Risk Of Clinically Definite Multiple Sclerosis Research Articles

Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis.

ObjectiveTo investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS).MethodsA cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model.ResultsThe data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes.ConclusionsThese results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach.

Smoking at time of CIS increases the risk of clinically definite multiple sclerosis

BackgroundCigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event.MethodsTwo hundred and fifty patients, aged 18–50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients.ResultsOne hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow-up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked.ConclusionsSmoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS.

Update on clinically isolated syndrome

Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome" (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10-15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of demyelinating lesions and of CSF oligoclonal bands. Available treatments of MS (immunomodulators or immunosuppressants) have also shown unequivocal efficacy to slow the conversion to RRMS after a CIS, but they could be unnecessary for patients with benign RRMS. Beyond diagnostic criteria, knowledge of established and potential risk factors of conversion to MS and of disability progression is essential for CIS patients' follow-up and initiation of disease modifying therapies.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

The Efficacy of Interferon Beta in Delaying Conversion to Clinically Definite Multiple Sclerosis

More than half of patients with a clinically isolated syndrome (CIS) develop clinically definite multiple sclerosis (CDMS). Patients at high risk for CDMS often present with asymptomatic lesions characteristic of CDMS on magnetic resonance imaging scans, although an absence of asymptomatic lesions is not atypical. Phase 3 studies of interferon beta in patients with a CIS suggest that this treatment can delay conversion to CDMS and reduce the risk of new asymptomatic white matter lesions. We reviewed phase 3 studies (CHAMPS, BENEFIT, and ETOMS) and post hoc analyses assessing the efficacy of interferon beta in delaying CDMS in patients with a CIS. The evidence supports early initiation of treatment.

Retinal Nerve Fiber Layer and Future Risk of Multiple Sclerosis

Optical coherence tomography (OCT)--measured retinal nerve fiber layer (RNFL) values may represent a surrogate biomarker for axonal integrity in multiple sclerosis (MS). The purpose of this study was to determine whether RNFL measurements obtained within two years of an optic neuritis (ON) event distinguish patients at increased risk of developing clinically-definite MS (CDMS). Fifty consecutively sampled patients who experienced a single ON event were followed prospectively for a mean period of 34 months with OCT testing. Values of RNFL in clinically-affected and non-affected eyes were compared between patients who developed CDMS and those that did not develop MS after ON. Twenty-one patients (42%) developed CDMS during the course of the study, with a mean conversion time of 27 months. Mean RNFL values were thinner in the clinically-affected eyes of non-MS patients than CDMS eyes after one year (p = 0.0462) due to more severe ON events in the former. By year two, CDMS patients manifested more recurrent ON events and RNFL thinning than non-MS patients. Temporal RNFL values were thinner in the non-affected eyes of CDMS patients with a trend towards significance (p = 0.1302). Our results indicate that RNFL thickness does not reliably distinguish patients at higher risk of converting to CDMS after ON. The severity of ON has a greater effect on RNFL thickness than risk of CDMS at one year. The CDMS patients demonstrate progressive RNFL thinning likely due to recurrent sub-clinical ON events, which may help differentiate them from non-MS patients over time.

MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study

The 2001 and 2005 McDonald criteria allow MRI evidence for dissemination in space (DIS) and dissemination in time (DIT) to be used to diagnose multiple sclerosis in patients who present with clinically isolated syndromes (CIS). In 2006, new criteria were proposed in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal-cord) and DIT requires a new T2 lesion on a follow-up scan. We applied all three criteria in a large cohort of CIS patients to assess their performance by use of conversion to clinically definite multiple sclerosis (CDMS) as the outcome. Patients who had two MRI scans within 12 months of CIS onset were identified in four centres in the Magnims European research network. The specificity and sensitivity of MRI criteria for CDMS after 3 years was assessed in 208 patients. A Cox proportional hazards model was applied in a larger cohort of 282 patients that included all patients irrespective of length of follow-up. The specificity of all criteria for CDMS was high (2001 McDonald, 91%; 2005 McDonald, 88%; new, 87%). Sensitivity of the new (72%) and 2005 McDonald (60%) criteria were higher than the 2001 McDonald criteria (47%). The Cox proportional hazards model showed a higher conversion risk for all three criteria in those with both DIS and DIT than those with either DIS or DIT alone. When all three criteria were included in the model, only the new criteria had an independent significant effect on conversion risk. The new criteria are simpler than the McDonald criteria without compromising specificity and accuracy. The presence of both DIS and DIT from two MRI scans has a higher specificity and risk for CDMS than either DIS or DIT alone.

