Clinical Neurology and Neurosurgery 109 (2007) 344349

The effect of interferon-beta1a on relapses and progression of disability in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis
Mohammad Reza Motamed a, , Neda Najimi b , Seyed-Mohammad Fereshtehnejad b
a

Department of Neurology, Faculty of Medicine, Iran University of Medical Sciences and Health Services, Hemmat Highway, Tehran, Iran b Medical Student Research Committee, Faculty of Medicine, Iran University of Medical Sciences and Health Services, Tehran, Iran Received 28 June 2006; received in revised form 6 January 2007; accepted 8 January 2007

Abstract Objectives: In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brain stem or spinal cord. The advent of disease-modifying treatments for MS has increased attention on early stages of the disease. Therefore, the aim of this study was to evaluate the effect of interferon on relapses and progression of disability in patients with a CIS. Patients and methods: This randomized, clinical trial was conducted in 25 patients who presented with a CIS indicative of MS. They were evaluated in two groups: 11 patients who were receiving interferon-beta1a (Rebif, Serono) subcutaneous injections three times a week (group A), and 14 patients who were not receiving disease-modifying treatment (group B). The progression of disability was determined using the Kurtzke Expanded Disability Status Scale (EDSS) and the numbers of new relapses were recorded during 21 months of follow-up. Results: The mean numbers of new relapses and changes in EDSS at the end of study period were 0.68 (standard deviation [S.D.] = 0.80) and 1.09 (S.D. = 0.49), and 1.79 (S.D. = 1.05) and 0.64 (S.D. = 0.49) in groups A and B, respectively. Statistical analysis showed that disease-modifying treatment with interferon-beta1a may reduce relapses (P = 0.007) and prevent progressive disability (P = 0.034). Conclusion: Interferon-beta1a signicantly delayed progression to disability and incidence of new relapses. 2007 Elsevier B.V. All rights reserved.
Keywords: Clinically isolated syndrome; Multiple sclerosis; Disease-modifying treatment; Interferon-beta; Kurtzke Expanded Disability Status Scale; Relapse

1. Introduction Multiple sclerosis (MS) is one of the most common causes of chronic neurological disability in young and middle-aged adults. In the UK, about 80,000 people have MS, and there are about 2500 newly diagnosed cases per year [1]. It also aficts approximately 250,000 Americans [2], and 1 in 1000 to 1 in 500 Canadians [3]. MS affects more women than men by a ratio of nearly 2 to 1, and it is most common between the ages of 20 and 40 years. The cause of MS is unknown and its pathophysiology remains poorly understood [2].

Corresponding author. Tel.: +98 9121371266. E-mail address: mrmotamed2005@yahoo.com (M.R. Motamed).

However, MS is a cell- and antibody-mediated whitematter disease in which myelin and oligodendrocytes are targets of tissue damage [4]. Unfortunately, MS usually begins at a time when it can have great impact on work, family and social life [1]. In addition, there is no predictable presentation pattern for patients with MS, which often makes diagnosis clinically challenging [4]. Variability and diversity characterize the symptoms and presentation of MS. There is virtually no neurologic complaint that has not been traced to MS at one time or another, and a comprehensive account of its clinical features can become little more than a recitation of a positive neurologic review of systems [2]. However, in 85% of patients who later develop MS, clinical onset is marked by an acute or subacute episode of neurological disturbance of the optic nerves, brain stem, or spinal cord due to a single white-matter lesion. This presentation

0303-8467/$ see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.01.007

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is known as a clinically isolated syndrome (CIS) [5,6]. A CIS of inammatory demyelination is associated with a high risk of development of clinically denite multiple sclerosis (CDMS) [7]. A review of a large database of patients with CIS found that 21% presented with optic neuritis, 46% with long-tract symptoms and signs, 10% with a brain-stem syndrome, and 23% with multifocal abnormalities [8]. The presentation of MS affects disease course and prognosis [922]. Although in most cases, CIS represents the rst episode of MS, not all CIS patients will develop MS, but the presence of lesions on brain magnetic resonance imaging (MRI) scans signicantly increases the risk that a patient will suffer a relapse leading to diagnosis of MS [23]. As mentioned above, CIS is typically the earliest clinical expression of MS. It seems that disease-modifying treatments such as interferon therapy may prevent further progression of disability and development of MS. Recent clinical trials demonstrated that starting preventive treatment with interferon-beta may delay the occurrence of further relapses in CIS [11,24]. Therefore, the aim of this study was to evaluate the effect of interferon on relapses and progression of disability in patients with a CIS.

