Lamotrigine overdose associated with generalised seizures

Abstract

This report describes the occurrence of generalised seizures in a 42-year-old woman who presented to hospital after deliberate lamotrigine overdose. Seizure activity was promptly terminated after intravenous benzodiazepine administration, and the patient subsequently made a complete recovery. Serum lamotrigine concentration was 30 mg/l at 1.3 h post-ingestion, which is substantially higher than the therapeutic reference range; the estimated elimination half life was 18.3 h. This case reminds us that lamotrigine toxicity may provoke generalised seizures in susceptible individuals.

BACKGROUND

Lamotrigine is a phenyltriazine derivative that is used to treat partial and generalised seizures. Its pharmacological effects are thought due to inhibition of sodium dependent glutamate release by presynaptic neurons.¹ The usual daily dosage varies between 50–400 mg daily, and peak serum concentrations occur 1–3 h after oral administration. Lamotrigine is subject to extensive hepatic metabolism, and the plasma elimination half life is around 25–35 h. Adverse effects include headache, nausea, sleep disturbance, rash, and hypersensitivity syndrome. Most patients do not experience any significant clinical effects after lamotrigine overdose.² However, toxic features may include drowsiness (20.9%), nausea or vomiting (16.1%), ataxia and dizziness (9.4%), tachycardia (4.3%), and in severe cases seizures (1.6%), coma (1.2%), and respiratory depression (0.6%).²

CASE PRESENTATION

A 42-year-old woman presented to the emergency department around 40 min after suspected ingestion of an unknown quantity of lamotrigine. She had been found unresponsive and was accompanied by empty drug packaging and a written suicide note. Past history included two previous drug overdoses (1 year and 5 years before) and alcohol withdrawal seizures 2 years before for which lamotrigine 100 mg twice daily had been prescribed. On initial assessment, conscious level was impaired (Glasgow coma scale 12), the patient was responsive to verbal stimuli, and there was increased tone and rigidity in upper and lower limbs. Other physical examination findings were normal: temperature was 35.9°C, heart rate 72/min, respiratory rate 16/min, and blood pressure 140/90 mm Hg. Peripheral oxygen saturation was 96%, resting 12 lead electrocardiogram was normal, and near-patient testing showed a capillary glucose value of 7.9 mmol/l and breath alcometer did not detect ethanol. Investigations showed normal electrolytes, liver biochemistry, full blood count, and coagulation. Neither paracetamol nor salicylates were detected in blood, and a urinary toxicology screen was negative for amphetamines, benzodiazepines, cannabinoids, cocaine metabolites, methadone, and opiates.

Around 20 min after presenting to hospital, the patient developed coarse jerking movements affecting her neck and shoulders. Within moments, the patient became unresponsive and suffered tonic-clonic seizure activity affecting all four limbs. Intravenous diazepam 10 mg was administered and the generalised seizure activity promptly terminated. The patient was admitted to the toxicology unit for observation where she remained drowsy for the next 12 hours. During the first 6 h the patient was responsive only to painful stimuli, and thereafter conscious level increased. A detailed neurological examination was normal. The patient claimed to have taken a deliberate lamotrigine overdose with the intention of ending her life, provoked by recent marital difficulties and an impending court case. She denied any co-ingested drugs, and had been abstinent from ethanol during the preceding 2 months.

OUTCOME AND FOLLOW-UP

After recovery from the acute effects, the patient was transferred to a local psychiatric unit for ongoing assessment. Confirmatory serum lamotrigine concentrations later became available (fig 1).

Figure 1. Serum lamotrigine concentrations determined at various intervals after overdose, shown with exponential best-fit line (y = 30.9 x e–0.038x) and broken lines indicating the normal therapeutic range (3–11 mg/l).

DISCUSSION

Significant lamotrigine overdose was thought responsible for partial seizure with secondary generalisation in this patient. A causal relationship is supported by a history of drug ingestion with corroborative serum lamotrigine concentrations, the lack of co-ingested drugs or ethanol, and the absence of any significant electrolyte disturbance. Seizures occurred at around 1 h after ingestion, and corresponded with high serum lamotrigine concentrations at that time. Other reports indicate that serum lamotrigine concentrations around 30 mg/l may be associated with severe neurological features, including ataxia, nystagmus, and coma.^3,4 Although somewhat unexpected, antiepileptic drugs including lamotrigine are a recognised cause of seizures, even in therapeutic dosages.^5,6 Generalised seizures are a recognised, albeit rare, feature of toxicity after lamotrigine overdose in adults and children.^7–9

Clinical management of lamotrigine overdose generally consists of supportive care, and correction of hydration status and any electrolyte imbalance. Peak concentrations are expected within 3 h, and patients do not normally require observation for more than 4 h post-ingestion if asymptomatic. Patients who develop symptoms should be closely observed until clinical features have resolved. Prolonged seizures should be treated conventionally with intravenous benzodiazepines; intravenous phenytoin may be considered in patients who do not respond to repeated benzodiazepine administration, and other supportive measures as indicated. The elimination half life given by the slope of the best-fit exponential decay curve was 18.3 h, which is similar to that reported after therapeutic doses. However, the toxicokinetics vary and half life has been variously reported at between 10 and 110 h.^3,4,10

A limitation is that the past history of alcohol withdrawal seizures might indicate an increased susceptibility to seizures in this patient. Notwithstanding, the patient had been abstinent from ethanol for a considerable period before the ingestion.

LEARNING POINTS

• Generalised seizures may be a manifestation of acute lamotrigine toxicity.

• Clinical effects of lamotrigine overdose might not occur immediately.

• Patients should be monitored for at least 4 h after lamotrigine ingestion, and longer in symptomatic patients.