Baseline MRI predicts future attacks and
`disability in clinically isolated syndromes
`
`M. Tintore´, MD; A. Rovira, MD; J. Rı´o, MD; C. Nos, MD; E. Grive´, MD; N. Te´llez, MD; R. Pelayo, MD;
`M. Comabella, MD; J. Sastre-Garriga, MD; and X. Montalban, MD
`
`Abstract—Objective: To determine the relation between baseline MRI and both conversion to multiple sclerosis (MS) and
`development of disability in a cohort of patients with clinically isolated syndromes (CIS). Methods: From 1995 to 1998, 175
`consecutive patients with CIS underwent brain MRI within 3 months of their first attack and again 12 months and 5 years
`later. We studied the number and location of lesions at baseline and development of new T2 lesions. We also analyzed
`conversion to MS and development of disability (Expanded Disability Status Scale [EDSS] ⱖ 3.0). Results: We included
`156 patients with CIS followed for a median of 7 years. Compared to the reference group with 0 Barkhof criteria at
`baseline MRI, patients with one or two Barkhof criteria showed an adjusted hazard ratio (HR) of 6.1 (2.2 to 16.6) and
`patients with three to four Barkhof criteria of 17.0 (6.7 to 43) for conversion to MS and differentiated patients with low,
`medium, and high conversion risk. EDSS at year 5 correlated with baseline number of Barkhof criteria (r ⫽ 0.46, p ⬍
`0.0001). When categorizing by number of baseline lesions, similar results were seen. Patients with a baseline MRI with
`three to four Barkhof criteria had an adjusted HR of 3.9 (1.1 to 13.6) for reaching EDSS ⱖ 3.0. Only 10% of the latter had
`disability at year 5, but 40% reached this at 8 years. Conclusions: Baseline MRI determines the risk for converting to
`clinically definite multiple sclerosis and correlates with disability at 5 years. The proportion of patients developing
`disability is low during the first 5 years but rapidly increases shortly after.
`NEUROLOGY 2006;67:968–972
`
`Multiple sclerosis (MS) is characterized by recurrent
`attacks of neurologic dysfunction in over 80% of pa-
`tients. These patients present initially with a clini-
`cally isolated syndrome (CIS),
`typically optic
`neuritis, internuclear ophthalmoplegia, or partial
`myelitis. Once a first CIS has occurred, it is impor-
`tant to estimate the future risk of developing MS
`and disability. A number of clinical features, labora-
`tory investigations, and MRI abnormalities have
`been associated with an increased risk of progression
`to MS. MRI, however, has been shown to be the most
`informative surrogate marker.1-6 The group from
`London National Hospital reported the initial find-
`ings from 109 CIS patients, 89 of whom were reas-
`sessed at 5 years.3 Sixty-four percent had an
`abnormal baseline MRI and 65% of these developed
`clinically definite MS (CDMS) at follow-up compared
`with only 3% in the group of patients without MRI
`abnormalities. The presence of MRI lesions was also
`associated with higher disability levels at 5 years.
`These data were further confirmed at 10 and 14
`
`Additional material related to this article can be found on the Neurology
`Web site. Go to www.neurology.org and scroll down the Table of Con-
`tents for the September 26 issue to find the title link for this article.
`
`years of follow-up.4-5 Several other prospective stud-
`ies performed mainly in patients with optic neuritis
`with a follow-up of at least 5 years have confirmed
`that the presence of even few lesions in the baseline
`MRI is associated with an increased risk of develop-
`ing MS.6,7 Nevertheless the relationship between
`baseline MRI and disability at follow-up remains
`controversial. Recently the 10th year follow-up of the
`Optic Neuritis Treatment Trial (ONTT) has failed to
`find correlations between baseline MRI and disabil-
`ity at follow-up.7 The aim of our study was to deter-
`mine the relation between baseline MRI and both
`conversion to MS and development of disability in a
`cohort of patients with first attacks.
`
`Methods. The present study is based on longitudinal clinical,
`CSF, and MRI data prospectively acquired from a cohort of pa-
`tients with CIS recruited in our center between 1995 and 1998.
`Patients presenting for the first time with monophasic neurologic
`symptoms of the type seen in MS were recruited at the Vall
`d’Hebron University Hospital in Barcelona. Inclusion criteria were
`as follows: 1) a CIS suggestive of CNS demyelination involving the
`optic nerve, brainstem, spinal cord, or other topography, not at-
`tributable to other diseases; 2) age ⬍ 50 years; 3) onset of symp-
`toms within 3 months of both clinical and MRI examinations; and
`4) follow-up of more than 5 years.
