Tim Betts

A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy

The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.

Diagnosis, management and prognosis of a group of 128 patients with non-epileptic attack disorder. Part I

Three hundred and forty three patients with attack disorder labelled as epilepsy were admitted for assessment to a Neuropsychiatry ward in a small English mental hospital over a 5 year period. After assessment it was decided that 63% (215) of these patients had epilepsy, but in 128 (37%) a diagnosis of non-epileptic seizures was made. Just over a third of these patients (46) had an additional history of present or past epileptic seizures as well, so that 24% of the total population had non-epileptic seizures only. The methods used to make this diagnosis are reviewed and an attempt made to classify the non-epileptic attacks from which the patients were suffering. A variety of management strategies were offered and at discharge from hospital the majority of patients had practically lost their non-epileptic seizures. At follow-up 2 years later, seizures had returned in most patients. In 8% of the patients it was clear that the diagnosis of non-epilepsy had been erroneous. The importance of classifying the kind of non-epileptic event the patient suffers from and of translating treatment in hospital to the community is emphasized.

Best practice guidelines for the management of women with epilepsy

Clinical guidelines for the treatment of epilepsy have been published. A statement on management issues for women with epilepsy has recently been produced by the American Academy of Neurology which has raised awareness of the issues facing women with epilepsy. The communication presented here aims to review current literature on specific issues relating to women with epilepsy, and proposes graded recommendations for its management within a UK health care framework.

Psychiatric symptoms after therapy with new antiepileptic drugs: Psychopathological and seizure related variables

The purpose of this paper is to understand the association between antiepileptic drugs (AEDs), patient characteristics, changes in seizure pattern and emergent psychiatric disorder, i.e. psychosis or affective disorder. To this end we carried out a retrospective casenote study on 89 patients who developed psychiatric symptoms during treatment with topiramate, vigabatrin or tiagabine. The psychiatric problem was either an affective or a psychotic disorder (not including affective psychoses). It was discovered that 99% of the patients suffered from complex partial seizures with or without secondary generalization. More than half were on polytherapy with two or more other AEDs. Nearly two-thirds had a previous psychiatric history. There was a strong association between the type of previous psychiatric illness and the type of emerging psychiatric problem, both for psychoses and for affective disorders. Patients on vigabatrin had an earlier onset of epilepsy and more neurological abnormalities than those on topiramate. Those patients on lower doses had a shorter interval between the start of the AED therapy and the onset of the psychiatric problem. A seizure-free period was observed in more than half of the patients before they developed the psychiatric symptoms, and of these more were likely to develop a psychosis rather than an affective disorder. There seemed to be an association of suppression of right-sided seizures and the onset of the psychiatric problem. The conclusions drawn were that patients with a previous history of psychosis or affective disorder tended to develop the same psychiatric problem with new AEDs. Those with a seizure-free period before the onset of the psychiatric problem were more likely to develop a psychosis than an affective disorder.

An epilepsy needs document

Services for epilepsy in the UK are poor in quality, fragmentary and poorly organized. We attempt to define and quantify the scope, content and standards of medical, paramedical and nursing services required, from primary health care to specialist centres. This document has been approved by the Joint Epilepsy Council of Great Britain and Ireland, representing all major patient organizations and care providers.

Human Safety of Lamotrigine

Summary: The clinical safety of lamotrigine (LTG), assessed in four completed randomized, double‐blind, placebo‐controlled crossover trials and an interim analysis of 27 12‐month open studies, is discussed. LTG was added to existing anti‐epileptic drugs (AEDs) of adult patients with refractory epilepsy, using a twice‐daily regimen. In the pooled data from the four double‐blind studies (n= 92), the incidence of adverse experiences with LTG and placebo did not differ significantly. Two patients were withdrawn on LTG due to adverse experiences (one rash, one nausea and vomiting). In the open studies (pooled data; n= 572) the most commonly reported adverse experiences were dizziness, diplopia, somnolence, headache, ataxia, and asthenia (10–14% incidence). Forty‐nine patients (8.6%) were withdrawn with adverse events, most commonly for rash (2.3%). No patients were withdrawn from any of the studies with physical, neurological, or ECG abnormalities thought attributable to LTG treatment. Laboratory measures, vital signs, and weight did not show any consistent changes of clinical significance, and no significant changes in plasma concentrations of concomitant AEDs after the addition of LTG were observed.

A study of anticonvulsant medication on ovarian function in a group of women with epilepsy who have only ever taken one anticonvulsant compared with a group of women without epilepsy

A group of 105 women (54 of whom were, and had only ever been, taking valproate for at least a year, and 51 who had only ever taken either lamotrigine or carbamazepine, for at least a year) were compared with a group of 50 women who did not have epilepsy: any oral contraceptive taken at the time of testing was recorded and blood levels of follicle stimulating hormone (FSH), luteinising hormone (LH), testosterone and prolactin were estimated from days 2 to 6 of the menstrual cycle (day 1 being the first day of bleeding) and an MRI scan made of their pelvis. Women with epilepsy in general were significantly more likely to exhibit evidence on MRI scanning, of polycystic ovaries (PCO): women taking valproate but not an oral contraceptive were significantly more likely to have clinical biochemical evidence of the polycystic ovarian syndrome (PCOS) with raised LH and/or testosterone levels between days 2 and 6 of their menstrual cycle than women who did not have epilepsy: this was not so for women taking lamotrigine or carbamazepine. Since the polycystic ovary syndrome has potentially serious consequences it is suggested that, where possible, valproate is avoided in women of child bearing potential.

Levetiracetam treatment of idiopathic generalised epilepsy

Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types-myoclonic, tonic-clonic and absence seizures--who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy.

Electro-oculography, electroretinography, Visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed Visual Field constriction

Summary: Purpose: Symptomatic visual field constriction thought to be associated with vigabatrin has been reported. The current study investigated the visual fields and visual electrophysiology of eight patients with known vigabatrin‐attributed visual field loss, three of whom were reported previously. Six of the patients were no longer receiving vigabatrin.

The effect of antiepileptic drugs on visual performance

Visual disturbances are a common side-effect of many antiepileptic drugs. Non-specific retino- and neurotoxic visual abnormalities, that are often reported with over-dosage and prolonged AED use, include diplopia, blurred vision and nystagmus. Some anticonvulsants are associated with specific visual problems that may be related to the mechanistic properties of the drug, and occur even when the drugs are administered within the recommended daily dose. Vigabatrin, a GABA-transaminase inhibitor, has been associated with bilateral concentric visual field loss, electrophysiological changes, central visual function deficits including reduced contrast sensitivity and abnormal colour perception, and morphological alterations of the fundus and retina. Topiramate, a drug that enhances GABAergic transmission, has been associated with cases of acute closed angle glaucoma, while tiagabine, a GABA uptake inhibitor, has been investigated for a potential GABAergic effect on the visual field. Only mild neurotoxic effects have been identified for patients treated with gabapentin, a drug designed as a cyclic analogue of GABA but exhibiting an unknown mechanism while carbamazepine, an inhibitor of voltage-dependent sodium channels, has been linked with abnormal colour perception and reduced contrast sensitivity. The following review outlines the visual disturbances associated with some of the most commonly prescribed anticonvulsants. For each drug, the ocular site of potential damage and the likely mechanism responsible for the adverse visual effects is described.