Background In patients with isolated syndromes that are clinicallysuggestive of multiple sclerosis, such as optic neuritis orbrain-stem or spinal cord syndromes, the presence of lesionsas determined by T2-weighted magnetic resonance imaging (MRI)of the brain increases the likelihood that multiple sclerosiswill develop. We sought to determine the relation between earlylesion volume, changes in volume, and long-term disability.
Methods Seventy-one patients in a serial MRI study of patientswith isolated syndromes were reassessed after a mean of 14.1years. Disability was measured with the use of Kurtzke's ExpandedDisability Status Scale (EDSS; possible range, 0 to 10, witha higher score indicating a greater degree of disability).
Results Clinically definite multiple sclerosis developed in44 of the 50 patients (88 percent) with abnormal results onMRI at presentation and in 4 of 21 patients (19 percent) withnormal results on MRI. The median EDSS score at follow-up forthose with multiple sclerosis was 3.25 (range, 0 to 10); 31percent had an EDSS score of 6 or more (including three patientswhose deaths were due to multiple sclerosis). The EDSS scoreat 14 years correlated moderately with lesion volume on MRIat 5 years (r=0.60) and with the increase in lesion volume overthe first 5 years (r=0.61).
Conclusions In patients who first present with isolated syndromessuggestive of multiple sclerosis, the increases in the volumeof the lesions seen on magnetic resonance imaging of the brainin the first five years correlate with the degree of long-termdisability from multiple sclerosis. This relation is only moderate,so the volume of the lesions alone may not be an adequate basisfor decisions about the use of disease-modifying treatment.
In patients who present with isolated syndromes that are clinicallysuggestive of multiple sclerosis, such as optic neuritis orbrain-stem or spinal cord syndromes, multiple sclerosis candevelop months or many years later.1,2 Ninety percent of patientswith multiple sclerosis first present in this way. The presenceof cerebral white-matter lesions as determined by T2-weightedmagnetic resonance imaging (MRI) at presentation (found in 50to 70 percent of patients with isolated syndromes)3,4,5 is associatedwith an increased risk of multiple sclerosis.6,7,8,9 Abnormalitieson MRI have therefore been used to select patients with isolatedsyndromes for trials of disease-modifying therapies aimed atdelaying the onset of multiple sclerosis.10,11
Little is known about the relation between early findings onMRI in patients with isolated syndromes and subsequent disabilityfrom multiple sclerosis. This presentation becomes importantin the consideration of new early disease-modifying treatmentsand their potential to reduce long-term disability.12 In a previousreport based on data from 10 years of follow-up, we found thata change in the number and volume of lesions correlated morestrongly with a concurrent change in disability over the first5 years than over the second 5 years.9,13 The number and volumeof base-line lesions correlated moderately with the degree ofdisability (r=0.45) at year 10. We have now followed the cohortfor a mean of 14.1 years. The primary aim was to evaluate thestrength of the relation between lesion volumes on earlier MRIscans and the degree of disability after 14 years.
Methods
Patients
All the patients presented to the National Hospital at QueenSquare or Moorfields Eye Hospital between 1984 and 1987. Isolatedsyndromes were presumed to be demyelinating central nervoussystem events reaching a peak within 14 days after the onsetof symptoms in subjects 10 to 50 years of age with no historysuggesting demyelination. Appropriate investigations were carriedout to rule out alternative diagnoses.
Patients were initially recruited for clinical and MRI examinationsat base line and after approximately one year; 109 patientswere studied at both times.14,15 Further assessments took placeafter 5 years (89 patients)6 and 10 years (81 patients).9 Thepatients seen at 10 years were invited back for another clinicalassessment and MRI examination. Progression to clinically definiteor probable multiple sclerosis was defined with the use of thecriteria of Poser at al.,16 solely on clinical grounds. Clinicallydefinite cases were classified as relapsing–remittingor secondary progressive.17 Disability was measured with theuse of the Kurtzke Expanded Disability Status Scale (EDSS; possiblerange, 0 to 10, with a higher score indicating a greater degreeof disability).18 For those who could not attend the examination,an EDSS score was obtained over the telephone with the use ofa standard questionnaire; this approach was previously validatedin a study of 110 patients, in which the intraclass correlationcoefficient for the examination and telephone scores was 94.8percent.19
MRI
MRI data were available for assessments at base line and at5, 10, and 14 years but not for the 1-year follow-up examination.Imaging was performed on a 0.5-T system (Picker, Cleveland)at base line and 5 years and on a 1.5-T scanner (General ElectricSigna, Milwaukee) at 10 and 14 years. Contiguous, T2-weighted,axial slices of the brain were obtained at all visits. The slicethickness was 10 mm on 38 of the 71 base-line scans of patientswho were followed up at 14 years and 5 mm on all other scans.The methods of counting lesions and quantifying lesion volumehave been described previously.9,13
Statistical Analysis
Comparisons between groups were performed with the use of chi-squareor Mann–Whitney tests as appropriate. The Spearman rank-correlationcoefficient was used to evaluate the relation between the volumesand numbers of lesions on MRI during follow-up and the EDSSscore after 14 years. Measures included the total volume ornumber of lesions at a given time point and changes in volumeor number between two time points. The 95 percent confidenceintervals of the r value for each correlation between lesionvolume and EDSS score were calculated as outlined by Altman.20Similar confidence intervals were obtained with the use of thenonparametric bootstrap method.21 Selected pairs of correlationcoefficients were compared with the use of a t-test–basedmethod for comparing nonindependent correlations.22 The resultsof the rank-correlation test were also calculated as r2, whichprovides a direct measure of the degree to which variabilityin the rank of the 14-year EDSS score is related to variabilityin the rank of each measure of volume on T2-weighted MRI.
