Black JA et al. (2007) Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Ann Neurol 62: 21–33

Several studies examining the use of sodium-channel blockers in patients with multiple sclerosis are currently underway. Questions about the long-term effects of these agents in neuroinflammatory disorders have, however, recently been raised by the demonstration of acute worsening of symptoms caused by withdrawal of these agents in a murine model of experimental autoimmune encephalomyelitis (EAE).

In this study, EAE mice were given feed supplemented with phenytoin from day 10 after disease induction. On day 28, a proportion of the population was switched to normal feed, while the remainder continued to receive phenytoin-supplemented feed. A separate control population of EAE mice received normal feed throughout the 40-day experiment. Consistent with earlier results, mice treated with phenytoin had markedly lower clinical EAE scores than did untreated mice. The withdrawal of phenytoin from EAE mice, however, resulted in a striking increase in clinical dysfunction within 1–2 days. The dramatic worsening of EAE symptoms following phenytoin withdrawal was accompanied by substantially increased inflammatory infiltrate and the death of 59.1% of the population between day 28 and day 40; none of the untreated mice or those that continued to receive phenytoin died during this period. Similar experiments were conducted with carbamazepine to determine whether the clinical worsening observed after phenytoin withdrawal is a general effect of sodium-channel blocker withdrawal. Following carbamazepine withdrawal, acute worsening of EAE symptoms, increased inflammatory infiltrate and the death of 7.7% of the carbamazepine-withdrawal population were observed. The authors highlight the need for the careful planning of clinical studies examining sodium-channel blockers in neuroinflammatory disorders.