The 58th Annual Meeting of the American Academy of Neurology San Diego, California April 1-8, 2006

The 58th Annual Meeting of the American Academy of Neurology San Diego, California April 1-8, 2006

The effects of intramuscular interferon beta-Ia in patients at high risk for development of multiple sclerosis: A post hoc analysis of data from CHAMPS

Background: In the Controlled High Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS), intramuscular (IM) interferon beta-1a (IFNβ-1a) delayed the development of clinically definite multiple sclerosis (CDMS) in patients with a single demyelinating event who had magnetic resonance imaging (MRI) evidence of previous subclinical disease activity (defined as ≥2 T2-weighted hyperintense lesions, 1 of which was periventricular or ovoid, on unenhanced MRI scans). Objective: This post hoc analysis was conducted to assess the effects of IM IFNβ-1a on delaying the development of CDMS in a subgroup of CHAMPS patients who met a more stringent definition of high risk than was used in that trial. Methods: Patients from the overall CHAMPS population were included in the present analysis if they had ≥9 T2-weighted hyperintense lesions and ≥1 gadolinium-enhanced lesion on the baseline MRI scan. The cumulative probability of developing CDMS in each treatment group was calculated using the Kaplan-Meier product-limit method and compared using the log-rank test. The actual proportions of patients who developed CDMS in each treatment group were calculated and compared using the chi-square test. Results: Ninety-one patients met the more stringent definition of high risk and were included in the subgroup analysis. Fifty-one patients (56.0%) received IFNβ-1a 30 μg IM once weekly and 40 (44.0%) received placebo. Baseline demographic and clinical characteristics were similar between the 2 groups. Seventy-four patients (81.3%) were female, 80 (87.9%) were white, and the mean age was 33.0 years. Overall, IM IFNβ-1a reduced the rate of development of CDMS by 66% compared with the placebo group ( P = 0.002, log-rank test) over the 3-year follow-up period. At 2 years, the Kaplan-Meier estimate of the cumulative probability of developing CDMS was 21% in the IM IFNβ-1a group and 56% in the placebo group, representing a 63% reduction in risk for CDMS with IFNβ-1a ( P = 0.002, log-rank test). The results based on the actual proportions of patients developing CDMS were similar to the Kaplan-Meier estimates. Conclusions: The results of this subgroup analysis are compatible with IM IFNβ-1a reducing the risk of a second demyelinating event in patients meeting the more stringent definition of high risk. Although the treatment effect of IFNβ-1a was significant in both the overall CHAMPS population (44% risk reduction vs placebo; P = 0.002) and in this high-risk subgroup (66%), the results of the present analysis suggest that the magnitude of treatment benefit with IFNβ-1a may be greater in patients with more disease activity, as measured by MRI parameters.

Acute demyelinating optic neuritis.

Acute demyelinating optic neuritis associated with multiple sclerosis (MS) is the most common cause of inflammation of the optic nerve. The Optic Neuritis Treatment Trial (ONTT) has provided important clinical data on the use of corticosteroids, and demonstrated that patients with characteristic inflammatory lesions within the brain on magnetic resonance imaging had a greater chance of developing clinically definite MS (CDMS). The current approach to patients with optic neuritis has been modified by the results of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS). Patients with an initial clinical episode of demyelination (optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome) and at least two characteristic demyelinating lesions within the brain were randomized to receive interferon beta-1a or placebo after initial treatment with intravenous corticosteroids. At the 3-year point patients treated with interferon beta-1a showed a 50% less risk of CDMS. The results of this study have set the standard for patients with a first bout of demyelinating optic neuritis.

Treatment of acute demyelinating optic neuritis

Patients with typical acute monosymptomatic demyelinating optic neuritis should receive gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and orbits to determine if they are at high risk for the subsequent development of clinically definite multiple sclerosis (CDMS). The presence of ≥2 white matter lesions (≥3 mm in diameter, at least 1 lesion periventricular or ovoid) indicates high risk for CDMS; the following treatment should be considered for such patients: 1. Intravenous methylprednisolone sodium succinate (1 gram IV/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days) with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4); 2. Interferon beta 1-a (Avonex 30μg intramuscularly [IM] weekly, or Rebif 22μg subcutaneously [SQ] weekly). These two drugs have been shown to reduce the short-term risk of CDMS in high risk monosymptomatic patients. In monosymptomatic patients with <2 white matter lesions, and in patients for whom CDMS has been established, IV methylprednisolone treatment followed by oral prednisone should be considered on an individual basis. Treatment in these patients may hasten visual recovery, but does not affect long-term visual outcome. Oral prednisone alone, without prior treatment with IV methylprednisolone, may increase the risk for recurrent optic neuritis and should be avoided.