A. Richens

LAMOTRIGINE-ASSOCIATED RASH: RISK/BENEFIT CONSIDERATIONS IN ADULTS AND CHILDREN

Summary: Purpose: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add‐on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice.

Controlled Trial of Lamotrigine (Lamictar) for Refractory Partial Seizures

Summary: The antiepileptic effect of lamotrigine (LTG) was assessed in a double‐blind, placebo‐controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty‐one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12‐week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p < 0.002), partial seizures (p <0.002), and secondarily generalized seizures (p <0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p <0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.

SERUM-PHENYTOIN LEVELS IN MANAGEMENT OF EPILEPSY

Steady-state serum-phenytoin levels were measured in five patients whose phenytoin dosage was changed three or more times for therapeutic purposes. Data from four of these patients and from fifteen others have been used to construct a nomogram which permits the clinician, given a single, accurate, steady-state phenytoin level, to adjust the dosage to achieve the desirable therapeutic concentration of 60 or 80 mumol per litre (15 or 20 mug. per ml.).

Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy

Twenty-three residential patients on chronic antiepileptic drugs (AEDs) were entered into an open study of 4 weeks duration. Baseline variables and seizure frequency were determined in the first week. All patients received a single dose of lamotrigine in the second week to determine single-dose pharmacokinetic parameters. Twenty patients then received daily or twice daily lamotrigine for a week. Post-treatment seizure frequency was observed for a further week. Patients taking liver enzyme inducing antiepileptic drugs showed a mean lamotrigine plasma elimination half-life (T1/2) of 14 h (+/- 7) (T1/2 of normal volunteers = 24 h) and those taking sodium valproate and an inducing AED showed a mean lamotrigine T1/2 of 30 h (+/- 10). The plasma concentrations of co-administered sodium valproate, phenytoin, carbamazepine, phenobarbitone and primidone were not altered by 1 week lamotrigine dosing. There was a significant reduction in complex partial seizures in the treatment week compared with baseline. Some patients showed a marked increase in seizure frequency on stopping lamotrigine. There was an increase in reports of drowsiness during lamotrigine administration, but there were no clinically significant changes in any safety measure.

Epilepsy and pregnancy: Report of an Epilepsy Research Foundation Workshop

Pregnancy in women with epilepsy (WWE) is known to be associated with a higher risk of congenital malformations than is associated with pregnancy in non-epileptic women. Several factors have been identified to account for the increased risk, including the direct teratogenic effects of antiepileptic drug (AED) therapy, indirect effects of these drugs by interfering with folate metabolism, genetic abnormalities in drug or folate metabolism, and possibly an arrhythmogenic effect of maternal drug therapy on the embryonic heart, leading to ischaemia in developing tissues. A harmful effect of maternal seizures on the developing embryo has not been proven, although seizures and status epilepticus account for most of the excess maternal mortality in women with epilepsy. Abrupt withdrawal of drug therapy by the mother may be an important contributory factor. Less is known about the psychomotor development of children born to mothers with epilepsy because few studies have been designed to follow their progress throughout childhood. Retrospective studies suggest that impaired cognitive development may be associated with maternal drug therapy, particularly valproate. There is an urgent need to evaluate these risks and, with this in mind, several prospective registers have been set up to collect data from pregnancies in women with epilepsy.

Adjunctive treatment of partial seizures with tiagabine: A placebo-controlled trial

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.

An Update on Sodium Valproate

Sodium valproate has been in clinical use for the treatment of epilepsy in Great Britain since 1973 and in the United States since 1978. It is chemically quite different from the existing antiepileptic drugs. Although most authorities concentrate on its modification of GABAergic inhibitory transmission in the central nervous system, its mechanism of action remains obscure. It has been shown to be an effective antiepileptic drug in a wide variety of seizure types, but clinically, its major use to date has been in generalized seizures. It is particularly effective in photosensitive epilepsy and myoclonus. Most adverse reactions to sodium valproate are mild and reversible, but with increasing experience, the drugs rare, idiosyncratic, adverse effects are becoming apparent, particularly hepatotoxicity and teratogenicity. The role of therapeutic drug monitoring in the management of patients taking sodium valproate is controversial.

Clobazam as adjunctive treatment in refractory epilepsy.

Case 1-This patient was investigated at the age of 18 for recurrent urinary infection. She had been aware of symptoms only for the preceding few months. The following year intravenous urography showed a normal right kidney and a shrunken left kidney with clubbing of the calyces (fig (a)) consistent with chronic pyelonephritis. On micturating cystography there was reflux up the left ureter as far as the renal pelvis but without dilatation of the renal tract. Cystoscopy showed a localised trigonitis. She was treated initially by urethral dilatation but, after a further recurrence of infection with haematuria, she underwent left nephrectomy at the age of 19. Histological examination confirmed the presence of severe chronic pyelonephritis. She continued to suffer from urinary infection and haematuria in the year after nephrectomy, at which point she was lost to follow up. Case 2 is the twin sister of case 1. They were always regarded as identical, and identity was confirmed in 19 red cell types and the four HLA-A and HLA-B types (courtesy of Dr Ann Collins). She presented to one of us in general practice with a history of recurrent urinary infection, in which the first proved attack was at the age of 24. In view of the family history she was referred for investigation; no evidence of chronic pyelonephritis was seen on intravenous urogram (fig (b)). Micturating cystogram showed reflux up the left ureter of similar extent to that shown in her twin sister and also slight reflux up the right ureter. She was followed up as an outpatient for about three years, during which time she ceased to suffer from urinary infections. Repeat intravenous urography after five years confirmed the normality of the kidneys. Analysis of urine gave consistently normal results, and plasma urea and creatinine concentrations were within normal ranges.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Interactions with Antiepileptic Drugs

SummaryMost of the currently available antiepileptic drugs have a low therapeutic ratio and therefore a drug interaction causing elevation of the serum level of one of these compounds can readily lead to drug intoxication. Phenytoin, in particular, is vulnerable because its metabolism is dose-related and at therapeutic serum levels the enzyme system involved in its degradation is easily inhibited by concurrent drug administration.As multiple drug therapy has traditionally been practised in the management of epilepsy, clinically important interactions are common. Furthermore, most of the drugs used in the treatment of major epilepsies are potent inducers of hepatic microsomal enzymes and can therefore stimulate the metabolism of concurrently-administered drugs to such an extent that they may be rendered ineffective. The use of one drug alone is recommended, where possible, in the management of epilepsy.