Institute, Mitsubishi Tanabe Pharma, Teijin Phar- Medical Research Council, MS Society of Great Britain, ma, Theva Pharmaceutical, Eisai Inc, Kowa Pharmaceu- Merck Serono, Biogen Idec, DIGNA Biotech, Novartis, tical, Ministry of Education, Science, and Technology of Eisai London Research Laboratories, Teva Pharmaceuticals; Japan, Ministry of Health, Labor, and Welfare of Japan; grants/grants pending, National Institute for Health speaking fees, Bayer Schering Pharma, Biogen Idec, Eisai Research, MS Society of Great Britain; speaking fees, Inc, Mitsubishi Tanabe Pharma, Astellas Pharma, Takeda Serono Symposia, Sanofi-Aventis; travel expenses, MS Pharmaceutical Company Ltd, Asahi Kasei Kuraray International Federation, US NMSS, Biogen Idec; honor- Medical Co; paid manuscript preparation, Cosmic Cor- aria, Editor-in-Chief of Multiple Sclerosis. E.W.: con- poration; royalties, Bunkodo. E.H.: travel expenses, US sultancy, Roche, Actelion; grants/grants pending, US NMSS, ECTRIMS, MSIF, MS Ireland; consultancy, NMSS, NIH; speaking fees, Teva; received free drug for Biogen Idec, Genzyme, Merck Serono, Novartis, Grifols; a trial given by Sanofi-Aventis and Biogen Idec. B.W.: grants/grants pending, Biogen Idec; speaking fees, Biogen travel support, US NMSS; European Committee for Idec, Genzyme, Merck Serono, Novartis, Bayer Healthcare, Treatment of MS; MS International Foundation; MS Ireland; consultancy, Novartis, Biogen Idec; employment, Sanofi-Aventis; paid educational presentations, Novartis. M.H.: consultancy, Biogen Idec; grant/grants pending, Mayo Clinic; royalties, RSR Ltd. J.S.W.: travel support, Health Research Board Ireland; speaking fees, Biogen Idec. US NMSS, ECTRIMS, MSIF, MS Ireland; board L.K.: travel expenses, US NMSS; board membership, membership, Antisense Therapeutics Ltd, BCDecker, Editorial Board of Multiple Sclerosis; grants/grants pend- Novartis Pharmaceuticals, Sanofi-Aventis, Teva Pharma- ing, National Research Foundation Switzerland, Rubatto ceuticals, Eli Lilly, UCB; consultancy, Genentech, Novartis Foundation, Swiss MS society, European Union, Roche Pharmaceuticals, Sanofi-Aventis, Teva Neuroscience, Teva Foundation, Novartis Foundation; speaking fees, various Pharmaceuticals, Acorda, Acetilon, Bayer HealthCare, companies involved in development of MS therapeutics; Facet Biotech, Peptimmune; grants/grants pending, NIH, paid educational presentations, Neurostatus System for Sanofi-Aventis, Clayton Foundation for Research, US Standardized Neurological Assessment. 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Annals of NeurologyPubmed Central

Published: Feb 1, 2011

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