Results
Information was obtained on 72 of the 81 patients included inthe 10-year follow-up; 8 could not be traced, and 1 declinedto participate. One of the 72 patients was excluded since thesymptoms were considered, in retrospect, to be due to cerebrovasculardisease (the decision was made with knowledge of the MRI findingsbut was based on the clinical data). Of the remaining 71, 3had died from complications of severe multiple sclerosis byyear 14 (1 between years 5 and 10 and 2 between years 10 and14), 55 visited the hospital and underwent a neurologic andMRI examination, and 13 underwent EDSS assessment over the telephone.
The cohort of 71 included in the 14-year follow-up did not significantlydiffer from the original cohort of 109 in age at presentation,sex, type of syndrome, or frequency and volume of abnormalitieson MRI at presentation (Table 1). The 68 surviving patientswere assessed after a mean of 14.1 years (range, 12.5 to 16.8)when their mean age was 45 years (range, 33 to 64). Interferonbeta had been prescribed after the 10-year follow-up in onlythree patients; treatment was stopped after a brief period intwo, and only one was continuing treatment at year 14.
Table 1. Characteristics of the Patients in the MRI Follow-up Studies.
Development of Multiple Sclerosis
Clinically definite multiple sclerosis developed in 48 of 71patients (68 percent) and probable multiple sclerosis in a further5 (7 percent). The median EDSS score of patients with clinicallydefinite multiple sclerosis was 3.25 (range, 0 to 10); 31 percenthad an EDSS score of 6 or more (including three patients whosedeaths were due to multiple sclerosis). Clinically definitemultiple sclerosis developed in 25 of the 36 patients with opticneuritis (69 percent), 9 of the 14 patients with brain-stemsyndromes (64 percent), and 14 of the 21 patients with spinalcord syndromes (67 percent).
Normal MRI Scans at Base Line
Clinically definite multiple sclerosis (all relapsing–remitting)developed in 4 of 21 patients with normal MRI scans at baseline (19 percent) with a median EDSS score of 1.75 (range, 1to 2). The median time to the development of multiple sclerosiswas 7.5 years (range, 5 to 11). Clinically probable multiplesclerosis developed in another patient. All five patients withnew clinical events and three others (who were 39, 49, and 64years of age) had new lesions on MRI. Thus, 8 of 21 patients(38 percent) exhibited clinical or imaging evidence of multiphasicdisease.
Abnormal MRI Scans at Base Line
Clinically definite multiple sclerosis developed in 44 of 50patients with abnormal MRI scans at base line (88 percent);27 had relapsing–remitting disease (20 with an EDSS scoreof no more than 3 and 7 with an EDSS score greater than 3),and 17 had secondary progressive disease (including 3 who diedfrom severe disease). The median EDSS score of these 44 patientswas 3.5 (range, 0 to 10), and the median time to the developmentof multiple sclerosis was 2 years (range, 0.5 to 12). Clinicallyprobable multiple sclerosis developed in four patients (8 percent).Of the two remaining patients, one had new lesions on MRI andthe other declined follow-up imaging. Overall, 49 of 50 patients(98 percent) had clinical or radiologic evidence of multiphasicdisease consistent with multiple sclerosis.
Development of Disability
Patients with worse clinical outcomes had larger numbers andvolumes of lesions on MRI at base line (Table 2) and largerincreases in lesion volume over time (Table 3). The median EDSSscore at follow-up in those with more than 10 lesions at baseline was 6. All three patients who died as a result of multiplesclerosis had accumulated large volumes (22, 44.8, and 76 cm3)at five years of follow-up.
Table 2. Number and Volume of Asymptomatic Lesions on T2-Weighted MRI of the Brain at Presentation in Patients with Isolated Syndromes, and Their Clinical Outcome after 14 Years.
Table 3. Lesion Volumes at Each Time Point, According to Clinical Outcome after 14 Years.