`Clinical, CSF, and MRI assessments have been previously de-
`tailed elsewhere.1,8
`Briefly, patients were initially asked about any previous his-
`tory of neurologic disturbances and seen every 3 to 6 months. IgG
`
`From the Unit of Clinical Neuroimmunology (Department of Neurology) (M.T., J.R., C.N., N.T., R.P., M.C., J.S.-G., X.M.), Magnetic Resonance Unit
`(Department of Radiology) (A.R., E.G.), Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Spain.
`Disclosure: Our unit has received research grants from drug companies named in the present study. J.R., M.T., and X.M. have received scientific honoraria
`and travel expenses from all companies mentioned in this study. No financial support has been received for the present study.
`Received January 18, 2006. Accepted in final form May 18, 2006.
`Address correspondence and reprint requests to Dr. Mar Tintore´, Unitat de Neuroimmunologia Clinica (UNIC), Edif. Escola d’Infermeria Planta 2, Hospital
`Universitari Vall d’Hebron, Pg Vall d’Hebron 119-129, 08035 Barcelona, Spain; e-mail: mtintore@vhebron.net
`
`968 Copyright © 2006 by AAN Enterprises, Inc.
`
` EXHIBIT NO. 1058 Page 1
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`
`

`
`OB were examined by agarose isolectric focusing combined with
`immunoblotting and avidin-biotin amplified double-antibody per-
`oxidase staining.9 Brain MRI was performed after the first demy-
`elinating event and repeated after 12 months and 5 years of
`follow-up. MRI was performed on a 1.0-T or 1.5-T machine with a
`standard head coil. MRI included the following pulses: transverse
`proton-density and T2-weighted conventional spin echo, and in
`some patients contrast-enhanced T1-weighted spin-echo. The MRI
`scans were assessed by two radiologists who were blinded to clin-
`ical follow-up. We applied the four Barkhof criteria.10 For patients
`in whom a contrast-enhanced T1-weighted sequence was obtained,
`the presence of at least one enhancing area related to a lesion
`seen on T2-weighted images was scored. Number of baseline le-
`sions and presence of new lesions at follow-up was also scored.
`Patients with one or two Barkhof criteria on one hand and
`patients with three or four Barkhof criteria on the other hand
`were grouped because of their very similar behavior, thus three
`different categories for MRI Barkhof criteria were specified. Four
`different categories for number of lesions were also considered: 0
`lesions; 1 to 3 lesions; 4 to 9 lesions; 10 or more lesions.
`In patients with brainstem syndromes, patients with a single
`symptomatic lesion were considered to have a normal MRI.
`According to the MRI component of the new McDonald criteria,
`evidence of dissemination in space (DIS) was provided in one of
`two ways11-12: (DIS1) presence of three out of four MRI Barkhof
`criteria; (DIS2) presence of at least two T2 lesions plus OB. Dis-
`semination in time (DIT) was fulfilled when at least one new T2
`lesion had appeared in the follow-up scan.11 The MRI criteria were
`met when patients fulfilled the MRI definitions for dissemination
`in time and space. In addition, patients with a second clinical
`attack also fulfilled the new criteria. A diagnosis of conversion to
`CDMS was made when new symptoms occurred after an interval
`of at least 1 month and only when other diagnoses had been
`excluded. CDMS was diagnosed when there was a second attack
`with a new neurologic abnormality that was confirmed by
`examination.13
`Time of follow-up was calculated on the difference between the
`date of the last visit and the date of the event.
`Disability was evaluated according to the Expanded Disability
`Status Scale (EDSS) score in each visit and only EDSS performed
`during stability periods were considered. The cutoff for defining
`the presence of disability at year 5 was established when EDSS
`was superior or equal to 3.0.14 Time to reach EDSS 3.0 considering
`the full follow-up was also considered.
`Statistical analysis. Parametric and nonparametric descrip-
`tive statistics were performed. Spearman rank correlation coeffi-
`cients were used to approximate association between continuous
`variables. Kaplan-Meier analysis was used to estimate cumulate
`survival probabilities and to build survival plots. In order to as-
`sess the association between baseline MRI (number of Barkhof
`criteria and number of lesions) and both the time to conversion to
`CDMS and the time to development of disability, multivariate
`analysis using Cox proportional hazard regression was performed.
