Fast track — ArticlesLamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial
Introduction
Disease-modifying treatments for multiple sclerosis reduce relapse frequency but have little effect on the disability that characterises progressive forms of the disease.1, 2 There is clear evidence that the primary cause of disability is axonal degeneration,3 and hence there is substantial interest in developing neuroprotective treatments.
Disease-modifying treatments generally act by modifying the immune response. Probably because immune attack is only one of several potential mechanisms of axonal injury, disease-modifying treatments have only a limited neuroprotective effect.3, 4 Excessive accumulation of sodium ions might occur in axons affected by inflammation or demyelination, which might make these axons vulnerable to injury by favouring calcium accumulation via the sodium–calcium exchanger.4 Partial blockade of voltage-gated sodium channels is neuroprotective in several experimental models of inflammatory axonal injury.5, 6, 7, 8, 9 For example, lamotrigine prevents axonal damage and preserves electrophysiological function in the dorsal column in experimental autoimmune encephalomyelitis.9
These findings raise the possibility that partial blockade of voltage-gated sodium channels could result in neuroprotection in multiple sclerosis. We aimed to assess whether the sodium-channel blocker lamotrigine has a neuroprotective, disease-modifying effect on tissue loss and disability in patients with secondary progressive multiple sclerosis.
Section snippets
Patients
We did a double-blind, parallel-group, randomised controlled trial. Patients with secondary progressive multiple sclerosis aged 18–55 years were eligible if they had an expanded disability status scale (EDSS) score of 4–6·5 and if their disability had increased in the preceding 2 years because of steady disease progression rather than relapse. Evidence of steady disease progression was either from clinical documentation or from an increase of at least 1 point in EDSS measurements. Patients were
Results
Patients were recruited between January and December, 2006, and final assessments were done in January, 2009. 120 participants were randomly assigned to receive lamotrigine (n=61) or placebo (n=59; figure 1). The lamotrigine and placebo groups were similar for all baseline variables (table 1). 12 patients (nine in the lamotrigine group and three in the placebo group) were lost to imaging follow-up, leaving 108 who had imaging for the primary outcome at 24 months (52 on lamotrigine and 56 on
Discussion
In this phase 2 clinical trial, we have tested for the first time whether partial blockade of voltage-gated sodium channels is neuroprotective in secondary progressive multiple sclerosis. We did not observe a neuroprotective effect of treatment with lamotrigine. However, further analysis of secondary imaging outcomes and exploratory analyses of the primary outcome suggested that use of lamotrigine was associated with complex brain volume changes: treatment did not affect grey matter volume
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