The EDSS score at 14 years correlated moderately with the changein lesion volume on MRI over the first 5 years (r=0.61) andthe lesion volume at 5 years (r=0.60) (Table 4). Significantbut weaker correlations were found between the EDSS score at14 years and the earlier base-line volume (r=0.48) as well aslater measures (lesion volume on MRI at 10 years, r=0.48; changein volume from year 5 to year 10, r=0.29; and change in volumefrom year 10 to year 14, r=0.45). Differences in the r valueswere marginally significant for two of six pairwise comparisons:volumes at base line as compared with volumes at year 5 andchanges in volume from year 0 to year 5 as compared with changesfrom year 5 to year 10 (Table 4).
Table 4. Relation between Lesion Volume and Changes in Volume Throughout the Study and EDSS Score after 14 Years.
The change in lesion volume on MRI correlated moderately withthe change in the EDSS score over the first 5 years (r=0.58)and was weaker though still significant over the 5-to-10-yearand 10-to-14-year periods (Table 5).
Table 5. Correlation between Change in Lesion Volume on MRI and Change in EDSS Score for All Available Patients.
The EDSS score at 14 years was correlated with the number oflesions on MRI at base line (r=0.47, P<0.001), 5 years (r=0.55,P<0.001), and 10 years (r=0.45, P=0.001) and with the numberof new lesions on MRI from year 0 to year 5 (r=0.51, P<0.001)and year 10 to year 14 (r=0.59, P<0.001) but not from year5 to year 10 (r=0.16, P=0.25).
Discussion
Although case ascertainment was not complete, the patients inthis 14-year follow-up cohort had similar clinical and imagingfeatures at base line as the original cohort (Table 1) and arelikely to be representative. Overall, 14 years after the firstpresentation, clinically definite multiple sclerosis had developedin 68 percent of the patients. This is in accordance with theprediction, based on actual follow-up for a mean of 11 yearsand life-table analysis, that multiple sclerosis would havedeveloped in 75 percent of a cohort with optic neuritis after15 years.23 Prospective studies of similar length in other countrieshave reported lower frequencies in patients with isolated opticneuritis, with multiple sclerosis developing in 38 to 58 percentof patients after 13 to 15 years of follow-up.1,2 Multiple sclerosisdeveloped in a similar proportion with brain-stem or spinalcord syndromes, and inclusion of these cases does not accountfor the difference. The higher conversion rate in our cohortmay reflect geographic variations in the course of the disease,or a higher proportion of patients in whom multiple sclerosisdid not develop may have been lost to follow-up. However, weknow of four patients who had multiple sclerosis when seen at10 years and who were lost to follow-up at 14 years.
Of those with abnormalities on MRI at base line, 98 percentexhibited either clinical or radiologic evidence of multiphasicdisease; this long-term follow-up study therefore confirms thatwhite-matter lesions on MRI in young adults with isolated syndromesare, in almost all instances, due to multiple sclerosis. Indeed,new diagnostic criteria for multiple sclerosis, based on serialMRI findings, have recently been promulgated for patients withclinically isolated syndromes.24 In contrast, prolonged follow-upof those with normal scans confirms the good prognosis alreadyobserved during short-term follow-up studies: clinically probableor definite multiple sclerosis had developed in only one fifthof patients, and none had become disabled. A significant proportionof this subgroup may nevertheless have multiple sclerosis, albeita mild form, since almost 40 percent had new lesions on follow-upMRI. Although one patient was at an age (64 years) when newlesions due to incidental vascular disease are common, the findingssuggest that more prolonged follow-up is warranted. Some patientshave had a second episode after 30 or more years.
The average degree of disability of patients was mild, thoughthe wide range included all levels of the EDSS scale. Whereasthe median EDSS score of patients with clinically definite multiplesclerosis was 3.25, other natural-history studies have foundthat after 15 years, 50 percent will require aid to walk (equivalentto an EDSS score of 6).25,26,27 There are several possible explanationsfor the difference. First, the largest subgroup had optic neuritis,which may have a milder disease course; 70 to 80 percent haveminimal disability after follow-up periods of 8 to 15 years.1,28Second, all patients were followed prospectively whether multiplesclerosis developed or not, with assessment at regular intervals(1, 5, 10, and 14 years after onset); this helped detect casesof multiple sclerosis in patients in whom relapses were mildand disability was minimal. Third, patients with primary progressivemultiple sclerosis were not included in the present study buthave been in other studies27,29; disability develops more rapidlyin this subgroup than in those with relapse.29
The EDSS score at 14 years correlated significantly with lesionvolumes on MRI at all of the earlier time points, indicatingthat the lesion volume at any time contributes to the developmentof later disability. Lesion numbers show broadly similar correlationsbut are less reliable than volumes as a measure of disease progression,because lesion sizes vary and enlargement and the confluenceof lesions are not accounted for. The volume on MRI after 5years and the change in volume during the first 5 years correlatedmore strongly with the EDSS score at 14 years than did measuresof volume at earlier or later time points, suggesting that thedevelopment of lesions in the early years has an important influenceon long-term disability.