`Age at disease onset, sex, topography of first attack, and treat-
`ment were considered as potentially relevant covariates. Age was
`categorized according to 25th–50th–75th percentiles.
`
`Results. Of 175 patients, 120 were women and 55 were
`men with a mean age at onset of 29 years. Sixty-five pa-
`tients (37%) presented with optic neuritis, 48 (27%) with
`brainstem symptoms, 49 (28%) with spinal cord syndrome,
`and 13 (7%) patients had a different presentation (hemi-
`spheric, polyregional, or undetermined topography presen-
`tation). The median clinical follow-up time was 84.4
`months (7 years) (IQR: 74 to 93 months).
`One patient was excluded because a diagnosis of cere-
`bral autosomal dominant arteriopathy with subcortical
`infarcts and leukoencephalopathy was finally made.
`Twenty-seven patients were initially considered to be lost
`to follow-up, whom we attempted to contact by phone to
`find out their current status (occurrence of a second attack
`and EDSS15). The 9 of the 27 patients lost to follow-up who
`were reached were included in the final analysis. Demo-
`graphic, clinical, and MRI characteristics of the 18 pa-
`
`tients (10% of the total cohort) lost to follow-up were
`similar to those of the whole group of patients (data not
`shown). A total of 156 patients (89%) were finally included
`in the analysis.
`CDMS was diagnosed in 66 patients (42%). Fifty-five
`(35%) converted during the first 5 years and 11 converted
`after this period. The median conversion time for the
`whole cohort is 104 months and the mean 75.5 (SE: 3.6)
`months.
`Baseline MRI. Fifty-three patients (34%) had a normal
`brain MRI. Of these, 4 patients (8%) developed a second
`relapse during follow-up and 5 (9%) developed MS accord-
`ing to McDonald criteria. A total of 103 patients (66%) had
`an abnormal baseline MRI. Of these 62 (60%) developed
`CDMS and 74 (72%) developed MS according to McDonald.
`The percentages of patients converting to CDMS during
`the study period according to the number of Barkhof crite-
`ria fulfilled and number of baseline lesions are shown in
`table 1. Conversion to CDMS ranges from 9% for 0 Barkhof
`criteria to 61% for three to four Barkhof criteria. Consider-
`ing number of lesions, percentages go from 8% for normal
`brain MRI to 73% for patients with 10 or more lesions.
`Hazard ratio (HR) and 95% CI (adjusted by age, sex, and
`topography of first attack) for Barkhof criteria, taking 0
`Barkhof criteria as the reference group, are shown in table
`1. HRs range from 6.1 to 17.0 for developing CDMS. Table
`1 also shows adjusted HR and 95% CI for each category
`taking 0 lesions as a reference category. HRs range from
`4.3 to 19.3 for developing CDMS. Survival curves for cu-
`mulative probability of developing CDMS during follow-up
`according to baseline MRI features are shown in figure 1
`and figure E-1 on theNeurology Web site at www.neurology.
`org. Figure 1 shows three different types of patient groups
`who were classified as having low, medium, and high risk
`for early development to CDMS. Figure E-1 shows the
`same approach dividing patients by number of baseline
`lesions. Mean time to CDMS according to each category is
`also shown in table 1. Note that time to CDMS is shorter
`in each category with respect to the previous.
`First year and 5-year MRI. A total of 145 patients
`(93%) had at least one MRI scan performed during follow-
`up. No differences were found between patients with and
`without at least one follow-up scan in terms of conversion
`or baseline MRI features. New lesions at follow-up were
`seen in 76 patients (52%).
`Poser vs McDonald criteria. Sixty-six patients (42%)
`presented a second attack (CDMS) during follow-up. Con-
`sidering the MRI definitions proposed by McDonald, a di-
`agnosis of MS could be made in 79 patients (51%). The
`number of patients fulfilling both definitions (CDMS by Poser
`and MS by McDonald) according to the Barkhof criteria or
`number of lesions at baseline MRI are presented in table 1.
