Disulfiram-induced seizure in a patient with alcohol dependence syndrome.

Sir,

Disulfiram (DSF) has been used in the management of alcohol dependence as a deterrent agent for over 50 years, and it has been shown to be efficacious when taken under supervision.

In addition to the physical symptoms associated with the concomitant use of alcohol, DSF may lead to adverse drug reactions (ADRs) when used alone, which are flushing, throbbing headache, perspiration, etc., DSF has an acceptable risk profile. However, it is associated with many adverse events and drug–drug interactions, including death. The most common less serious adverse effects include headache, sleepiness, tiredness, and halitosis (or metallic taste). Its toxicity may present different clinical aspects, though the mechanism (direct or idiosyncratic) remains unclear. Dermatological, neurological, psychiatric, and cardiac events have been reported. Serious side effects include hepatitis, hepatotoxicity, psychosis, seizures, peripheral neuropathy, and optic neuritis.[1]

There are very few case reports regarding DSF-induced seizures.[23] This shows the need for research, especially in the Indian context, when alcohol consuming population and the wide use of DSF (sometimes surreptitiously) in de-addiction centers are considered. However, because of the ADRs and the dangerous effects of DSF with alcohol, it has to be prescribed with caution and always monitored by medical supervision.

Mr. SD, a 40-year-old married male, diagnosed with alcohol dependence for the past 5 years, presented with uncomplicated withdrawal symptoms. Detoxification was done using benzodiazepines in tapering dose, and oral thiamine supplementation was initiated. Investigations including complete blood count, blood sugar, and liver and renal function tests were within normal limits. After he gave written informed consent, DSF was started at a dose of 250 mg at daytime as an aversive agent and increased to 500 mg per day after 1 week. He was also receiving quetiapine 50 mg for sleep disturbances. His birth and developmental history was unremarkable. There was no past or family history of major medical or psychiatric illness. He had been on regular medications under the supervision of a family member and abstinent from alcohol.

After 6 weeks, he presented with an episode of generalized tonic–clonic seizure, characterized by sudden-onset, tonic–clonic movements of the extremities with up rolling of the eyeball, frothing from the mouth, and tongue bite. Although there was no incontinence, the whole episode lasted for about 1–2 min. The patient remained confused for few minutes after the event. Subsequently, he was rushed to the hospital and admitted in the neurology ward. There was no history of alcohol intake during this period, or history of other substance abuse. After admission, he was treated with tablet phenytoin 300 mg/day. All routine blood investigations (random blood sugar, serum electrolytes, serum creatinine, and complete blood count) were normal. Computed tomography (CT) scan of the brain revealed mild cortical atrophy, and electroencephalogram showed generalized spikes. He was discharged after 2 days with tablet quetiapine 50 mg/day, tablet lorazepam 1 mg at night, and tablet phenytoin 300 mg/day. After discharge, he continued to follow-up in the psychiatric outpatient department (OPD). Tablet phenytoin was tapered up after 1 month. After 4 months of discharge, there was no relapse of seizure. We did not restart tablet DSF considering a possibility of DSF-induced seizure. The patient is continuing to follow-up in the psychiatry OPD, maintaining abstinence now and seizure free without antiepileptic.

Isolated seizure episode in a patient with alcohol dependence can be because of various reasons such as alcohol withdrawal, head injury under the influence of alcohol, or electrolyte imbalance or related to drugs. The Possibility of withdrawal seizure was ruled out as he had one episode of seizure after 6 weeks of stopping alcohol. As per family members and his gamma-glutamyl transferase level, it was clear that he did not take alcohol before admission to the hospital. As CT scan of the brain did not reveal any head injury and his electrolyte levels were normal, these two reasons can be excluded as the reason for seizure. When the patient had seizure, he was on tablet DSF 500 mg/day, tablet lorazepam 1 mg/day, and tablet quetiapine 50 mg/day. As there was no history of seizure in the past and no relapse of seizure after stoppage of DSF and antiepileptic, it indicates a possibility of DSF-induced seizure. To substantiate our assumption, we applied Naranjo Scale for adverse effect and the score was 7, which indicates its probable causal relation between DSF and seizure.[4]

This pattern of adverse effects appearing with increase in duration of drug exposure has been described in the nervous system. There is literature to suggest that the latency time from the start of treatment to the manifestation of the ADR differed according to the organ. Hepatitis occurred with a distinct peak after 2 months of treatment, skin reactions peaked after 2 weeks, and the rate of neurological ADR increased with the duration of therapy.[5] There are rare case reports of seizures associated with DSF. A recent review of literature revealed few reports in which the patients had generalized convulsions.[6]

Diethyldithiocarbamate (DDC), a toxic metabolite of DSF, increases the release of glutamate from striato-cortical synaptic vesicles, suggesting a possible mechanism for DDC-mediated neuronal damage and development of seizures.[7] Norepinephrine depletion with DSF exacerbates seizures and facilitates seizure kindling.[8]

DSF has a moderate record of adverse effects. Apart from DSF alcoholic reaction, evidence suggest that DSF when used alone can cause various side effects including seizures, which are rare but need to be considered. Awareness among clinicians about DSF-induced seizures in the management of alcohol dependence appears practical to prevent misdiagnosis of seizures attributable to other reasons.

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Conflicts of interest

There are no conflicts of interest.