Natural-history studies have identified a relation between clinicalfeatures during the early years and long-term disability. Thefrequency of relapse and the interval between relapses duringthe first 2 years,26 incomplete recovery from relapses duringthe first 5 years,27 and the degree of disability after 5 years30have been associated with the development of disability up to25 years later. The apparent influence of relapses at this earlystage contrasts with the situation in patients who have enteredthe progressive phase of multiple sclerosis, in whom relapsesno longer influence progressive disability.29 The present MRIstudy and previous clinical studies suggest that both MRI andclinical measures of disease activity in the first two to fiveyears after the development of an isolated syndrome are importantin the long-term prognosis for disability in patients with multiplesclerosis.
Lesions on MRI correspond to demyelinating plaques at autopsy,31and most new lesions develop from a focal region of breakdownof the blood–brain barrier32 associated with active inflammationand demyelination.33 A large lesion volume in the early yearsimplies that extensive inflammation and demyelination have alreadyoccurred. On the other hand, a likely mechanism of progressivedisability is axonal loss, which can be extensive in chroniclesions.34 Putative magnetic resonance markers of axonal loss(e.g., tissue atrophy or reduced N-acetyl aspartate on magneticresonance spectroscopy) indicate that axonal loss is more abundantin disabled patients with a progressive course.35,36
The extent of inflammation and demyelination early in the diseasecourse may influence the extent of later axonal loss in severalways. First, acute inflammation is associated with axonal damage,including transection37,38; widespread axonal loss will diminishthe amount of axonal reserve, and a threshold may be reachedat an early point when continuing axonal loss — by whatevermechanism — begins to manifest as disability. Second,widespread inflammation could expose a range of potential autoantigensto immune surveillance, resulting in complex immunopathogenicevents due to epitope spreading39; such a process may be lessregulated and may be likely to cause axonal damage. Third, widespreadearly demyelination itself may create an environment that isnot conducive to long-term axonal survival.
Pathologic features other than the total volume of the lesionsare likely to contribute to disability: these include axonalloss in lesions, abnormalities in the normal-appearing tissues,diffuse atrophy, and spinal cord disease. Magnetic resonancetechniques such as T1-weighted imaging (for hypointense andcontrast-enhancing lesions), magnetic resonance spectroscopy,magnetization-transfer imaging, and diffusion tensor imagingare more pathologically specific than T2-weighted MRI and shouldbe incorporated into future studies.
This study provides MRI data over many years. Although therewas a change in scanner and slice thickness during the study,this had little influence40,41 on the large increases seen inthe lesion volumes, which included an increase in the medianvolume by a factor of 11 over a 14-year period. Furthermore,none of these patients were treated with disease-modifying drugsduring the first 10 years; three patients received interferonbeta after year 10. Now that agents that substantially modifylesion volume on MRI are being widely used in patients withrelapsing–remitting multiple sclerosis,42 it is unlikelythat similar data from long-term natural-history studies onthe development of lesions on MRI will be obtained.
The study demonstrates that lesion volume on MRI in patientswith isolated syndromes and early multiple sclerosis (the firstfive years of the disease) is of prognostic value in assessingthe risk of future disability. The correlations are only moderate,which cautions against the use of lesion volume alone to decideabout the use of disease-modifying treatments for individualpatients. Although the results suggest a potential long-termclinical benefit of therapies that suppress lesion formationin the early years of disease, the mechanisms underlying theobserved relation between clinical and MRI data are uncertain,and prospective long-term follow-up of cohorts receiving disease-modifyingtreatments will be needed to clarify this issue.
Supported by a program grant from the Multiple Sclerosis Societyof Great Britain and Northern Ireland, by Schering, by the InternationalFederation of Multiple Sclerosis Societies, and by the Universityof Rome La Sapienza.
We are indebted to Prof. W.I. McDonald, Dr. I.F. Moseley, Dr.D.P.E. Kingsley, Dr. K. Miszkiel, Dr. S. Morrissey, and Mr.D.G. MacManus for their contributions and to Dr. M. King forstatistical advice and analysis.
Source Information
From the Nuclear Magnetic Resonance Research Unit, Institute of Neurology, Queen Sq., London (P.A.B., O.C., A.J.T., D.H.M.); the Tayside Multiple Sclerosis Research Unit, Ninewells Hospital, Dundee, United Kingdom (J.I.O.); and Otto-von-Guericke Universität, Magdeburg, Germany (M.S.).
Address reprint requests to Dr. Miller at the NMR Research Unit, Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom.