`Development of disability. EDSS at year 5. EDSS at
`year 5 was missing in three patients. Ten patients (7%) had
`an EDSS of 3.0 or higher at year 5. Of these, 7 patients had
`10 or more lesions on the MRI at baseline. The correlation
`between EDSS at year 5 and the number of baseline Barkhof
`criteria (Spearman rho coefficient) was 0.46 (p ⬍ 0.001). Cor-
`relations between EDSS at year 5 and MRI measures were
`as follows: number of baseline lesions 0.43 (p ⬍ 0.001), pres-
`ence of new T2 lesions at 12 months 0.39 (p ⬍ 0.001), and
`presence of new lesions at year 5, 0.51 (p ⬍ 0.01).
`Time to reach EDSS 3.0. Kaplan-Meier curves show
`September (2 of 2) 2006 NEUROLOGY 67 969
`
` EXHIBIT NO. 1058 Page 2
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`

`
`Table 1 Patients converting to CDMS or MS according to number of Barkhof criteria or number of lesions in baseline MRI
`
`CDMS
`
`MS (McDonald)
`
`N1/N2
`
`%
`
`HR
`
`95% CI
`
`Mean survival
`time (SE)
`
`5/59
`16/34
`45/61
`
`4/52
`7/23
`9/18
`46/63
`
`9
`44
`61
`
`7.7
`30.4
`50
`73
`
`1*
`6.1
`17.0
`
`1*
`4.3
`7.4
`19.3
`
`2.2–16.6
`6.7–43.5
`
`1.3–14.8
`2.3–24.5
`6.8–54.6
`
`103.3 (3.5)
`77.7 (6.9)
`46.8 (5.3)
`
`104.8 (3.2)
`83.6 (9.1)
`71.3 (9.6)
`47.7 (5.3)
`
`N1/N2
`
`6/59
`20/36
`53/61
`
`5/52
`8/23
`14/18
`52/63
`
`%
`
`10.2
`55.6
`86.9
`
`9.6
`34.8
`77.8
`82.5
`
`No. Barkhof criteria
`0
`1–2
`3–4
`No. lesions
`0
`1–3
`4–9
`10 or more
`
`* 1: Reference category.
`
`CDMS ⫽ clinically definite multiple sclerosis; N1/N2 ⫽ ratio between patients fulfilling CDMS or MS and total number of patients
`fulfilling the baseline MRI criteria; HR ⫽ hazard ratio (adjusted by age, sex, and topography of first attack); 95% CI ⫽ confidence
`interval. Mean survival time to CDMS is expressed in months.
`
`that the great majority of patients have not reached EDSS
`3.0 within the first 5 years. Table 2 shows that the mean
`time for reaching a disability level of 3.0 is greater than 98
`months (8 years) in all groups of patients. Adjusted HR for
`reaching EDSS 3.0 was 3.9 (1.1 to 13.6) for patients with 3
`or 4 Barkhof criteria and 3.6 (1.1 to 12.7) for patients with
`10 or more lesions at baseline. After 8 years, around 40%
`of patients with CDMS had reached an EDSS of 3.0 and
`the same was true for patients with a baseline MRI with 3
`or 4 Barkhof criteria or 10 or more lesions at baseline MRI
`(figure 2, A and B, and figure E-2).
`In summary, only 10% of patients with a baseline MRI
`with high risk had an EDSS of 3.0 or more at year 5, but
`40% reached this outcome at 8 years according to Kaplan
`Meier curves.
`
`Figure 1. Development of clinically definite multiple scle-
`rosis according to baseline MRI. Number of Barkhof crite-
`ria: no Barkhof criteria (low risk) dotted line, one or two
`Barkhof criteria (intermediate risk) dashed line, and three
`or four Barkhof criteria (high risk) solid line. Note that
`curves for Barkhof criteria 1 and 2 have been unified into
`one single category because of their very similar behavior
`and the same approach has been used for Barkhof criteria
`three and four.
`
`970 NEUROLOGY 67 September (2 of 2) 2006
`
`Disease-modifying drugs. At year 5, 29% of the pa-
`tients were on disease- modifying drugs, mainly one of the
`three available beta- interferons, all of whom had started
`treatment after their second attack. When patients had at
`least two relapses within 3 years, disease-modifying drugs
`were proposed and discussed with the patients. The mean
`time from CIS onset to drug prescription was 37 months
`(SD 24). The mean time on treatment was 47 months (SD
`23). Mean EDSS at 5 years for patients on treatment was
`2.2 (SD 1.3) compared to 0.9 (SD 0.9) (p ⬍ 0.001) in pa-
`tients not receiving disease-modifying drugs.
