Ventricular enlargement in MS: one-year change at various stages of disease.

OBJECTIVES: To investigate ventricular enlargement (VE) over 1 year at three different stages of multiple sclerosis (MS). METHODS: A semi-automated technique for measuring VE was applied to MRI scans in 26 patients with clinically isolated syndromes (CIS) suggestive of MS, 30 with early relapse-onset MS of 1 year duration, 41 with established relapsing remitting (RR) MS, and 23 with secondary progressive (SP) MS. RESULTS: VE at 1 year was seen in early MS (median increase 0.3 mL [p = 0.003]), RRMS (median increase 0.5 mL [p = 0.001]), and SPMS (median increase 1.1 mL [p = 0.001]). Allowing for age there was more VE in the SPMS group (p = 0.005). No VE was observed in the CIS only group (median decrease -0.001 mL [p = 0.829]). Significant increases in T2 and T1 hypointense lesion load volume were seen in all MS subgroups: there were no differences between the groups in T2 volume increase but there was a larger increase in T1 hypointense lesion volume in the SPMS group compared with early RRMS. CONCLUSIONS: Ventricular enlargement is a sensitive measure of progressive cerebral atrophy that is seen at all stages of multiple sclerosis (MS) and is more marked in secondary progressive than relapsing remitting MS.

A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.

BACKGROUND: Teriflunomide, a dihydro-orotate dehydrogenase inhibitor, has immunomodulatory effects, including the ability to suppress experimental allergic encephalomyelitis. In this randomized, double-blind, placebo-controlled Phase II study, the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis (MS) with relapses. METHODS: Patients (n = 179) with relapsing-remitting MS (n = 157) or secondary progressive MS with relapses (n = 22) were randomized to receive placebo, teriflunomide 7 mg/day, or teriflunomide 14 mg/day for 36 weeks. MRI brain scans were performed every 6 weeks. The primary endpoint was the number of combined unique active lesions per MRI scan. Secondary endpoints included MRI-defined disease burden, relapse frequency, and disability increase. RESULTS: The median number of combined unique active lesions per scan was 0.5, 0.2, and 0.3 in the placebo, teriflunomide 7 mg/day (p < 0.03 vs placebo), and teriflunomide 14 mg/day (p < 0.01 vs placebo) groups during the 36-week double-blind treatment phase. Teriflunomide-treated patients also had significantly fewer T1 enhancing lesions per scan, new or enlarging T2 lesions per scan, and new T2 lesions. Patients receiving teriflunomide 14 mg/day had significantly reduced T2 disease burden. Teriflunomide treatment resulted in trends toward a lower annualized relapse rate and fewer relapsing patients (14 mg/day only) vs placebo. Significantly fewer patients receiving teriflunomide 14 mg/day vs placebo demonstrated disability increase. Treatment was well tolerated; numbers of adverse events and serious adverse events were similar in all treatment groups. CONCLUSION: Oral teriflunomide was effective in reducing MRI lesions and was well tolerated in patients with relapsing multiple sclerosis.

The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.

The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.

A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis.

BACKGROUND: Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis (MS) prevalence. OBJECTIVE: To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study. METHODS: 15 ambulatory patients with relapsing-remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol (target dose: 2.5 microg/d) for 48 weeks. Dietary calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the expanded disability status scale (EDSS), and brain magnetic resonance imaging (MRI). RESULTS: Two patients withdrew because of symptomatic hypercalcaemia (serum calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion. Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia. Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point. Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks. CONCLUSIONS: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.

Randomized study of once-weekly interferon beta-1la therapy in relapsing multiple sclerosis: three-year data from the OWIMS study.

BACKGROUND: Once weekly interferon beta-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) beta-1a at 48 weeks, but no significant effect on relapses. OBJECTIVE: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: Placebo patients were rerandomized to IFN beta-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. RESULTS: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. CONCLUSIONS: In RRMS, once weekly IFN beta-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN beta-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

Genetic loading in familial migraine with aura.

Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi(2)=6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi(2)=9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.

Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.

Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.