Antiepileptic Drug Treatment of Nonconvulsive Seizures Induced by Experimental Focal Brain Ischemia

Abstract

Nonconvulsive seizures (NCSs) after traumatic and ischemic brain injury are often refractory to antiepileptic drug therapy and are associated with a decline in patient outcome. We recently characterized an in vivo rat model of focal brain ischemiainduced NCS and here sought to evaluate potential pharmacological treatments. Electroencephalographic activity was recorded continuously for 24 h in freely behaving rats subjected to permanent middle cerebral artery occlusion (MCAo). Rats were treated with an antiepileptic drug from one of seven different drug classes at ED 50 and 2ϫ ED 50 doses (as reported in other rat seizure models), delivered as a single i.v. injection 20 min post-MCAo. Vehicle-treated rats (n ϭ 9) had an 89% incidence of NCS with an average number of NCS of 8.6 Ϯ 1.9.The latency to onset of NCS was 32.5 Ϯ 3.4 min post-MCAo with an average duration of 49.1 Ϯ 8.2 s/event. The high doses of ethosuximide, gabapentin, fos-phenytoin, and valproate significantly reduced the incidence of NCS (11, 14, 14, and 38%, respectively), whereas midazolam, phenobarbital, and dextromethorphan had no significant effect at either dose. Across treatment groups, there was a low but significant correlation between the number of NCS events per animal and volume of brain infarction (r ϭ 0.352). Antiepileptic drug therapy that prevented the occurrence of NCS also reduced mortality from 26 to 7%. Based on combined effects on NCS, infarction, neurological recovery, and mortality, ethosuximide and gabapentin were identified as having the best therapeutic profile.

NNZ-2566, a Glypromate Analog, Attenuates Brain Ischemia-Induced Non-Convulsive Seizures in Rats

“…In that report, 81% of the animals experienced NCS after MCAo, which manifested as generalized 1-4 Hz rhythmic spikes or ictal discharge detected by continuous cortical EEG recording. This high incidence of MCAo-induced NCSs was subsequently confirmed in studies designed to control MCAo-induced NCSs with conventional AEDs (Williams et al, 2004(Williams et al, , 2006(Williams et al, , 2008.…”

“…The off-line EEG traces were reviewed at a display resolution of 30 mm/sec and analyzed by individuals who were blinded to the treatments using the NCS criteria defined previously (Hartings et al, 2003;Williams et al, 2004). An NCS episode was defined as repetitive spikes or spike-and-wave discharges recurring at frequencies of > 1 Hz with amplitude greater than spontaneous activity and duration greater than 10 secs.…”

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

“…Although electric seizures and acute brain injury work synergistically to worsen outcome, the underlying pathomechanism is still unclear. In a comprehensive study testing antiepileptic drugs in the rat MCAO model Williams and colleagues found that there was no significant correlation between infarct volume and the number of NCS events for vehicle-treated animals (Williams et al, 2004). However, when data from all treatment groups were considered together, there was a low (but positive) correlation.…”

“…Criteria for identifying NCS events were as follows (Williams et al, 2004): (a) the occurrence of repetitive spikes or spike and wave discharges recurring at frequencies > 1 Hz, or continuous polyspiking; (b) spike amplitude greater than background activity; (c) duration of continuous seizure activity (defined by (a) and (b)) longer than 10 s. Consecutive seizure episodes were considered a single event if not separated by more than 10 s.…”

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis

“…Nonetheless, it does appear that LPR increases during seizures, which is evidence that post-traumatic electrographic seizures play an adverse role on brain metabolism. In experimental studies, anticonvulsants can worsen outcome after TBI (15), but in some models of brain injury the administration of anticonvulsants to stop posttraumatic seizures actually improves outcome (20). Given our within-subjects design and time-locked data, we do not think that administration of anticonvulsants elicited changes in glutamate or LPR.…”