`Multivariate analysis for time to reach EDSS of 3.0
`controlling for covariates such as sex, age, topography of
`first attack, and disease-modifying drug treatment showed
`that disease-modifying drugs was an important predictor
`of disability. Nevertheless, we consider that this is not a
`cause but a consequence. Patients were put on treatment
`because their disease was active. All patients on disease-
`modifying drugs had an abnormal baseline MRI compared
`to 55% of the non-treated patients. Seventy-nine percent of
`the treated patients vs 26% of the non-treated patients
`fulfilled three to four Barkhof criteria at baseline (p ⬍
`0.0001). In the same sense, 97% of the treated patients had
`new lesions on the follow-up scans vs 38.5% in the non-
`treated group (p ⬍ 0.0001).
`
`Discussion. Of 156 patients followed for at least 5
`years, 60% of patients with a CIS and an abnormal
`baseline MRI have developed CDMS. When adding
`MRI McDonald definitions, the percentage increases
`to beyond 70%. Patients with a normal baseline MRI
`developed CDMS in less than 8%, which could in-
`crease to 10% considering McDonald criteria. These
`results are in agreement with other published da-
`ta.3,6,16,17 As shown by the Kaplan-Meier curves, the
`number of lesions at baseline is related to the time to
`reach CDMS, therefore patients with fewer lesions at
`baseline require a longer follow-up to reach conver-
`sion rates similar to the groups with higher number
`
` EXHIBIT NO. 1058 Page 3
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`
`Table 2 Patients reaching EDSS 3.0 according to baseline MRI or clinical status
`
`No. Barkhof criteria
`0
`1–2
`3–4
`No. lesions
`0
`1–3
`4–9
`10 or more
`Clinical status
`CIS
`CDMS
`
`* 1: Reference category.
`
`N1/N2
`
`3/59
`5/36
`15/61
`
`3/52
`2/23
`2/18
`16/63
`
`5/90
`18/66
`
`%
`
`5.1
`13.4
`24.6
`
`5.8
`8.7
`11.1
`25.4
`
`5.6
`27.3
`
`HR
`
`1*
`1.9
`3.9
`
`1*
`1.3
`1.4
`3.6
`
`1*
`4.3
`
`EDSS ⱖ 3.0
`
`95% CI
`
`Mean survival time (SE)
`
`0.4–8.1
`1.1–13.6
`
`0.2–8.0
`0.2–8.7
`1.0–12.7
`
`1.6–11.7
`
`114.2 (3.0)
`100.5 (3.5)
`98.2 (3.9)
`
`105.9 (3.1)
`113.8 (3.9)
`98.6 (4.3)
`97.8 (3.9)
`
`106.7 (2.1)
`100.1 (3.9)
`
`EDSS ⫽ Expanded Disability Status Scale; N1/N2 ⫽ ratio between patients reaching an EDSS of 3.0 and total number of patients in
`each category according to baseline MRI or clinical status; HR ⫽ hazard ratio (adjusted by age, sex, topography of first attack, and
`disease-modifying drugs); 95% CI ⫽ confidence interval. Mean survival time to CDMS is expressed in months; CIS ⫽ clinically isolated
`syndromes;
`CDMS ⫽ clinically definite multiple sclerosis.
`
`of baseline lesions. Kaplan-Meier curves very clearly
`differentiate three groups of patients with low, inter-
`mediate, and high risk of developing CDMS at short
`term (figures 1 and E-1). Patients with 0 Barkhof
`criteria have a low risk of developing CDMS, pa-
`tients with 1 and 2 Barkhof criteria an intermediate
`risk and patients with three or four Barkhof criteria
`will develop CDMS in a very short lapse of time.
`These figures allow us to identify those patients that
`are at high risk to present a second attack shortly
`after the first one. In this sense, the cutoff estab-
`lished for the Barkhof criteria (three or more) looks
`very useful.10 Nevertheless it is also true that pa-
`tients fulfilling one or two Barkhof criteria will prob-
`ably develop CDMS after a longer follow-up.