2.2. Treatment assignment and monitoring Patients were randomly assigned in approximately equal numbers to the two treatment groups: one group consisted of 11 patients who received interferon-beta1a (Rebif, Serono) 22 g subcutaneously three times a week (group A), and another group consisted of 14 patients who did not receive disease-modifying treatment (group B). All patients in both groups with moderate or severe relapses during the study period were treated with a routine standard dose of 1.0 g intravenous methylprednisolone for 35 consecutive days. After enrollment, neurological and safety assessments were performed at the end of months 1, 2, 3, 9, 15, and 21 by a neurologist. Demographic data and the number of new attacks were recorded for each patient. Standard neurological examination with neurological impairment assessed using the Kurtzke Expanded Disability Status Scale (EDSS) [26] was performed at the time of enrollment in the study and at every routine visit. This scale (EDSS) is based on data from the neurologic examination and the patients ability to walk. Scores range from 0 (indicating no neurologic abnormality) to 10 (death caused by MS). This means that higher scores indicate more severe disability. To evaluate each CIS presentation, the functional system (FS) of the EDSS was used [26], therefore, it is possible to show changes in isolated syndromes. Symptomatic therapy was administered as necessary for all patients. 2.3. Statistical analysis The data were analyzed using SPSS v.13 software for Windows. Parameters such as frequency, mean, mode and standard deviation (S.D.) were reported. The analyses were performed using statistical tests. To test the differences between parametric and non-parametric variable means in the two study groups, the independent T-test and MannWhitney U-test were used, respectively. To compare the differences among the variable means of different CIS subgroups, analysis of variance (one-way ANOVA) was used. A two-way ANOVA procedure was used to assess the probable confounding effect of baseline CIS presentations on the main result of our study. In addition, to compare the changes in parametric and non-parametric EDSS means, repeated-measure ANOVA and Friedmann tests were performed, respectively. In summary, this analysis involved repeated independent T-test, oneand two-way ANOVA, Friedmann, and MannWhitney tests. A 5% probability of a type I error (two-tailed), and a power of 80% were considered in the analysis. All reported p-values are two-tailed.

2. Methods and subjects 2.1. Patients The study was conducted at Firoozgar University Hospital in Tehran, Iran, from October 2002 to March 2005. It was a randomized clinical trial of 25 individuals. Eligible subjects were patients who had a rst, isolated, well-dened neurologic event consistent with demyelination involving the optic nerve (unilateral optic neuritis), spinal cord (incomplete transverse myelitis), or brain stem or cerebellum (brain stem or cerebellar syndrome) and which was conrmed on ophthalmologic or neurologic examination. At the time of enrollment, brain MRI scan, cerebrospinal uid (CSF) analysis and Visual Evoked Potential (VEP) tests were done as part of the pre-study evaluation. The results of the test were assessed using McDonald criteria (revision of 2005) [25]. An MRI scan was judged to be positive when three of the following criteria were met: (1) at least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium-enhancing lesion; (2) at least one infratentorial lesion; (3) at least one juxtacortical lesion; and (4) at least three periventricular lesions. Patients with a prior neurologic or visual event consistent with the occurrence of demyelination that lasted longer than 48 h were excluded from the study. Other reasons for exclusion were: any previous immunomodulatory treatment; participation in any experimental procedure in the year before the study; other serious intercurrent systemic illnesses or psychiatric disorders; pregnancy; and an unwillingness to use reliable methods of contraception during the study.

3. Results We recruited 25 patients with a CIS to the study. Of these, 17 (68%) were female and 8 (32%) were male. At the time

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M.R. Motamed et al. / Clinical Neurology and Neurosurgery 109 (2007) 344349

Table 1 Clinical features and mean of EDSSs during study period in two groups of study Variable Age (year) Gender distribution Female Male Type of CIS Brain stem Spinal-cord Optic neuritis Cerebellar MRI ndings Positive Negative CSF ndings Positive Negative VEP ndings Abnormal Normal 1st EDSS (at admission) EDSSs during study period 2nd EDSS (month 2) 3rd EDSS (month 3) 4th EDSS (month 9) 5th EDSS (month 15) 6th EDSS (month 21)
a

