Mefkure Eraksoy

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

BACKGROUND Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. METHODS 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. FINDINGS Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. INTERPRETATION The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Survival and predictors of disability in Turkish MS patients

Objective: To examine the natural history, survival, and prognostic factors in a sample of Turkish MS patients. Method: This multicenter study included 1,259 definite MS patients diagnosed according to the criteria of Poser et al. Actuarial analysis of selected disability levels of 3, 6, 8, and 10 achieved with the Expanded Disability Status Scale (EDSS); a multivariate Cox regression analysis for prognostic factors related to time to reach EDSS ≥ 6; and Pearsons correlation coefficient for individual factors were performed. Results: The survival (±SE) at 15 years from onset was 94.6 ± 2.9%, and at 25 years was 89.0 ± 5.8%. The disability reached by 15 years was EDSS ≥ 3 in 66.4%, EDSS ≥ 6 in 41.2%, EDSS ≥ 8 in 10.5%, and EDSS = 10 in 5.4%. The most significant unfavorable prognostic factors were progressive course (relative risk [RR], 3.73; CI, 2.71 to 5.13) and sphincter symptoms at onset (RR, 1.86; CI, 1.23 to 2.82), followed by male sex, motor symptoms at onset, and a high attack frequency within the first 5 years. Primary progressive disease was correlated positively with male sex (r = 0.0895, p = 0.001), older age (r = 0.1807, p = 0.000), and motor (r = 0.1433, p = 0.000) or sphincter symptoms (r = 0.1001, p = 0.000) at onset, unlike relapsing-remitting and secondary progressive disease. Conclusions: Although a slightly better prognosis is observed in the Turkish MS population, early prognostic factors are similar to most of the previous Western series. Primary progressive disease, mostly seen in older men with motor and sphincter involvement at onset, has a worse prognosis and may represent a distinct behavioral variant of MS.

A meta-analysis of whole genome linkage screens in multiple sclerosis

Linkage studies in complex diseases like multiple sclerosis, where the effects attributable to individual loci are modest, are critically dependent upon the number of families included. We have combined the raw genotyping data from all published genome linkage screens in multiple sclerosis and thereby performed a linkage analysis including 719 families studied with a weighted average of 359 microsatellite markers per family (range 257-453) providing an average marker separation of 10.2 cM. Linkage with genome-wide significance is confirmed in the HLA region on chromosome 6p21. In addition, two novel regions suggestive of linkage are seen (17q21 and 22q13). Our simulations would imply that the number of peaks with NPL scores >/=2.1 exceeds the number expected by chance alone.

Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

Subacute sclerosing panencephalitis: clinical and magnetic resonance imaging evaluation of 36 patients.

We studied 36 patients (24 males, 12 females), all of whom had definite subacute sclerosing panencephalitis with typical periodic complexes in their electroencephalograms and increased titers of measles antibody in serum and cerebrospinal fluid. Their clinical and laboratory findings on admission were reviewed retrospectively. The age at onset of symptoms varied from 4 to 23 years. The average age at onset of disease was 13.1 ± 4.18 years. The mean of the duration from the infection to the onset of subacute sclerosing panencephalitis was 9 years. Unusual symptoms, especially in the early periods of disease, included hemiparesis (7 patients), headache (3), generalized tonic-clonic seizures (6), absence seizure (1), nausea (3), and vomiting (3). Twenty-six cranial magnetic resonance imaging (MRI) and 12 computed tomography examinations were performed. Nine patients had normal MRI. In the early stages, lesions usually involved parieto-occipital corticosubcortical regions asymmetrically. In time, symmetric periventricular white-matter changes became more prominent. In addition to the common clinical findings in cases of subacute sclerosing panencephalitis reported in the literature, there were some different clinical features of the disease. Eventually, we concluded that there seems to be no correlation between the clinical stages and either the duration from the onset of subacute sclerosing panencephalitis or the MRI findings. (J Child Neurol 2002;17:25-29).