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(2007). Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis. Neurology
69: 63-67
[Abstract][Full Text]
Nielsen, J.M., Moraal, B., Polman, C.H., Poppe, P., de Vos, M., Freedman, M.S., Kappos, L., Barkhof, F., Bauer, L., Pohl, C., Sandbrink, R., Hartung, H.-P., Uitdehaag, B.M.J.
(2007). Classification of patients with a clinically isolated syndrome based on signs and symptoms is supported by magnetic resonance imaging results. Mult Scler
13: 717-721
[Abstract]
Pelayo, R., Tintore, M., Rovira, A., Rio, J., Nos, C., Grive, E., Tellez, N., Comabella, M., Montalban, X.
(2007). Polyregional and hemispheric syndromes: a study of these uncommon first attacks in a CIS cohort. Mult Scler
13: 731-736
[Abstract]
Gauthier, S. A., Mandel, M., Guttmann, C.R.G., Glanz, B. I., Khoury, S. J., Betensky, R. A., Weiner, H. L.
(2007). Predicting short-term disability in multiple sclerosis. Neurology
68: 2059-2065
[Abstract][Full Text]
Khan, O.
(2007). Can clinical outcomes be used to detect neuroprotection in multiple sclerosis?. Neurology
68: S64-S71
[Abstract][Full Text]
Rovaris, M., Comi, G., Rocca, M., Valsasina, P., Ladkani, D., Pieri, E., Weiss, S., Shifroni, G., Wolinsky, J., Filippi, M., European/Canadian Glatiramer Acetate Study Group,
(2007). Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial. Mult Scler
13: 502-508
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Hahn, J. S., Pohl, D., Rensel, M., Rao, S., for the International Pediatric MS Study Group,
(2007). Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology
68: S13-S22
[Abstract][Full Text]
Banwell, B., Shroff, M., Ness, J. M., Jeffery, D., Schwid, S., Weinstock-Guttman, B., for the International Pediatric MS Study Group,
(2007). MRI features of pediatric multiple sclerosis. Neurology
68: S46-S53
[Abstract][Full Text]
Davies, G R, Hadjiprocopis, A, Altmann, D R, Chard, D T, Griffin, C M, Rashid, W, Parker, G J, Tofts, P S, Kapoor, R, Thompson, A J, Miller, D H
(2007). Normal-appearing grey and white matter T1 abnormality in early relapsing-remitting multiple sclerosis: a longitudinal study. Mult Scler
13: 169-177
[Abstract]
Lopatinskaya, L, Zwemmer, J, Uitdehaag, B, Lucas, K, Polman, C, Nagelkerken, L
(2006). Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years. Mult Scler
12: 704-709
[Abstract]
Weinshenker, B. G
(2006). Review: magnetic resonance imaging alone is of limited usefulness in diagnosing multiple sclerosis. Evid. Based Med.
11: 155-155
[Full Text]
Tintore, M., Rovira, A., Rio, J., Nos, C., Grive, E., Tellez, N., Pelayo, R., Comabella, M., Sastre-Garriga, J., Montalban, X.
(2006). Baseline MRI predicts future attacks and disability in clinically isolated syndromes.. Neurology
67: 968-972
[Abstract][Full Text]
Young, P. J., Lederer, C., Eder, K., Daumer, M., Neiss, A., Polman, C., Kappos, L., on behalf of the Sylvia Lawry Centre for Multiple,
(2006). Relapses and subsequent worsening of disability in relapsing-remitting multiple sclerosis.. Neurology
67: 804-808
[Abstract][Full Text]
Swanton, J K, Fernando, K, Dalton, C M, Miszkiel, K A, Thompson, A J, Plant, G T, Miller, D H
(2006). Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison. J. Neurol. Neurosurg. Psychiatry
77: 1070-1072
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Casanova, B, Bosca, I, Parra, S, Pascual, A, Coret, F
(2006). Letter to the Editor. Mult Scler
12: 521-522
Rauer, S, Euler, B, Reindl, M, Berger, T
(2006). Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event.. J. Neurol. Neurosurg. Psychiatry
77: 739-742
[Abstract][Full Text]
Li, D.K.B., Held, U., Petkau, J., Daumer, M., Barkhof, F., Fazekas, F., Frank, J. A., Kappos, L., Miller, D. H., Simon, J. H., Wolinsky, J. S., Filippi, M., for the Sylvia Lawry Centre for MS Research,
(2006). MRI T2 lesion burden in multiple sclerosis: A plateauing relationship with clinical disability. Neurology
66: 1384-1389
[Abstract][Full Text]
Oreja-Guevara, C., Charil, A., Caputo, D., Cavarretta, R., Sormani, M. P., Filippi, M.