A 25.55 (6.73)a 8 (72.7%) 3 (27.3%) 2 (18.2%) 3 (27.3%) 4 (36.4%) 2 (18.2%) 11 (100%) 0 5 (45.5%) 6 (54.5%) 11 (100%) 0 1.63 (0.74)a 1.27 (0.87)a 0.86 (0.67)a 0.63 (0.45)a 0.54 (0.47)a 0.54 (0.47)a

B 24.79 (6.29) 9 (64.3%) 5 (35.7%) 4 (28.6%) 4 (28.6%) 4 (28.6%) 2 (14.3%) 9 (64.3%) 5 (35.7%) 5 (35.7%) 9 (64.3%) 10 (71.4%) 4 (28.6%) 1.82 (0.79) 1.57 (0.87) 1.21 (0.64) 1.35 (0.74) 1.32 (0.74) 1.17 (0.74)

Fig. 1. Changes of EDSSs after 21 months of follow-up in groups A and B.

Mean (S.D.).

with the EDSSs of the patients in groups A and B during 21 months of follow-up. The changes in these scales and the numbers of new relapses in different periods of study are compared between the two groups (Table 2). The results of the Friedman tests demonstrated that the changes in disability (as shown by the EDSS scores) were signicant in groups A and B (p = 0.000 and 0.006, respectively), but the prevention of disability progression was signicantly better in group A (Fig. 1). Further statistical analysis showed that disease-modifying treatment with interferonbeta1a (Rebif) may reduce relapses and prevent progressive disability. As shown in Table 2, there were signicant differences in the total changes in EDSS after 21 months of study (1.09 versus 0.64; p = 0.034) and in the number of new relapses during the study period (0.64 versus 1.79; p = 0.007) between groups A and B. Two-way ANOVA analyses showed that the effect of disease-modifying therapy on total changes of

of inclusion in the study, mean age of patients was 25.12 (S.D. = 6.36) years (range 1739 years). The most common types of CIS were optic neuritis (32%), spinal-cord syndrome (28%), brain-stem syndrome (24%) and cerebellar symptoms (16%). The mean number of new relapses during the study period was 1.28 (S.D. = 1.1) and the mean EDSS of patients at baseline was 1.74 (S.D. = 0.76). Of all the patients, 20 (80%) patients met the sets of MRI criteria used, 10 (40%) patients had oligoclonal bands (OBs) in their CSF analysis and 21 (84%) patients had abnormal VEPs. The patients were studied in two groups: 11 patients who received interferon therapy (group A) and 14 patients who did not receive disease-modifying treatment (group B). Demographic data of groups A and B are shown in Table 1, together

Fig. 2. EDSSs changes of CIS patients with different baseline presentations after 21 months of follow-up in groups A and B.

Table 2 The mean changes of EDSS and number of new attacks during the study period in two groups of study Group Changes of EDSS between 1st and 2nd months Changes of EDSS between 2nd and 3rd months 0.40 (0.43) 0.35 (0.49) 0.787* Changes of EDSS between 3rd and 9th months 0.22 (0.34) 0.14 (0.77) 0.125* Changes of EDSS between 9th and 15th months 0.90 (0.20) 0.03 (0.36) 0.723* Changes of EDSS between 15th and 21st months 0.00 (0.00) 0.14 (0.23) 0.058* Total changes of EDSS after 21 months of study 1.09 (0.49) 0.64 (0.49) 0.034** Number of new attacks 0.64 (0.80) 1.79 (1.05) 0.007**

A 0.36 (0.45) B 0.25 (0.47) p-Value 0.548* Values in parenthesis are S.D. * Not signicant. ** Signicant.

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EDSS after 21 months of study (p = 0.003) and number of new attacks (p = 0.013) are independent of the baseline CIS presentation. EDSS changes in CIS patients with different baseline presentations after 21 months of follow-up in groups A and B are shown in Fig. 2. The greatest changes in disability were seen in patients with spinal-cord symptoms in groups A and B, but these differences were not statistically signicant (p = 0.851 and 0.452 for groups A and B, respectively).

