Lidocaine-induced Seizures in Patients with History of Epilepsy: Effect of Antiepileptic Drugs

A 36-yr-old diabetic woman was admitted to the hospital because of chest pain and ventricular tachycardia. She had a 14-yr history of focal motor seizures involving the right side of the body. Previous electroencephalograms showed left hemispheric spikes. Seizures had been well controlled on 400 mg/day phenytoin. After she was given 100 mg lidocaine intravenously for the ventricular tachycardia (1.3 mg/kg), the patient developed a typical focal seizure involving the right side of her face and the right arm. She was given a loading dose of 1,500 mg phenytoin intravenously, which increased the serum concentration of phenytoin from 6.8 to 22.3 μg/ml. She recovered uneventfully from the seizure. As the ventricular tachycardia persisted, she was given an additional lidocaine bolus of 50 mg (0.65 mg/kg) followed by a continuous infusion of 2 g lidocaine in 500 ml D5%, at a rate of 3.3 mg/min. Approximately 6 h after the beginning of the infusion, she had a witnessed generalized seizure. Her electroencephalogram, which had previously shown complete cessation of the previous seizure pattern, now showed the abrupt onset of generalized spike and polyspike and waves (fig. 1). The concentration of lidocaine in venous blood was 21 μg/ml. Lidocaine infusion was stopped, and she was given 10 mg intravenous diazepam, which suppressed the spike and wave discharges.

A 41-yr-old woman had a history of focal and secondarily generalized seizures since the age of 23. Previous ictal and interictal electroencephalograms showed a right frontal focus. The patient had finished an electroencephalographic telemetry evaluation for epilepsy surgery and was restarted on carbamazepine, 200 mg. During a cerebral arteriogram and Wada test performed that same day, she was mistakenly given a 20-mg lidocaine bolus (which had been used to anesthetize the groin) via  the intraarterial catheter into the right internal carotid artery. She developed a focal seizure originating in the right hemisphere within 20 s of the injection (fig. 2). The seizure was clinically and electrographically identical to her usual focal seizures. The seizure did not generalize. The serum concentration of carbamazepine was 1.6 μg/ml at the time of the seizure.

These two cases illustrate two distinct presentations of lidocaine-induced seizures in patients with a previous history of epilepsy: precipitation of a patient's typical partial seizure when concentrations of anticonvulsant medications were low and precipitation of a generalized tonic clonic when the patient had therapeutic concentrations of phenytoin. Lidocaine is known to have a concentration-dependent effect on seizures. At concentrations between 0.5 and 5 μg/ml, lidocaine can suppress the clinical and electroencephalographic manifestations of seizures, whereas at higher concentrations, lidocaine can cause seizures. 3,5,6This bimodal response has been demonstrated in cats with penicillin-induced epileptogenic foci in which concentrations between 2 and 3 μg/ml cause suppression of epileptiform electroencephalographic discharges. This suppression persists until the lidocaine concentration drops below 1 μg/ml. Concentrations between 4.5 and 7 μg/ml, however, increase cortical irritability, culminating in status epilepticus at concentrations above 7.5 μg/ml. 6In epileptic cats, the presence of epileptiform EEG discharges indicates that serum concentrations of lidocaine are either below 1 μg/ml or above 7 μg/ml.

At serum concentrations below 5 μg/ml, lidocaine abolishes cortically induced facilitation of motoneurons, 7which may account for its anticonvulsant action. The mechanisms governing the anticonvulsant actions of the drug are not completely understood. 8Intravenous administration of lidocaine inhibits l-glutamate–induced transcallosal inhibition of contralateral neurons in cats, 9which is independent of γ-aminobutyric acid or its receptor sites. 10The mechanisms mediating the proconvulsant properties of lidocaine are not completely understood, either. Supratherapeutic concentrations of lidocaine produce a selective blockade of inhibitory cortical neurons, 5,11which ultimately lead to convulsions.

In humans, slow intravenous infusions of lidocaine have been successfully used to treat convulsive status epilepticus and epilepsia partialis continua. 3Lidocaine concentrations above 8 to 9 μg/ml, 2,5however, are associated with increased risk of generalized tonic–clonic convulsions. 1–3Continuous intravenous infusions of lidocaine given to 11 healthy volunteers at rates ranging from 1.5 to 3 mg · kg^{− 1}· min⁻¹resulted in generalized con-vulsions in all after an average total dose of 6–8 mg/kg. 2Convulsions occurred abruptly and without prodrome in 15 of the 17 volunteers. Several of the volunteers had recurrence of seizures over the 20–30 min following the end of the infusion. One of them had seven seizures following the infusion. All volunteers had postictal confusion after the lidocaine-induced seizures, and the average time for neurologic recovery was 37 min. 2Although slower rates of infusion, 0.5 mg · kg^{− 1}· min⁻¹given over 25 min, are usually considered safe, another study showed that 1 out of 12 healthy volunteers developed a generalized convulsion with this rate of infusion. 12 

Lidocaine is converted to monoethylglycinexylidide by oxidative N -deethylation, part of which is then hydrolyzed to 2,6-glycine xylidide. 13Both monoethylglycinexylidide and, to a lesser extent, 2,6-glycine xylidide can lower seizure threshold 14and potentiate lidocaine-induced seizures. The role played by lidocaine versus  its metabolites in the causation of seizures is not always clear. Circumstantial evidence suggests that the rapid metabolism of lidocaine and the potentiating effects of monoethylglycinexylidide and 2,6-glycine xylidide on seizures are of clinical relevance for some patients. 8,13,15Patients with lidocaine-induced central nervous system toxicity usually have concentrations above 5 μg/ml and low concentrations of its metabolites. 15Conversely, there are individuals with signs and symptoms of toxicity who have low lidocaine concentrations but high concentrations of monoethylglycinexylidide. This seem to be more common after extended infusions of lidocaine. 15 

Results from animal studies suggest that different anticonvulsants confer different degrees of protection against lidocaine-induced seizures. 4However, the effects of anticonvulsants on lidocaine-induced seizures in patients with a previous history of epilepsy have not been reported. These two patients had their typical partial seizure triggered by the administration of high doses of lidocaine. In both instances, the serum concentration of anticonvulsants was low at the time of the focal seizure. After she had a partial seizure, the first patient received a loading dose of phenytoin. She was given a second bolus of lidocaine and kept on a continuous lidocaine infusion, and she had a second seizure. This seizure, however, was generalized. This patient had been monitored with electroencephalography, and there was no evidence that this generalized seizure evolved from the left frontal seizure focus. In this instance, the therapeutic concentration of phenytoin did not protect against the diffuse lowering of seizure threshold produced by the high concentration of lidocaine but may have prevented the activation of her frontal focus by the lidocaine.

Our findings have to be viewed with reservation as they are based on two cases. Nevertheless, these cases show that lidocaine can activate the seizure focus in patients with a previous history of partial seizures. 16These cases also suggest that the activation of a preexisting seizure focus is more likely if the serum concentration of anticonvulsants is low. Conversely, therapeutic concentrations of antiepileptic drugs may not prevent generalized seizures, which derive from the widespread lowering of seizure threshold caused by the high concentration of lidocaine. 17