(2006). Magnetization transfer magnetic resonance imaging and clinical changes in patients with relapsing-remitting multiple sclerosis.. Arch Neurol
63: 736-740
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Whiting, P., Harbord, R., Main, C., Deeks, J. J, Filippini, G., Egger, M., Sterne, J. A C
(2006). Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ
332: 875-884
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Bruna, J, Martinez-Yelamos, S, Martinez-Yelamos, A, Rubio, F, Arbizu, T
(2006). Idiopathic acute transverse myelitis: a clinical study and prognostic markers in 45 cases. Mult Scler
12: 169-173
[Abstract]
Pittock, S. J., Weinshenker, B. G., Noseworthy, J. H., Lucchinetti, C. F., Keegan, M., Wingerchuk, D. M., Carter, J., Shuster, E., Rodriguez, M.
(2006). Not every patient with multiple sclerosis should be treated at time of diagnosis.. Arch Neurol
63: 611-614
[Full Text]
Frohman, E. M., Havrdova, E., Lublin, F., Barkhof, F., Achiron, A., Sharief, M. K., Stuve, O., Racke, M. K., Steinman, L., Weiner, H., Olek, M., Zivadinov, R., Corboy, J., Raine, C., Cutter, G., Richert, J., Filippi, M.
(2006). Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis.. Arch Neurol
63: 614-619
[Full Text]
Simon, J.H., Li, D., Traboulsee, A., Coyle, P.K., Arnold, D.L., Barkhof, F., Frank, J.A., Grossman, R., Paty, D.W., Radue, E.W., Wolinsky, J.S.
(2006). Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines.. Am. J. Neuroradiol.
27: 455-461
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Kallmann, B A, Fackelmann, S, Toyka, K V, Rieckmann, P, Reiners, K
(2006). Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis. Mult Scler
12: 58-65
[Abstract]
Fernando, K. T. M., Tozer, D. J., Miszkiel, K. A., Gordon, R. M., Swanton, J. K., Dalton, C. M., Barker, G. J., Plant, G. T., Thompson, A. J., Miller, D. H.
(2005). Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis. Brain
128: 2911-2925
[Abstract][Full Text]
Rovaris, M., Gambini, A., Gallo, A., Falini, A., Ghezzi, A., Benedetti, B., Sormani, M. P., Martinelli, V., Comi, G., Filippi, M.
(2005). Axonal injury in early multiple sclerosis is irreversible and independent of the short-term disease evolution. Neurology
65: 1626-1630
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Frisoni, G. B., Filippi, M.
(2005). Multiple Sclerosis and Alzheimer Disease through the Looking Glass of MR Imaging. Am. J. Neuroradiol.
26: 2488-2491
[Full Text]
Bielekova, B., Kadom, N., Fisher, E., Jeffries, N., Ohayon, J., Richert, N., Howard, T., Bash, C. N., Frank, J. A., Stone, L., Martin, R., Cutter, G., McFarland, H. F.
(2005). MRI as a marker for disease heterogeneity in multiple sclerosis. Neurology
65: 1071-1076
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Rocca, M A, Hickman, S J, Bo, L, Agosta, F, Miller, D H, Comi, G, Filippi, M
(2005). Imaging the optic nerve in multiple sclerosis. Mult Scler
11: 537-541
[Abstract]
Lisanti, C. J., Asbach, P., Bradley, W. G. Jr.
(2005). The Ependymal "Dot-Dash" Sign: An MR Imaging Finding of Early Multiple Sclerosis. Am. J. Neuroradiol.
26: 2033-2036
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Zajicek, J
(2005). Diagnosis and disease modifying treatments in multiple sclerosis. Postgrad. Med. J.
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Pestalozza, I F, Pozzilli, C, Di Legge, S, Piattella, M C, Pantano, P, Caramia, F, Pasqualetti, P, Lenzi, G L
(2005). Monthly brain magnetic resonance imaging scans in patients with clinically isolated syndrome. Mult Scler
11: 390-394
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Soilu-Hanninen, M., Koskinen, J. O., Laaksonen, M., Hanninen, A., Lilius, E. -M., Waris, M.
(2005). High sensitivity measurement of CRP and disease progression in multiple sclerosis. Neurology
65: 153-155
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Rocca, M. A., Mezzapesa, D. M., Ghezzi, A., Falini, A., Martinelli, V., Scotti, G., Comi, G., Filippi, M.
(2005). A Widespread Pattern of Cortical Activations in Patients at Presentation with Clinically Isolated Symptoms Is Associated with Evolution to Definite Multiple Sclerosis. Am. J. Neuroradiol.
26: 1136-1139
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Gallo, A., Rovaris, M., Riva, R., Ghezzi, A., Benedetti, B., Martinelli, V., Falini, A., Comi, G., Filippi, M.
(2005). Diffusion-Tensor Magnetic Resonance Imaging Detects Normal-Appearing White Matter Damage Unrelated to Short-term Disease Activity in Patients at the Earliest Clinical Stage of Multiple Sclerosis. Arch Neurol
62: 803-808
[Abstract][Full Text]
Carmosino, M. J., Brousseau, K. M., Arciniegas, D. B., Corboy, J. R.