4. Discussion Clinically isolated syndromes of the brain stem, optic nerve, spinal cord and cerebellum may represent the start of MS and are associated with a high risk of development of clinically denite multiple sclerosis (CDMS) [6,7]. In such clinical settings, and when other diagnoses have been reasonably excluded, the risk of development of MS has been shown to be affected by the results of paraclinical studies [23,27]. This risk is particularly increased in patients with evidence of occult lesions in MRI scans of the brain observed at the time of the initial presentation [17,2830]. In addition, the presence of OBs in the CSF, as shown by isoelectric focusing, has been associated with an increased risk of developing MS [16,31]. Neurophysiological studies, mainly VEPs, also have a role in detecting dissemination in space [32]. In the present study, 20 (80%) patients met the sets of MRI criteria used, 10 (40%) patients had OBs in their CSF analysis and 21 (84%) patients had abnormal VEPs. By contrast, in the study of Sastre-Garriga et al. in 2003, 18 of 51(35%) CIS patients did not meet any of the sets of MRI criteria and OBs were found in 8 of 16 (50%) CSF analyses [6]. The most common initial syndromes in patients that later develop conrmed MS include partial transverse myelitis (50% of patients), optic neuritis (25%), and brain-stem abnormalities (15%) [33]. In our study, optic neuritis (32%), spinal-cord syndrome (28%), brain-stem syndrome (24%) and cerebellar symptoms (16%) were the most common CIS syndromes. As CIS is typically the earliest clinical expression of MS, it seems that disease-modifying treatments such as interferon therapy may prevent further progression of disability and development of MS. Recent clinical trials have shown that starting preventive treatment with interferon-beta may prevent further relapses in CIS [11,24]. In addition, interferon-beta has been shown to have benets in the treatment of patients with established MS, including slowing the progression of physical disability [34,35], reducing the rate of clinical relapses [3436], and reducing the development of brain lesions, as assessed by MRI scans [3437] and brain atrophy [38]. Recent studies using interferon-beta have shown modest disease-modifying effects in relapsing/remitting MS [34,36,39]. And suggest that only a part of MS patients treated

with interferon-beta respond positively to the applied treatment [40]. However, it is unknown whether treatment of patients earlier in the course of MS would be benecial. However, treatment of patients in the early phases of the disease may be advantageous for two reasons. First, pathology and MRI studies indicate that axonal damage is an early event in MS lesions and can be present in white matter that has a normal appearance [4144]. Second, many patients who present with CIS indicative of demyelinating events develop new neurological symptoms and are eventually diagnosed with CDMS [23,28,45,46]. Interferon-beta is known to markedly reduce the extent of active MRI lesions and, as a consequence, reduce accumulation of the MRI-measured lesion burden [3436,47]. When given early in the course of MS, this treatment might therefore affect the subsequent course of the disease by reducing the amount of inammation [48]. In a 2-year follow-up study of patients with isolated optic neuritis, treatment with high-dose intravenous methylprednisolone reduced the early risk of conversion to CDMS [49]. Although this benet seemed to be lost after 4 years [29], the ndings indicate that early initiation of treatment might be important for patients presenting with CIS indicative of MS [11]. Our results indicate that administration of diseasemodifying treatment (interferon-beta1a ) in CIS patients signicantly delays progression to disability and reduces the incidence of relapse. As shown by our results, CIS patients in group A who were receiving disease-modifying treatment (interferon-beta1a ) showed signicantly greater reductions in EDSS after 21 months (1.09 versus 0.64; p = 0.034) and had fewer new relapses during the study period (0.64 versus 1.79; p = 0.007). A study by Jacob et al. in 2000 involving 383 patients showed that once-weekly intramuscular injections of interferon-beta1a , initiated at the time of a rst clinical demyelinating event, are benecial in patients who have evidence of prior subclinical demyelination in the brain, as shown by MRI [24]. It should be noted that the patients also received interferon-beta1a (Avonex) 30 g weekly. By contrast, in 2001, Comi et al. reported that in their placebo-controlled 2-year trial on 375 CIS patients interferon-beta therapy had no effect on disability and postulated that this lack of effect might be due to the fact that the study included patients with early stages of MS and to the short study duration. They added that longer follow-up is needed to determine if the reduced disease activity seen with early treatment will result in long-term reductions in disability [11]. As in our study, the study of Comi et al. used interferon-beta1a (Rebif); however, we used a dose of 22 g three times a week and Comi et al. used a dose of 22 g weekly. Indeed, available data indicate that dose may affect outcome [35,36]. In the most recent study by Kappos et al. in 2006, they concluded that high-dose interferon therapy (interferonbeta1b 250 g administered subcutaneously every other day)