Enhanced IL-6 Production in Aquaporin-4 Antibody Positive Neuromyelitis Optica Patients

ABSTRACT Anti-aquaporin-4 (Aqp-4) antibody and complement system have emerged as major pathogenic factors in neuromyelitis optica (NMO). To test the significance of interleukin-6 (IL-6), another important humoral immunity factor, in NMO pathogenesis, we measured serum and cerebrospinal fluid (CSF) IL-6 levels of 23 NMO, 11 transverse myelitis, 16 optic neuritis, 27 relapsing remitting multiple sclerosis patients, and 20 neurologically normal controls. NMO and transverse myelitis patients had higher serum and CSF IL-6 levels than other groups. Particularly, anti-Aqp-4 positive NMO patients (n == 12) had higher serum/CSF IL-6 levels than anti-Aqp-4 negative patients (n == 11) and CSF IL-6 levels correlated with anti-Aqp-4 levels and disease severity of the NMO patients. Our results suggest that IL-6 is involved in NMO pathogenesis presumably via anti-Aqp-4 associated mechanisms.

Group exercise training for balance, functional status, spasticity, fatigue and quality of life in multiple sclerosis: a randomized controlled trial

Objective: To determine the effectiveness of group exercise training on balance, functional status, spasticity, fatigue and quality of life in patients with multiple sclerosis. Design: A randomized single-blind controlled study. Setting: University hospital, outpatient physical therapy department. Subjects: Ambulatory patients with multiple sclerosis. Interventions: Exercise group completed a 12-week group exercise programme under the physical therapists’ supervision. Control group was included in the waiting list. Main measures: The primary outcome measures were the Berg Balance Scale, 10-metre walk test, 10-steps climbing test and secondary outcome measures were the Modified Ashworth Scale, Fatigue Severity Scale and Multiple Sclerosis International Quality of Life. Results: Ninety-nine patients completed the study. There were statistically significant improvements for all outcome measures in the group exercise group (n = 51) (p < 0.01). In the control group (n = 48), there were statistically significant negative change in the Berg Balance Scale and 10-metre walk test measures (p = 0.002, p = 0.001) and statistically significant increment only in the Fatigue Severity Scale score (p = 0.002). The Berg Balance Scale score was increased 4.33 in the exercise group, while a decreased of 2.33 in control group. The 10-metre walk test duration (second) was decreased 2.72 in exercise group, while increased 1.44 in control group. In comparing inter-groups changes, both primary and secondary outcome mesures showed significant improvements in favour of the exercise group after the training (p < 0.05). Conclusion: The study demonstrated that supervised group exercise training is effective in improving balance, functional status, spasticity, fatigue and quality of life in moderately affected people with multiple sclerosis, with no worsening of their clinical status.

Anti-αB-crystallin immunoreactivity in inflammatory nervous system diseases

AbstractαB-Crystallin, a small heat shock protein, is an immuno-dominant antigen with increased tissue expression in demyelination. To investigate the humoral response against αB-crystallin, the sera and CSF samples of patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS), neuro-Behçets disease (NBD) and other non-inflammatory neurological disease (NIND) were screened by enzyme-linked immunosorbent assay for anti-αB-crystallin IgG and IgM antibodies. Serum and CSF IgG antibody responses to αB-crystallin were significantly elevated only in NBD patients (serum IgG, NBD 1.29±0.49 vs NIND 0.95±0.39, p=0.01; CSF IgG, NBD 1.22±0.64 vs. NIND 0.81±0.35, P=0.01). Similarly, high serum IgM antibody titres were also detected in NBD (1.83±0.72 vs. 1.16±0.49, P=0.0005) and in MS (1.57±1.07, P=0.046), whereas elevated CSF IgM responses were observed to be high only in GBS (2.09±1.09 vs. 1.41±0.7, P=0.007). Humoral responses against αB-crystallin are increased in NBD and GBS, which may implicate this central nervous system antigen in the causation and pathogenesis of these inflammatory nervous system disorders.

Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study.

Background: In a phase 2b study in patients with relapsing–remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo. Objective: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics. Methods: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo. Results: BG-12 240 mg three times daily significantly reduced the number of new Gd+ lesions compared with placebo in the following subgroups: Expanded Disability Status Scale (EDSS) score ≤ 2.5 (74%), EDSS score > 2.5 (63%), no Gd+ lesions (80%), ≥ 1 Gd+ lesion (55%), age < 40 years (49%), age ≥ 40 years (89%), female patients (81%), disease duration ≤ 6 years (81%) and disease duration > 6 years (54%) (all comparisons p < 0.05). Conclusion: BG-12 demonstrated efficacy in patients with RRMS by decreasing new Gd+ lesion development across a range of subgroups defined by baseline disease characteristics or demographics.