(2005). Initial Evaluations for Multiple Sclerosis in a University Multiple Sclerosis Center: Outcomes and Role of Magnetic Resonance Imaging in Referral. Arch Neurol
62: 585-590
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Polman, C. H, Wolinsky, J. S, Reingold, S. C
(2005). Multiple sclerosis diagnostic criteria: three years later. Mult Scler
11: 5-12
[Abstract]
Cohen, B. A., Khan, O., Jeffery, D. R., Bashir, K., Rizvi, S. A., Fox, E. J., Agius, M., Bashir, R., Collins, T. E., Herndon, R., Kinkel, P., Mikol, D. D., Picone, M. A., Rivera, V., Tornatore, C., Zwibel, H.
(2004). Identifying and treating patients with suboptimal responses. Neurology
63: S33-S40
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Jeffery, D. R.
(2004). Use of combination therapy with immunomodulators and immunosuppressants in treating multiple sclerosis. Neurology
63: S41-S46
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Bakshi, R., Hutton, G. J., Miller, J. R., Radue, E.-W.
(2004). The use of magnetic resonance imaging in the diagnosis and long-term management of multiple sclerosis. Neurology
63: S3-S11
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Colucci, M, Roccatagliata, L, Capello, E, Narciso, E, Latronico, N, Tabaton, M, Mancardi, G L
(2004). The 14-3-3 protein in multiple sclerosis: a marker of disease severity. Mult Scler
10: 477-481
[Abstract]
Optic Neuritis Study Group,
(2004). Long-term Brain Magnetic Resonance Imaging Changes After Optic Neuritis in Patients Without Clinically Definite Multiple Sclerosis. Arch Neurol
61: 1538-1541
[Abstract][Full Text]
Optic Neuritis Study Group,
(2004). Neurologic Impairment 10 Years After Optic Neuritis. Arch Neurol
61: 1386-1389
[Abstract][Full Text]
Pirko, I., Blauwet, L. K., Lesnick, T. G., Weinshenker, B. G.
(2004). The Natural History of Recurrent Optic Neuritis. Arch Neurol
61: 1401-1405
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Mikaeloff, Y., Adamsbaum, C., Husson, B., Vallee, L., Ponsot, G., Confavreux, C., Tardieu, M., Suissa, S., the KIDMUS Study Group on Radiology,
(2004). MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain
127: 1942-1947
[Abstract][Full Text]
Rovaris, M., Gallo, A., Riva, R., Ghezzi, A., Bozzali, M., Benedetti, B., Martinelli, V., Falini, A., Comi, G., Filippi, M.
(2004). An MT MRI study of the cervical cord in clinically isolated syndromes suggestive of MS. Neurology
63: 584-585
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Lim, E T, Grant, D, Pashenkov, M, Keir, G, Thompson, E J, Soderstrom, M, Giovannoni, G
(2004). Cerebrospinal fluid levels of brain specific proteins in optic neuritis. Mult Scler
10: 261-265
[Abstract]
Fernando, K. T. M., McLean, M. A., Chard, D. T., MacManus, D. G., Dalton, C. M., Miszkiel, K. A., Gordon, R. M., Plant, G. T., Thompson, A. J., Miller, D. H.
(2004). Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain
127: 1361-1369
[Abstract][Full Text]
Dalton, C. M., Chard, D. T., Davies, G. R., Miszkiel, K. A., Altmann, D. R., Fernando, K., Plant, G. T., Thompson, A. J., Miller, D. H.
(2004). Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain
127: 1101-1107
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Simmons, R. D, Ponsonby, A.-L., van der Mei, I. A., Sheridan, P.
(2004). What affects your MS? Responses to an anonymous, Internet-based epidemiological survey. Mult Scler
10: 202-211
[Abstract]
Minneboo, A., Barkhof, F., Polman, C. H., Uitdehaag, B. M. J., Knol, D. L., Castelijns, J. A.
(2004). Infratentorial Lesions Predict Long-term Disability in Patients With Initial Findings Suggestive of Multiple Sclerosis. Arch Neurol
61: 217-221
[Abstract][Full Text]
Sastre-Garriga, J., Tintore, M., Rovira, A., Nos, C., Rio, J., Thompson, A. J., Montalban, X.
(2004). Specificity of Barkhof Criteria in Predicting Conversion to Multiple Sclerosis When Applied to Clinically Isolated Brainstem Syndromes. Arch Neurol
61: 222-224
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Chard, D T, Brex, P A, Ciccarelli, O, Griffin, C M, Parker, G J M, Dalton, C, Altmann, D R, Thompson, A J, Miller, D H
(2003). The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study. J. Neurol. Neurosurg. Psychiatry
74: 1551-1554
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Dalton, C M, Brex, P A, Miszkiel, K A, Fernando, K, MacManus, D G, Plant, G T, Thompson, A J, Miller, D H
(2003). Spinal cord MRI in clinically isolated optic neuritis. J. Neurol. Neurosurg. Psychiatry
74: 1577-1580
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Ingle, G. T., Stevenson, V. L., Miller, D. H., Thompson, A. J.
