Denson G. Fujikawa

Human status epilepticus (SE) is consistently associated with cognitive problems, and with widespread neuronal necrosis in hippocampus and other brain regions. In animal models, convulsive SE causes extensive neuronal necrosis. Nonconvulsive SE in adult animals also leads to widespread neuronal necrosis in vulnerable regions, although lesions develop more slowly than they would in the presence of convulsions or anoxia. In very young rats, nonconvulsive normoxic SE spares hippocampal pyramidal cells, but other types of neurons may not show the same resistance, and inhibition of brain growth, DNA and protein synthesis, and of myelin formation and of synaptogenesis may lead to altered brain development. Lesions induced by SE may be epileptogenic by leading to misdirected regeneration. In SE, glutamate, aspartate, and acetylcholine play major roles as excitatory neurotransmitters, and GABA is the dominant inhibitory neurotransmitter. GABA metabolism in substantia nigra (SN) plays a key role in seizure arrest. When seizures stop, a major increase in GABA synthesis is seen in SN postictally. GABA synthesis in SN may fail in SE. Extrasynaptic factors may also play an important role in seizure spread and in maintaining SE. Glial immaturity, increased electronic coupling, and SN immaturity facilitate SE development in the immature brain. Major increases in cerebral blood flow (CBF) protect the brain in early SE, but CBF falls in late SE as blood pressure falters. At the same time, large increases in cerebral metabolic rate for glucose and oxygen continue throughout SE. Adenosine triphosphate (ATP) depletion and lactate accumulation are associated with hypermetabolic neuronal necrosis. Excitotoxic mechanisms mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors open ionic channels permeable to calcium and play a major role in neuronal injury from SE. Hypoxia, systemic lactic acidosis, CO2 narcosis, hyperkalemia, hypoglycemia, shock, cardiac arrhythmias, pulmonary edema, acute renal tubular necrosis, high output failure, aspiration pneumonia, hyperpyrexia, blood leukocytosis and CSF pleocytosis are common and potentially serious complications of SE. Our improved understanding of the pathophysiology of brain damage in SE should lead to further improvement in treatment and outcome.

We investigated the neuroprotective effect of the noncompetitive N-methyl-D-asparatate (NMDA) antagonist ketamine when administered after onset of lithium-pilocarpine-induced status epilepticus (SE). Seizures were induced in Wistar rats with lithium chloride (3 mEq/kg) and pilocarpine (PC) (30-60 mg/kg intraperitoneally, i.p.). Fifteen minutes after SE onset, either ketamine 100 mg/kg or normal saline was injected i.p., and 3 h after SE onset atropine, diazepam (DZP), and phenobarbital (PB) were administered i.p. to terminate the seizures. Twenty-four hours later, rats underwent brain perfusion-fixation, with subsequent brain processing for light-microscopic examination. Rats adminstered saline (n = 5) had neuronal damage in 24 of 25 brain regions examined. Rats administered ketamine (n = 7) had significant neuroprotection in 22 of 24 damaged regions. Ketamine reduced the amplitude of seizure discharges, and in 3 rats EEG seizure activity ceased in 30 min; none of these rats had neuronal damage. In the other 4 rats, EEG seizure discharges persisted > 90 min; in these animals, 21 of 24 damaged regions were protected. In contrast, rats with 1-h high-dose PC-induced SE (400 mg/kg i.p. without lithium chloride preadministration) had 14 damaged regions, of which 7 were significantly different from the undamaged regions of the ketamine subgroup with persistent electrographic seizures. Thus, ketamine is remarkably neuroprotective when administered after onset of SE, whether or not seizure discharges are eliminated.