`Therefore this group of patients without DIS criteria
`according to McDonald criteria should be also care-
`fully followed as with longer follow-up, they will
`probably develop the disease. In this sense, the
`McDonald criteria have been claimed to be more
`prognostic than diagnostic.18 Moreover, the conver-
`sion rate applying Poser or McDonald criteria is sim-
`ilar after a certain time of follow-up. Our group
`showed that after 12 months of
`follow-up, the
`McDonald criteria more than tripled the number of
`patients diagnosed with MS vs the Poser criteria.8
`The present study shows that after 5 years of follow-
`up, we could only identify 10% more patients using
`the McDonald vs Poser criteria. This percentage may
`obviously increase depending on the number of MRI
`scans performed during the follow-up period.
`As for development of disability, our study con-
`firms that the disability development defined as
`EDSS of three or higher at year 5 correlates with
`
`Figure 2. Time to reach an Expanded Disability Status
`Scale score of 3.0 according to baseline MRI. (A) Patients
`with (solid line) and without (dotted line) clinically defi-
`nite multiple sclerosis. (B) Number of Barkhof criteria: 0
`Barkhof criteria (low risk) (dotted line), one or two Bark-
`hof criteria (intermedium risk) (dashed line), and three or
`four Barkhof criteria (high risk) (solid line).
`
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`
`MRI at baseline and that the number of baseline
`lesions and the number of Barkhof criteria have sim-
`ilar Spearman rho coefficients 0.43 and 0.46. Others
`also found a significant correlation of 0.45 between
`the number of MRI lesions at presentation and dis-
`ability at follow-up.3 In the ONTT study group, the
`disability level after 10 years appeared to be unre-
`lated to the number of baseline lesions.7 Unfortu-
`nately, the ONTT study was not designed to assess
`long-term disability in MS. Surprisingly, moderate
`or severe disability was present in 29% of the pa-
`tients with no lesions on the baseline MRI. In our
`study, the presence of new lesions at follow-up was
`also correlated with disability at year 5 with a corre-
`lation index of 0.41 (p ⬍ 0.001). The occurrence of
`disability in our cohort, at 5 years of follow-up, de-
`fined as an EDSS of 3.0 or higher, was seen in 10
`patients (7%), all of whom developed MS. This per-
`centage is considerably lower than the 20% reported
`by the London National Hospital group.3 Although
`we cannot exclude that patients lost to follow-up
`(10%) may be partially responsible for this differ-
`ence, the patients lost to follow-up were similar to
`the whole populations as to baseline characteristics
`and severe cases are usually less prone to giving up
`on clinical control. Another explanation can be found
`in recent updates of natural history cohorts where
`the degree of disability achieved by these popula-
`tions is clearly lower than previously reported.19 The
`ONTT Study Group also pointed to a milder disease
`course after 10 years of follow-up.7 Genetic back-
`ground may also contribute to these differences. In
`Northern European countries, MS is two- to fourfold
`more prevalent than in Mediterranean countries.20-22
`This difference in susceptibility to develop MS may
`also have a translation into clinical characteristics,
`such as disability. Disease-modifying drugs were
`specifically prescribed to patients with a more ag-
`gressive disease course, which probably explains the
`observation that this population was then more dis-
`abled than non-treated patients. Although disease-
`modifying drugs have consistently demonstrated a
`reduction in relapses in treated patients, their con-
`tribution to delay disability remains unproven.23-25
`Genetic or environmental factors may be responsible
`for the milder character in terms of disability seen in
`our cohort at 5 years. After this time point, disability
`clearly worsens.
`
`Acknowledgment
`The authors thank Xavier Vidal for statistical advisement and
`Joseph Graells for language editing. The authors also thank FEM
`(Fundacio´ Esclerosi Multiple), Marı´a Jose´ Vicente and Rosalı´a
`Hornos (nurses of the MS Unit), and Red CIEN and Institut
`Catala` de Investigacio´ en Neurocie`ncies (ICIN) for supporting in
`part the MS Unit at their center.
`
`References
`1. Tintore M, Rovira A, Rio J, et al. Are optic neuritis really more benign
`than other first attacks? Ann Neurol 2005;57:210–215.
`2. Tintore´ M, Rovira A, Brieva L, et al. Isolated demyelinating syndromes:
`comparison of CSF oligoclonal bands and different MRI criteria to pre-
`dict conversion to CDMS. Mult Scler 2001;7:359–363.
`3. Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain
`magnetic resonance imaging abnormalities at presentation with clini-
`cally isolated syndromes suggestive of multiple sclerosis. A 5-year
`follow-up study. Brain 1993;116:135–146.