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M.R. Motamed et al. / Clinical Neurology and Neurosurgery 109 (2007) 344349 [8] Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:14308. [9] Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003;126:77082. [10] Nilsson P, Larsson EM, Maly-Sundgren P, Perfekt R, SandbergWollheim M. Predicting the outcome of optic neuritis- evaluation of risk factors after 30 years of follow up. J Neurol 2005;252(4):396402. [11] Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O. Effect of early interferon treatment on conversion to denite multiple sclerosis. Lancet 2001;357:157682. [12] Eriksson M, Andersen O, Runmarker B. Long-term follow-up of patients with clinically isolated syndromes, relapsing remitting and secondary progressive multiple sclerosis. Mult Scler 2003;9:26074. [13] Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographical based study2. Predictive value of the early clinical course. Brain 1989;112:141928. [14] Kuetzke JF, Beebe GW, Nagler B, Kurland LT, Auth TL. Studies on the natural history of multiple sclerosis8. Early prognostic features of the later course of the illness. J Chronic Dis 1997;30:81930. [15] Miller DH, Hornabrook RW, Purdie G. The natural history of multiple sclerosis: a regional study with some longitudinal data. J Neurol Neuroserg Psychiatry 1992;55:3416. [16] Jacobs LD, Kaba SE, Miller CM, Priore RL, Brownscheidle CM. Correlation of clinical, magnetic resonance imaging and cerebrospinal uid ndings in optic neuritis. Ann Neurol 1997;41:3928. [17] Brex PA, Ciccarelli O, ORiordan JI, Sailer M, Thompson AI, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346:15864. [18] Optic Neuritis Study Group. High- and low-risk proles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophtalmol 2003;121:9449. [19] Minneboo A, Barkhof F, Polman CH, Uitdehaag BM, Knol DL, Castelijns JA. Infratentorial lesions predict long term disability in patients with initial ndings suggestive of multiple sclerosis. Arch Neurol 2004;61:21721. [20] Frederiksen JL, Larsson HB, Olesen J, Stigsby B. MRI, VEP, SEP and biothesiometry suggest monosymptomatic acute optic neuritis to be a rst manifestation of multiple sclerosis. Acta Neurol Scand 1991;83:34350. [21] Morrissey SP, Miller DH, Kendall BE, Kingsley DP, Kelly MA, Francis DA, et al. The signicance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Brain 1993;116:13546. [22] Soderstorm M, Lindqvist M, Hillert J, Kall TB. Link: Optic neuritis: ndings on MRI, CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up. Neurology 1994;241:3917. [23] ORiordan JI, Thompson AJ, Kingsley DP, MacManus DG, Kendall BE, Rudge P, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A ten year follow-up. Brain 1998;121:495503. [24] Jacobs L, Beck R, Simon J, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during the rst demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898904. [25] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Ann Neurol 2005;58:8406. [26] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:144452. [27] Miller DH, Ormerod IE, Rudge P, Kendall BE, Moseley IF, McDonald WI. The early risk of multiple sclerosis following isolated acute syndromes of the brainstem and spinal cord. Ann Neurol 1989;26:6359. [28] Filippi M, Horseld MA, Morrissey SP, MacManus DG, Rudge P, McDonald WI, et al. Quantitative brain MRI lesion load predicts the

delayed development of CDMS and should be considered as a therapeutic option in patients presenting with a rst clinical event indicative of MS [50]. Similar to our study, they administered high-dose interferon three times a week, but they used interferon-beta1b and conducted a double-blind study. One of the limitations of our study is the absence of blinding. In both studies, treatment was well tolerated. However, increased incidences of usual side effects of interferon such as skin reactions, headache and pain in the site of injection were seen in our study. In conclusion, in addition to the previously demonstrated benets of interferon-beta in patients with established MS [3538], our results show that subcutaneous injection of interferon-beta1a (Rebif) three-times a week, initiated at the time of a rst clinical demyelinating event, provides benets in patients who are considered likely to develop CDMS. In addition, interferon-beta1a (Rebif) signicantly delayed the progression of disability and reduced the incidence of new relapses. However, a better understanding of pathologic and pathogenetic processes in patients with CIS will facilitate the development of disease-modifying treatments for patients with MS to prevent progression of disability. Continued clinical and laboratory investigation of patients with CIS should be encouraged [51]. With the advent of long-term partially effective drugs for the treatment of MS, it may become unethical to perform a placebo-controlled trial [52]. Future trials will need to use historical controls obtained from this and other natural history studies. In addition, more research is needed to assess the probable side effects of high-dose interferon therapy and to identify patients who will gain most benet from disease-modifying treatments. Research must also focus on the development of more-effective therapies to prevent the progression of CIS to CDMS. References
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