Antiepileptic drugs - treating populations

Stephen, Linda J. (2010) Antiepileptic drugs - treating populations. MD thesis, University of Glasgow.

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Epilepsy affects 50 million people world-wide. Since 1982, the Western Infirmary Epilepsy Unit has provided a specialist service for over 6900 people with suspected and established seizure disorders. The twelve studies detailed in this thesis discuss the management of epilepsy in different patient populations, and explore beneficial and adverse effects of antiepileptic drugs (AEDs).

AED development has allowed advances in pharmacological treatment of localisation-related epilepsies. Thus, outcomes were investigated in 550 such patients followed-up at the epilepsy clinic over 13 years (Paper i). Of these, 312 (57%) became seizure-free on medication. Those with hippocampal sclerosis had the poorest outcome (p<0.01), and a higher incidence of febrile convulsions (p<0.001). Although many patients benefited from AED therapy, results may be biased, given this cross-sectional study analysed data from both newly diagnosed patients, and those with drug-resistant seizures.

Many people with epilepsy take more than one AED, although supportive evidence is sparse. Hence, polytherapy outcomes in 2881 patients registered with the Epilepsy Unit database were examined (Paper ii). Of these, 1617 (56%) were seizure-free, with 332 (21%) taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 duotherapy and 28 triple therapy combinations resulting in seizure freedom. Therefore, combining two or three, but rarely four AEDs may be useful for patients not responding to monotherapy. Because this was a retrospective analysis of newly treated patients and those with refractory epilepsy, the analysis was subject to bias. Lack of a control group was also a weakness. Epilepsy Unit staff are therefore now examining similar outcomes in a large population of newly treated patients only.

To establish the place of recently marketed AEDs in clinical practice, four studies examined prospectively the efficacy and tolerability of the novel agent, topiramate, in uncontrolled epilepsy. Adjunctive topiramate was administered in 170 patients with refractory seizures (Paper iii). Seizure frequency and adverse events were monitored. Patients were followed-up until seizure freedom for ≥ 6 months, ≥ 50% or <50% seizure reduction, intolerable side-effects, or lack of efficacy occurred. Seizure freedom was achieved in 39 (23%) patients. A ≥50% reduction in seizure frequency was reported in 80 (47%) others. Doses were often lower than those in regulatory studies. Efficacy as monotherapy was also demonstrated. Using the same end-points, topiramate was added to AED regimens of 64 patients with learning disabilities and epilepsy (Paper iv). Remission from seizures was established in 16 (25%).

In similar fashion, levetiracetam was started in 156 patients with uncontrolled epilepsy (Paper v). Of these, 40 (26%) became seizure-free, many on low doses. When the drug was added to AED regimens in 64 patients with learning disabilities, 24 (38%) became seizure-free for at least 6 months (Paper vi). Caregiver quality-of-life scores improved significantly with levetiracetam (p<0.001). It is important to recognise that for all four audits results may be biased due to their observational nature, and the fact that they were undertaken at a single centre, with no control group. For patients with learning disabilities, small numbers, and retrospective baseline recordings for some could also have introduced bias.

In Papers vii, viii and ix, findings from longitudinal studies in teenagers, people with learning disabilities and epilepsy, and newly diagnosed elderly patients attending the Epilepsy Unit, are reported. At the Teenager Clinic, 301 adolescents were reviewed over four years (Paper vii). Epilepsy was excluded in 135 (45%), five taking AEDs. A single seizure occurred in 22 others. In the 144 with epilepsy, seizure freedom for ≥ 12 months was attained in 76 (53%), but outcomes were poorer than expected. Neuroimaging was abnormal in 27 (43%). Newly diagnosed patients fared better than those taking treatment (p<0.05). More teenagers with primary generalised seizures (60%) attained remission, compared to those with focal-onset seizures (46%) (p<0.02). The retrospective natures of the analysis, and lack of control group may have biased results, thus making statistical conclusions inaccurate. Findings suggested the need for improved services.