`4. O’Riordan JI, Thompson AJ, Kingsley DPE, et al. The prognostic value
`of brain MRI in clinically isolated syndromes of the CNS: a 10 year
`follow-up. Brain 1998;121:495–503.
`5. Brex PA, Ciccarelli O, Jonathon I, et al. A longitudinal study of abnor-
`malities on MRI and disability from multiple sclerosis. N Engl J Med
`2002;346:158–164.
`6. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis:
`experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:
`1404–1413.
`7. Beck RW, Smith CH, Gal RL, et al. Optic Neuritis Study Group. Neuro-
`logic impairment 10 years after optic neuritis. Arch Neurol 2004;61:
`1386–1389.
`8. Tintore M, Rovira A, Rio J, et al. New diagnostic criteria for multiple
`sclerosis: application in first demyelinating episode. Neurology 2003;60:
`27–30.
`9. Andersson M, Alvarez-Cermen˜ o J, Bernardi G, et al. Cerebrospinal
`fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol
`Neurosurg Psychiatry 1994;57:897–902.
`10. Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at
`first presentation to predict conversion to clinically definite multiple
`sclerosis. Brain 1997;120:2059–2069.
`11. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic
`criteria for multiple sclerosis: guidelines from the international panel
`on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127.
`12. Tintore M, Rovira A, Martı´nez MJ, et al. Isolated demyelinating syn-
`dromes: comparison of different MRI criteria to predict conversion to
`clinically definite multiple sclerosis. Am J Neuroradiol 2000;21:702–
`706.
`13. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for
`multiple sclerosis: guidelines for research proposals. Ann Neurol 1983;
`13:227–231.
`14. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an
`expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.
`15. Lechner-Scott J, Kappos L, Hofman M, et al. Can the Expanded Dis-
`ability Status Scale be assessed by telephone? Multiple Scler 2003;9:
`154–159.
`16. Paolino E, Fainardi E, Ruppi P, et al. A prospective study on the
`predictive value of CSF oligoclonal bands and MRI in acute isolated
`neurological syndromes for subsequent progression to multiple sclero-
`sis. J Neurol Neurosurg Psychiatry 1996;60:572–575.
`17. Jacobs LD, Kaba SE, Miller CM, Priore RL, Brownscheidle CM. Corre-
`lation of clinical, MRI and CSF findings in optic neuritis. Ann Neurol
`1997;41:392–398.
`18. Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in
`suspected MS. Report of the therapeutics and technology assessment
`subcommittee of the American Academy of Neurology. Neurology 2003;
`61:602–611.
`19. Pittock SJ, Mayr WT, McClelland RL, et al. Change in MS-related
`disability in a population-based cohort: a 10-year follow-up study. Neu-
`rology 2004;62:51–59.
`20. Miller D, Barkhof F, Montalban X, Thompson AJ, Filippi M. Clinically
`isolated syndromes suggestive of multiple sclerosis, part I: natural his-
`tory, pathogenesis, diagnosis and prognosis. Lancet Neurol 2005;4:281–
`288.
`21. Bufill E, Blesa R, Galan I, Dean G. Prevalence of multiple sclerosis in
`the region of Osona, Catalonia, northern Spain. J Neurol Neurosurg
`Psychiatry 1995;58:577–581.
`22. McDonnell GV, Hawkins SA. An epidemiologic study of multiple sclero-
`sis in Northern Ireland. Neurology 1998;50:423–428.
`23. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effec-
`tive in relapsing-remitting multiple sclerosis. I. Clinical results of a
`multicenter, randomized, double-blind, placebo-controlled trial. Neurol-
`ogy 1993;43:655–661.
`24. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon
`beta1a for disease progression in relapsing multiple sclerosis. Ann Neu-
`rol 1996;39:285–294.
`25. PRIMS Study Group. Randomised double-blind placebo-controlled
`study of interferon beta-1a in relapsing-remitting multiple sclerosis.
`Lancet 1998;352:1498–1504.
`
`972 NEUROLOGY 67 September (2 of 2) 2006
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` EXHIBIT NO. 1058 Page 5
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` AMNEAL
`
`

`
`Baseline MRI predicts future attacks and disability in clinically isolated syndromes
`M. Tintoré, A. Rovira, J. Río, et al.
`2006;67;968-972
`Neurology(cid:160)
`DOI 10.1212/01.wnl.0000237354.10144.ec
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` EXHIBIT NO. 1058 Page 6
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` AMNEAL