Walker, Matthew Charles; (1998) The treatment of status epilepticus: Experimental and clinical aspects. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is concerned with the treatment of status epilepticus (SE), a prolonged epileptic state, which has a high morbidity and mortality. 1) Knowledge about the pharmacokinetics of drugs used in SE at their point of action (brain) is necessary for the optimisation of treatment. Using a rat model, I was able to determine: (i) the temporal interrelationship between serum and brain extracellular fluid concentrations of phenytoin, a drug used in SE, and lamotrigine, a drug with a putative role in SE, and (ii) the regional specificity of these drugs. In addition, I was able to confirm the hypothesis that with repeat dosing there is potentially dangerous peripheral and central nervous system accumulation of diazepam. 2) It has been proposed that seizures result in rises in brain extracellular fluid concentrations of glutamate, and that these rises in prolonged seizures can result in neuronal death. Using an in vivo dialysis biosensor in a rat model of serial seizures, I was able to demonstrate a dissociation between electrographic activity and rises in extracellular glutamate. There also appeared to be effective mechanisms following seizures that increase glutamate uptake, and release ascorbate, a putative neuroprotectant. 3) Neuroprotectants given early in SE prevent neuronal death, but little is known about their effects in the later stages. Having established an animal model of SE, I determined that the putative neuroprotectants, phenytoin, lamotrigine and MK-801, were not neuroprotective or anticonvulsant in the late stages of SE. However, diazepam and pentobarbitone, drugs that act on the GABA system, were effective in halting SE at this stage. 4) In an audit of Intensive Care Physicians in the UK and of patients referred to a specialist neurological intensive care unit with a diagnosis of refractory SE, I identified ways in which our present management of SE can be improved.

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