H. Meinardi

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

Summary: Purpose: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and poly‐therapy.

Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine).

Summary: A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine‐10,11‐epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine‐10,11‐epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine‐10,11‐epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.

Acute Effects of Lamotrigine (BW430C) in Persons With Epilepsy

Summary: Sixteen epileptic patients took single doses of lamotrigine, 120 mg or 240 mg. Six photosensitive patients showed reduction (with abolition in two) in photo‐sensitivity after lamotrigine administration. Five subjects with frequent interjetai spikes showed reduction in spike frequency over 24 h after lamotrigine administration. The half‐life (t1/2) of lamotrigine in subjects taking sodium val‐proate was prolonged, whereas the t1/2 in subjects taking carbamazepine and/or phenytoin was reduced. The area under the curve of co‐medication plasma levels was not affected by a single dose of lamotrigine. Five patients reported mild and generally transitory side effects; some of which represented exacerbation of preexisting complaints.

Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy

A double-blind, placebo-controlled trial is reported of lamotrigine as add-on treatment in therapy-resistant epilepsy. A within-patients serial design was used, with two 3-month treatment periods and an intervening 6-week washout/crossover period. An unblinded investigator adjusted lamotrigine dosage to achieve a plasma concentration within a previously predicted therapeutic range. All patients had therapy-resistant partial seizures, some in combination with other seizure types and were without serious neurological or intellectual deficit. Of 34 patients recruited only one was withdrawn because of an adverse experience (maculo-papular rash) probably related to the experimental drug and 30 completed the trial. The other 3 withdrawals were due to default during baseline, dispensing error and cholecystectomy. There was a modest statistically significant reduction in total and partial seizures on lamotrigine compared to placebo treatment. There was no difference in adverse experiences or abnormal biochemical or haematological findings between the lamotrigine and placebo periods. The plasma concentrations of concomitantly administered antiepileptic drugs were not affected by lamotrigine treatment. It is concluded that lamotrigine shows promise as an antiepileptic drug with low toxicity.

Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine?

Summary: A double‐blind randomized crossover design trial of carbamazepine (CBZ) and oxcarbazepine (OCBZ) was performed with 48 in‐patients with epilepsy. All were stabilized on polytherapy including CBZ and had at least two seizures per week. CBZ was replaced by the trial medication. Each trial period started with a titration, followed by a 12‐week steady state. Concomitant medications were kept constant during the trial. The criteria for assessment were seizure fit frequency and severity; tolerability; hematology and blood chemistry; plasma levels of antiepileptic drugs; EEG; cardiovascular parameters; and treatment preference. The following differences regarding OCBZ were detected: 9% reduction of the total number of seizures, with a significant reduction of tonic‐clonic (20%) and tonic (31%) seizures; increased alertness and concentration ability in five patients; an allergic skin reaction with CBZ that completely disappeared in two patients while receiving OCBZ; an increase of valproate and phenytoin plasma levels in a number of patients, probably caused by reduced enzyme induction; a slight but significant reduction of serum Na, not causing clinical symptoms; less seizures than in the CBZ period in 25 patients (52%); and a preference for OCBZ in 23 patients (48%). We consider OCBZ at least as effective as CBZ with a slightly better tolerability. In severe cases, the wider therapeutic window might improve seizure control.

The influence of subclinical epileptiform EEG discharges on driving behaviour

EEG and driving behaviour were monitored in 6 patients with subclinical focal and generalised epileptiform EEG discharges during 420 km of actual motorway driving in a suitably instrumented vehicle. Evidence of impaired driving performance during subclinical discharges was significant in 3 subjects (P < 0.025 or < 0.05) and was suggestive (P < 0.1) in 1. The two patients with greatest impairment had active epilepsy, whereas the others had been seizure-free for upwards of 4 years. No other features appeared to be predictive of altered driving behaviour during discharges.

Carbamazepine and serum sodium levels.

Summary: : Serum sodium levels of 674 epileptic patients were tabulated according to the following categories: <135 mmol/L, hyponatremia (28 patients); 135–145 mmol/L, normonatremia (530 patients); > 145 mmol/L, hy‐pematremia (116 patients). One hundred one patients were treated with antiepileptics without carbamazepine (CBZ), 113 with CBZ monotherapy, and 460 with CBZ plus other antiepileptic drugs. Twenty‐three patients could be followed up after the first detection of a serum sodium level of <135 mg/L. Ten patients were consistently hyponatremic (>50% of the follow‐up measurements were <135 mg/L), whereas the remaining 13 were occasionally hyponatremic. The following facts could be derived from the study: (1) The hyponatremic group was significantly older compared with the other groups. (2) In patients not treated with CBZ, no hyponatremia was seen. Only two patients on CBZ monotherapy showed hyponatremia. (3) The combination of CBZ, valproic acid, especially in high dosages, and barbiturates seemed to lead to hyponatremia. (4) The excretion of antidiuretic hormone, measured in 12 patients, was subnormal (<25 ng/24 h) in seven hyponatremic patients and in three nor‐monatremic patients and normal (25–250 ng/24 h) in two other normonatremic patients. (5) Cyclic AMP, measured in five hyponatremic patients, was normal. (6) In all patients the hyponatremia was slight and did not cause any clinical symptoms. Special treatment was not required.

Photosensitive patients: symptoms and signs during intermittent photic stimulation and their relation to seizures in daily life.

Thirty six patients were studied with a classical photoparoxysmal EEG response to intermittent photic stimulation (IPS). Clinical observations and complaints reported by patients during standardised IPS were recorded and compared with historical data. Twenty seven patients experienced impaired consciousness or showed motor phenomena such as involuntary opening of the eyes or jerking on one or both sides of the body. Twenty five patients had sensations such as pain in the eyes, jerking etc. There existed no relation between the duration of the evoked discharges (0.5-3 seconds) and observed signs or complaints. In 11 instances the clinical features found during IPS were not reported in a history taken from the patient and relatives.

Seven day administration of lamotrigine in epilepsy: placebocontrolled add-on trial

A double-blind placebo-controlled trial of 7 days administration of lamotrigine as add-on therapy was performed in 10 patients with frequent therapy-resistant, chiefly partial, seizures. Dosage was adjusted on the basis of estimated half-life. Six patients showed a 50% seizure reduction on lamotrigine and two an increase. Side effects (ataxia, dizziness and apathy) occurred in 3 patients, but only at blood levels above 3 micrograms/ml, and were rapidly relieved when the dose was reduced in two. EEG spike counts were significantly reduced on lamotrigine. There was no evidence of interactions with co-medication.

Lateralized effects of subclinical epileptiform EEG discharges on scholastic performance in children.

Summary: The interaction between lateralization of subclinical epileptiform discharges and cognitive tasks was investigated in 21 children (12 girls and 9 boys, mean age 10.6 years). Seventeen had a diagnosis of epilepsy (partial or secondarily generalized). Testing was by reading, arithmetic, and intelligence subtests during continuous telemetric EEG and video monitoring. Children with left‐sided discharges had significantly lower reading performance than children with right‐sided discharges. During reading, epileptiform discharges occurred relatively less frequently and with a shorter total duration over the left hemisphere than the right. This supports the view that cognitive tasks suppress epileptiform discharges when they activate a region of the brain within the epileptogenic zone. Discharges from other epileptogenic zones not directly activated by the tasks are increased, however.