(2003). Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain
126: 2528-2536
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Rovaris, M., Agosta, F., Sormani, M. P., Inglese, M., Martinelli, V., Comi, G., Filippi, M.
(2003). Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain
126: 2323-2332
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Simon, J. H., Thompson, A. J.
(2003). Is multiple sclerosis still a clinical diagnosis?. Neurology
61: 596-597
[Full Text]
Frohman, E. M., Goodin, D. S., Calabresi, P. A., Corboy, J. R., Coyle, P. K., Filippi, M., Frank, J. A., Galetta, S. L., Grossman, R. I., Hawker, K., Kachuck, N. J., Levin, M. C., Phillips, J. T., Racke, M. K., Rivera, V. M., Stuart, W. H.
(2003). The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology
61: 602-611
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Berger, T., Rubner, P., Schautzer, F., Egg, R., Ulmer, H., Mayringer, I., Dilitz, E., Deisenhammer, F., Reindl, M.
(2003). Antimyelin Antibodies as a Predictor of Clinically Definite Multiple Sclerosis after a First Demyelinating Event. NEJM
349: 139-145
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Optic Neuritis Study Group*,
(2003). High- and Low-Risk Profiles for the Development of Multiple Sclerosis Within 10 Years After Optic Neuritis: Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol
121: 944-949
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Eriksson, M., Andersen, O., Runmarker, B.
(2003). Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler
9: 260-274
[Abstract]
Rovaris, M., Rocca, M. A, Filippi, M.
(2003). Magnetic resonance-based techniques for the study and management of multiple sclerosis. Br Med Bull
65: 133-144
[Abstract][Full Text]
Frohman, E. M, Frohman, T. C
(2003). Horizontal monocular saccadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis. Mult Scler
9: 55-58
[Abstract]
Filippi, M., Bozzali, M., Rovaris, M., Gonen, O., Kesavadas, C., Ghezzi, A., Martinelli, V., Grossman, R. I., Scotti, G., Comi, G., Falini, A.
(2003). Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain
126: 433-437
[Abstract][Full Text]
Giovannoni, G., Bever, C. T. Jr.
(2003). Patients with clinically isolated syndromes suggestive of MS: Does MRI allow earlier diagnosis?. Neurology
60: 6-7
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Rovaris, M., Comi, G., Ladkani, D., Wolinsky, J. S., Filippi, M.
(2003). Short-Term Correlations between Clinical and MR Imaging Findings in Relapsing-Remitting Multiple Sclerosis. Am. J. Neuroradiol.
24: 75-81
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Simone, I. L., Carrara, D., Tortorella, C., Liguori, M., Lepore, V., Pellegrini, F., Bellacosa, A., Ceccarelli, A., Pavone, I., Livrea, P.
(2002). Course and prognosis in early-onset MS: Comparison with adult-onset forms. Neurology
59: 1922-1928
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Sriram, S., Yao, S.-y., Stratton, C., Calabresi, P., Mitchell, W., Ikejima, H., Yamamoto, Y.
(2002). Comparative Study of the Presence of Chlamydia pneumoniae in Cerebrospinal Fluid of Patients with Clinically Definite and Monosymptomatic Multiple Sclerosis. CVI
9: 1332-1337
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CHAMPS Study Group,
(2002). Predictors of short-term disease activity following a first clinical demyelinating event: analysis of the CHAMPS placebo groupy. Mult Scler
8: 405-409
[Abstract]
O'Connor, P.
(2002). Key issues in the diagnosis and treatment of multiple sclerosis: An overview. Neurology
59: S1-33
[Full Text]
Dalton, C M, Brex, P A, Jenkins, R, Fox, N C, Miszkiel, K A, Crum, W R, O'Riordan, J I, Plant, G T, Thompson, A J, Miller, D H
(2002). Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry
73: 141-147
[Abstract][Full Text]
Traboulsee, A., Dehmeshki, J., Brex, P. A., Dalton, C. M., Chard, D., Barker, G. J., Plant, G. T., Miller, D. H.
(2002). Normal-appearing brain tissue MTR histograms in clinically isolated syndromes suggestive of MS. Neurology
59: 126-128
[Abstract][Full Text]
Paty, D. W., Arnold, D. L.
(2002). The Lesions of Multiple Sclerosis. NEJM
346: 199-200
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Soilu-Hanninen, M., Koskinen, J. O., Laaksonen, M., Hanninen, A., Lilius, E. -M., Waris, M.
(2005). High sensitivity measurement of CRP and disease progression in multiple sclerosis. Neurology
65: 153-155
[Abstract][Full Text]
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