Over four years, 214 patients with learning disabilities and refractory epilepsy were followed-up (Paper viii). Although it is generally thought these individuals’ seizures are difficult to control, 59 (43%) became seizure-free for ≥ 12 months with AEDs. There was no change in quality-of-life scoring during this time, and no relationship between extent of learning disability and seizure control. The observational nature of the audit, and lack of control group may have biased results.

Currently, there are few data on elderly people with epilepsy. Thus, outcomes over a 20-year period in 117 newly diagnosed senior citizens were examined (Paper ix). After starting AED treatment, 93 (79%) became seizure-free for ≥ 12 months, 73 (62%) with their first drug. Prognosis was better than in younger patients, and for those with fewer pre-treatment seizures (p=0.0078). Again bias may have been introduced because of the study’s observational nature and lack of control group.

The final studies concentrate on AED-related adverse effects (Papers x, xi and xii). Bone changes have been reported with AED use. Hence, the relationship between bone mineral density, and long-term AED treatment in 78 older adults (47 post-menopausal women, 31 men), taking hepatic enzyme-inducing or non-inducing AEDs, was explored in a case-controlled study (Paper x). Men had significantly lower bone mineral density than controls at the lumbar spine (p<0.01), and neck of femur (p<0.005). Women had statistically reduced bone mineral density at the femoral neck (p<0.05). It was concluded that long-term AED treatment is an independent risk factor for reduced bone mineral density in people with epilepsy.

As sodium valproate may be associated with metabolic changes and polycystic ovarian syndrome, hormone profiles were compared in 76 young men and women taking sodium valproate or lamotrigine monotherapy, to assess whether a pharmacological effect of valproate was responsible (Paper xi). Results revealed only four obese females exhibiting biochemical characteristics of polycystic ovarian syndrome (p=0.05), with obese patients of both sexes (p=0.01), and valproate-treated men (p=0.03) having higher insulin concentrations. Results are not significant when corrected for multiple comparisons. It can therefore be concluded that no differences in metabolic indices between patients taking sodium valproate or lamotrigine existed.

To examine further effects on androgenic hormones, and the efficacy and tolerability of sodium valproate and lamotrigine monotherapy, a randomised, prospective study in 225 patients was performed (Paper xii). Patients were recruited if they presented with a minimum of two unprovoked seizures of any type, or a single seizure and underlying neuropathology. Of patients with partial-onset seizures, 81 received sodium valproate and 80 were randomised to receive lamotrigine. Of those with idiopathic generalised epilepsies, 30 received sodium valproate and 34 took lamotrigine. Seizure-free rates were identical in both arms at twelve months between the valproate and lamotrigine cohorts. There was a trend towards superiority for valproate (57% seizure-free) over lamotrigine (35% seizure-free) for patients with idiopathic generalised epilepsies (p=0.09), but a converse separation of outcomes for localisation-related epilepsies (43% seizure-free with valproate, 53% seizure-free with lamotrigine, p=0.24). More patients taking sodium valproate withdrew due to adverse events (p=0.046), eight because of weight gain. Neither drug altered testosterone, sex-hormone binding globulin, and androstenedione concentrations, or changed the free androgen index, at six and twelve months, but lack of further formal monitoring may have biased results.

These studies report results from different patient populations, including those with refractory epilepsy. Successful pharmacological outcomes were achieved in people with localisation-related epilepsies, and those taking polytherapy. Patients with learning disabilities and elderly individuals fared better than expected, although results were disappointing in adolescents. AEDs, can, however, be associated with adverse effects, and data show how certain patients may require screening for such changes, and/or avoidance of certain drugs. These findings have to be considered in the context that the design of several of the projects may have introduced inherent bias.

Item Type: Thesis (MD)
Qualification Level: Postdoctoral
Keywords: Antiepileptic drugs, epilepsy, seizures, treatment
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Supervisor's Name: Brodie, Prof. Martin
Date of Award: 2010
Depositing User: Dr Linda Stephen
Unique ID: glathesis:2010-2005
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 15 Jul 2010
Last Modified: 10 Dec 2012 13:49

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