Refractory Epilepsy: Natural History and Pathogenesis

Kwan, Patrick Kwok Leung (2000) Refractory Epilepsy: Natural History and Pathogenesis. PhD thesis, University of Glasgow.

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Despite antiepileptic drug (AED) treatment, up to one third of patients continue to have seizures. Refractory epilepsy is a poorly understood subject, both in terms of its development and pathogenesis. Outcome studies have focused on terminal remission, but little is known about the natural history of epilepsy in terms of its progression to eventual remission or persistent refractoriness. Such an understanding is essential to the formulation of a rational management approach. Natural history of treated epilepsy Long-term outcome of newly diagnosed patients was investigated longitudinally for up to 15 years. Response to the first drug and successive substitution monotherapy or polytherapy was analysed. Outcome among patients with different neuropathologies was compared in a separate study. Among 470 newly diagnosed patients, 64% became seizure-free for at least a year. Patients with high numbers of pre-treatment seizures were less likely to become seizure- free. Epilepsy was controlled by the first AED in 47% of patients. Patients with symptomatic or cryptogenic epilepsy were less likely to become seizure-free on the first AED, partly because they were more likely to develop intolerable side-effects compared to those with idiopathic epilepsy. The majority of such withdrawals occurred at low doses of the three most commonly prescribed AEDs, carbamazepine (CBZ), sodium valproate (VPA) and lamotrigine (LTG). Over 90% of seizure-free patients also required only a moderate daily dose (up to 800mg CBZ, ISOOmg VPA, 300mg LTG). The probability of attaining seizure-freedom declined progressively with successive AED regimens. While 47% became seizure-free on the first drug, only 10% did so on the second drug and 1% on the third monotherapy. Three percent became seizure-free on a combination of two AEDs. The subsequent seizure-free rate was 41% among those failing the first drug due to intolerable side effects, but only 11% among those in whom the first AED was well tolerated but did not control the seizures completely. Among patients with inadequate seizure control on the first well tolerated AED, those who received substituted monotherapy and those who received add-on treatment had similar seizure-free rates and incidence of intolerable side effects. More patients became seizure- free on combinations involving an AED that blocked sodium channels and one with multiple mechanisms of action than on other combinations. Combination treatment was more effective when prescribed immediately after the first drug failed due to inadequate seizure control than w'hen it was delayed until a substitution also proved unsuccessful. In a separate study, compared with other pathologies identified on magnetic resonance imaging, mesial temporal sclerosis (MTS) was associated with the worst prognosis, although 42% did become seizure-free on AED treatment. Pathogenesis of refractory epilepsy Two candidate biological mechanisms in the pathogenesis of refractory epilepsy were studied. Glutamic acid decarboxylase (GAD) autoantibody titres were compared between patients with controlled and uncontrolled epilepsy. GAD catalyses the conversion of glutamate to y-aminobutyric acid, the major inhibitory neurotransmitter. Autoantibodies against GAD are prevalent in insulin dependent diabetes mellitus, and have been documented in anecdotal cases of refractory epilepsy. The drug transporter P-glycoprotein (P-gp) was investigated in a series of laboratory-based pilot experiments. Encoded by the multidrug resistance gene family (MDRl in man and mdrla and lb in rodents), P-gp actively extrudes a wide range of xenobiotics out of cells. Its over-expression is thought to underlie the resistance of some cancers to multiple chemotherapeutics. P-gp is physiologically expressed at high level in the cerebral capillary endothelium where it contributes to the integrity of the blood-brain barrier. Overexpression of P-gp in brain tissues resected from patients with refractory epilepsy has been reported in surgical case series. Mdrla(-/-) mice devoid of cerebral P-gp were used to determine whether AEDs were substrates of the drug transporter. The pharmacokinetic profiles of four established and four new AEDs in mdrla(-/-) mice and wild-type mice were compared. The technique of quantitative reverse transcriptase-polymerase chain reaction was developed and validated to determine tissue concentration of mdrl mRNA as an indicator of gene expression. Expression was determined in different regions of the normal rat brain, and in brains of genetically epilepsy-prone rats (GEPRs) subject to a single audiogenic seizure. To explore the effect of tissue damage, a laser beam was impinged upon the cerebral cortex of rats. Mdrl expression was measured in tissues surrounding the focal necrosis. Human brain tissues resected during epilepsy surgery were also analysed for MDRl gene expression. There was no difference in GAD autoantibody titres between patients with controlled and uncontrolled epilepsy. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Martin Brodie
Keywords: Neurosciences
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-75749
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15

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