Abstracts

Rationale: Refractory epilepsy occurs in up to a third of patients. Happily surgeries have rendered many of these patients seizure free, but little is confirmed about what predisposes a person to become refractory. In 2001, Hersdorffer et al. identified diuretic use a protective risk factor against first time, unprovoked seizures in adults. In 2002, Cohen and Miles described spontaneous interictal discharges generated in the hippocampal subiculum of temporal lobe epilepsy (TLE) patients. In their study, GABA signaling, which is normally inhibitory in the mature brain, caused excitatory discharges. Dzahla et al. in 2005 explained the apparent contradiction of GABA excitation as being a result of increased expression of the Na+K+2Cl- transporter. Overexpression of this transporter in rodent hippocampal slices, resulted in a reversal of normal intracellular Cl- concentration, and cellular depolarazation during GABA activation. They found the diuretic, bumetanide, a selective NKCC1 blocker, to have anticonvulsant activity in their model. Palma et al. in 2006 demonstrated increased NKCC1 mRNA in the subiculum of adult human TLE patients. TLE patients may become refractory because native inhibitory signalling is dysfunctional. If the dysfunctional changes are related to the reverse Cl- gradient described above, then the selective NKCC1 transporter blocker, bumetanide, may be an effective anticonvulsant in refractory epilepsy patients.Methods: A series of refractory TLE patients were treated with oral bumetanide if epilepsy surgery was deemed to be unsafe or likely not to be successful (bilateral independant onset, regional onset, etc...). In addition to their current anti-epileptic regimen, patients were initiated on bumetanide 1 mg po upon awaking and 1 mg po at noon. Within 2 weeks patients were titrated to 2 mg upon awaking and 2 mg at noon, if seizure frequency had not changed and if sideffects were still tolerable to the patient. Titration ended at 2 mg po bid. Laboratories were followed monthly. We retrospectively reviewed changes in their seizure frequency before and after bumetanide exposure, and report adverse events.Results: Six patients attempted oral bumetanide therapy after consent within the clinical setting. Three of six experienced a dramatic drop in seizure frequency, with one becoming seizure free except in the context of initial non-adherence. The remaining two had a short-lived reduction of over 50% seizure frequency that lasted about 1 month. All patients reported dramatic diuresis and required oral supplementation with potassium for borderline low K serum levels. Two of six decided to stop bumetanide after reporting no effect or loss of sustained effect after 6 months.Conclusions: Oral bumetanide therapy for refractory temporal lobe epilepsy may be a useful adjunct in this difficult patient population. Effective dosing strategies can be determined through a prospective study. Diuresis and hypokalemia may be limiting factors in its overall usefullness.