Sodium channel blockers for neuroprotection in multiple sclerosis.

Abstract

Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS), which can occur in many parts of the CNS and result in a wide range of symptoms including sensory impairment, fatigue, walking or balance problems, visual impairment, vertigo and cognitive disabilities. At present, the most commonly used MS treatments are immunomodulating agents, but they have little effect on the disability. Experimental studies show that sodium (Na(+)) accumulation leads to intracellular calcium (Ca(2+)) release, and the increased calcium levels can activate nitric oxide synthase and harmful proteases and lipases. These factors contribute to axonal injury in people with MS. If partial blockade of voltage-gated sodium channels could result in neuroprotection, this would be of benefit for preventing disability progression in these people. Neuroprotection is emerging as a potentially important strategy for preventing disability progression in people with MS. To assess the efficacy and safety of sodium channel blockers for neuroprotection in people with MS to prevent the occurrence of disability and alleviate the burden of the disease. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 August 2015) which, among other sources, contains references from the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue (8), MEDLINE (1966 to August 2015), EMBASE (1974 to August 2015), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1981 to August 2015), Latin American and Caribbean Health Science Information Database (LILACS) (1982 to August 2015), ClinicalTrials.gov (http://clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Portal (ICTRP) search portal (http://apps.who.int/trialsearch). In addition, we searched four Chinese databases, ongoing trials registers and relevant reference lists. Randomised controlled trials (RCTs) that examined sodium channel blockers used alone or as an add-on to any approved treatments for MS. Two review authors independently selected trials, assessed trial quality and extracted the data. Only one study evaluating lamotrigine in secondary progressive MS was eligible. One hundred and twenty people were included, 61 randomly assigned to lamotrigine treatment and 59 to placebo treatment. The average age of participants in the two groups was 51.9 years and 50.1 years, respectively. The proportion of male participants was 27.5%. The period of follow-up was 2 years. No data were found on disability progression and people who experienced relapses. No significant differences were found for serious adverse events between the two groups. Treatment with lamotrigine was associated with more rashes (20% vs 5%, P value 0.03) and transient, dose-related deterioration of mobility (66% vs 34%, P value 0.001) than placebo. Furthermore, no significant difference between the two groups was found in the magnetic resonance imaging (MRI) measurements of cerebral atrophy, Expanded Disability Status Score changes, Multiple Sclerosis Functional Composite score changes. This study was judged to be at high risk of bias. This review will be updated when the three ongoing studies we identified are completed. The quality of evidence was judged to be very low due to the low number of available studies and included participants. There is a lack of evidence to address the review question on the efficacy of sodium channel blockers for people with MS. Assessment of the three ongoing trials might change this conclusion. Further high-quality large scale studies are needed.