Temporal lobe epilepsy is the most common partial epilepsy syndrome seen in adult humans. The hippocampus is a key structure in the evolution of temporal lobe seizures. The axons of the dentate granule cells, the mossy fibres, constitute a major hippocampal excitatory input. Inhibitory phenomena at mossy fibre synapses may therefore prevent seizure propagation through the hippocampus. One such inhibitory phenomenon is heterosynaptic depression. In this thesis I studied the role of GABAB receptors in temporal lobe epilepsy. In particular I studied changes in GABAB receptor-mediated heterosynaptic depression at the mossy fibre synapse following status epilepticus. I have shown that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hours later by a loss of GABAB receptor-mediated heterosynaptic depression among populations of mossy fibres. This was accompanied by a decrease in the sensitivity of mossy fibre transmission to the exogenous GABAB receptor agonist baclofen. Autoradiography revealed a reduction in GABAB receptor binding in stratum lucidum after status epilepticus. I then addressed the question: what is the source of the GABA that mediates heterosynaptic depression I have also shown that the GABAB receptor agonist baclofen has antiepileptic properties. In addition, GABAB receptors do not appear to be involved in the function of the antiepileptic drug tiagabine. Failure of GABAB receptor-mediated modulation of mossy fibre transmission may contribute to the development of spontaneous seizures after status epilepticus. The GABAB receptor may be useful as a target for antiepileptic drugs.

The thesis describes the epidemiology of selected somatic and psychiatric conditions in epilepsy and the health care demands of people with epilepsy, and presents broad estimates of life expectancy in people with epilepsy in the community in comparison to people without epilepsy. A cross-sectional study was conducted extracting data from the General Practice Research Database for the period 1995-1998. Psychiatric disorders occurred twice as often and the risk of groups of most somatic disorders across categories was increased in people with epilepsy. The risk of neoplasia excluding intracranial tumours was not increased in epilepsy. The risk of brain tumours, meningiomas and neurodegenerative disorders was particularly increased. Other conditions occurring more frequently in epilepsy include upper gastrointestinal bleed, cardio- and cerebrovascular disorders, fractures, pneumonia and chronic lung diseases, and diabetes. Analysis of data from the fourth national survey of morbidity in general practice (1991-92) revealed that patients with epilepsy used health services (consultations with a general practitioner, home visits, referrals to secondary care) more often than people without epilepsy, irrespective of age, sex and social class. A higher proportion of patients with epilepsy consulted for neoplasms, haematological and mental health disorders, dementia, stroke and gastrointestinal bleeding. Previous studies have shown that epilepsy carries a risk of premature death. Life expectancy was estimated using data from a cohort of 564 patients with definite epilepsy followed for nearly 15 years (177 deaths) (registered through the National General Practice Study of Epilepsy) by employing a parametric survival model based on the Weibull distribution. Reduction in life expectancy can be up to 2 years for people with a diagnosis of idiopathic/cryptogenic epilepsy and the reduction can be up to 10 years in people with symptomatic epilepsy. Reductions in life expectancy are highest at the time of diagnosis but diminish with time. People with epilepsy can be affected by a number of psychiatric and somatic conditions more frequently than people without the condition. They make a higher use of health services at all levels of care, which may be partly related to the presence of coexisting disorders. It appears that higher mortality rates in epilepsy translate into reductions in life expectancy.

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