Effect of lamotrigine treatment on epileptogenesis: an experimental study in rat

Prevention of epileptogenesis in patients with acute brain damaging insults like status epilepticus (SE) is a major challenge. We investigated whether lamotrigine (LTG) treatment started during SE is antiepileptogenic or disease-modifying. To mimic a clinical study design, LTG treatment (20 mg/kg) was started 2 h after the beginning of electrically induced SE in 14 rats and continued for 11 weeks (20 mg/kg per day for 2 weeks followed by 10 mg/kg per day for 9 weeks). One group of rats (n = 14) was treated with vehicle. Nine non-stimulated rats with vehicle treatment served as controls. Outcome measures were occurrence of epilepsy, severity of epilepsy, and histology (neuronal loss, mossy fiber sprouting). Clinical occurrence of seizures was assessed with 1-week continuous video-electroencephalography monitoring during the 11th (i.e. during treatment) and 14th week (i.e. after drug wash-out) after SE. LTG reduced the number of electrographic seizures during SE to 43% of that in the vehicle group (P < 0.05). In the vehicle group, 93% (13/14), and in the LTG group, 100% (14/14) of the animals, developed epilepsy. In both groups, 64% of the rats had severe epilepsy (seizure frequency >1 per day). The mean frequency of spontaneous seizures, seizure duration, or behavioral severity of seizures did not differ between groups. The severity of hippocampal neuronal damage and density of mossy fiber sprouting were similar. In LTG-treated rats with severe epilepsy, however, the duration of seizures was shorter (34 versus 54s, P < 0.05) and the behavioral seizure score was milder (1.4 versus 3.4, P < 0.05) during LTG treatment than after drug wash-out. LTG treatment started during SE and continued for 11 weeks was not antiepileptogenic but did not worsen the outcome. These data, together with earlier studies of other antiepileptic drugs, suggest that strategies other than Na(+)-channel blockade should be explored to modulate the molecular cascades leading to epileptogenesis after SE.