Disulfiram-induced epileptic seizures

Background

Disulfiram (DSF), or tetraethylthiuram disulfide, is a quaternary ammonium compound that converts to active metabolite diethyldithiocarbamate (DDC) in the stomach, being subsequently broken down into diethylamine and carbon disulfide (CS₂). As its most relevant toxic metabolites, DDC and CS₂ irreversibly inhibit aldehyde dehydrogenase, alcohol dehydrogenase and dopamine-β-hydroxylase (DBH).1–3 DBH is a norepinephrine biosynthetic enzyme which catalyses the conversion of dopamine to norepinephrine. 2 Inhibition of DBH activity leads to an accumulation of dopamine and simultaneous depletion of presynaptic norepinephrine in the mesolimbic region.

It has also been demonstrated that metabolite DDC increases glutamate release from striato-cortical synaptic vesicles both in vitro and in rats, suggesting yet another possible mechanism for DDC-mediated neuronal damage.

Other major target for DSF neurotoxicity is the basal ganglia, and this mechanism may involve CS₂ metabolite.3

As a therapeutic agent, DSF is useful in maintaining alcohol abstinence in patients with a diagnosis of alcohol dependence, and who are motivated to discontinue alcohol consumption. It is estimated that about 25%–75% of patients going through treatment with DSF maintain concomitant alcohol consumption.2 DSF causes a hypersensitivity reaction to alcohol, leading to a constellation of symptoms known as ‘ethanol–disulfiram reaction’. The aldehyde syndrome, as it is also known, occurs due to the accumulation of toxic acetaldehyde along with histamine release. It is characterised by diaphoresis, palpitations, facial flushing, nausea, vertigo, hypotension and tachycardia. Ethanol–disulfiram reactions have been reported in patients exposed to environmental chemical compounds containing alcohol.1

Likewise, DSF is used as a second-line agent in the management of the impulsive drive to drink in patients highly motivated for abstinence, through a strong aversive behaviour; DSF is not an anti-craving drug nor does it modulate the neurobiological mechanism of addiction.

Additional targets of DSF have been highlighted recently, namely: in cocaine dependence, by attenuating cocaine craving and seeking behaviour, possibly because of higher levels of dopamine (through DBH inhibition) in the mesolimbic region; in the treatment of drug-resistant fungal infections (particularly those caused by Candida) as a proteasome inhibitor and DNA demethylating agent, through inhibition of ATP binding-cassette drug transport protein; against diverse cancer types, by inducing p53-mediating apoptosis.

Pharmacokinetics of DSF are well known, and DSF is considered a safe and well-tolerated drug at recommended dosage. However, there are several documented adverse reactions. In addition to physical symptoms associated with alcohol consumption, evidence suggests that DSF may also cause side effects even in the absense of alcohol consumption with reports of dermatological, neurological, psychiatric and cardiac events. Serious consequences of DSF use include encephalopathy, convulsions, cranial and peripheral neuropathy, toxic optic neuropathy, irreversible injury of basal ganglia with permanent neurological deficits, catatonia, hypertension and drug-induced psychosis (presumably due to the inhibition of DBH). Neurological complications of DSF may occur as early as 10 days after initiation; these are usually dose-dependent and may be reversible if the drug is promptly discontinued after adverse symptoms are identified. Some risk factors for DSF-induced psychosis are: prior history or family history of psychosis, overly rapid increase in dosage, older age, impaired liver function and concurrent dopaminergic medications or psychostimulant abuse.3

DSF has been found to lower seizure threshold, and to increase the severity and lethality of convulsive episodes. However, seizure induction by DSF is still not well understood and there are various mechanisms that might explain this occurrence. First, DSF reduces norepinephrine levels through DBH inhibition while increasing dopamine levels in the brain; there might be a lower seizure threshold even without synergic effect of alcohol consumption. Furthermore, the accumulation of CS₂ (either through intoxication or chronic exposure) may induce convulsions by causing a pyridoxine deficiency. These might result in reduced formation of gamma-aminobutyric acid, a natural anticonvulsant. Lastly, high concentrations of DSF might inhibit tissue oxygen intake, leading to tissue hypoxia in the central nervous system. Hypoxia could then result in delirium, which might be responsible for electroencephalogram (EEG) changes, such as increased amplitude and slowing of cortical rhythms. These EEG alterations gradually clear with no further occurrence of seizures on discontinuation of DSF.1–3 DSF-induced seizures seem to occur in close association with DSF-induced hypertension and psychosis, which suggests common neurobiological underpinnings like central DBH inhibition.2

Additional concerns with DSF use are related to the simultaneous use of other drugs, with subsequent interactions through the CYP450, CYP2E1 and other pathways. These can have a major impact on levels of other prescribed drugs, such as warfarin, phenytoin, opioids, tricyclic anti-depressants and benzodiazepines. Slow elimination of DSF may give rise to the DSF-alcohol reaction up to 14 days after medication has been discontinued. Coronary artery disease and heart failure are absolute contraindications for DSF use. Psychosis is a relative contraindication for DSF use. Caution is necessary for patients with history of liver disease, seizures, diabetes, thyroid disorders, traumatic brain injury and renal disease.1

Case presentation

A 47-year-old male patient with an alcohol dependence diagnose for 10 years previously was committed to an elective hospitalisation for the third time to undergo alcohol detoxification in a specialised unit. In previous hospitalisations (2015 and 2018) he was discharged to an ambulatory programme for alcoholic patients to maintain abstinence, which included psychiatry appointments and regular attendance at a psychotherapeutic group.

He had a medical history of chronic liver disease complicated with one episode of variceal haemorrhage in 2018. There was a history of multiple inhaled drugs use for almost 20 years, including cannabinoids, heroin and cocaine; the patient had been abstinent since 2018. Finally, he had a family history of bipolar disorder and alcohol dependence.

The patient was referenced for hospitalisation after resuming alcoholic consumption, as his situation was not manageable in ambulatory. Prior to admission, we was referred to the emergency department where an extensive evaluation was performed, including: ECG; complete blood screening (including blood count, coagulation, glucose, urea, creatinine, serum electrolytes, hepatic transaminases, thyroid function, group B vitamins); urinalysis, with toxic screening; chest radiograph. This evaluation revealed normocytic normochromic anaemia (9.3×10 g/L), thrombocytopenia (101×10⁹/L) and elevated liver enzymes (aspartate aminotransferase 69 U/L, alanine aminotransferase 42 U/L and gamma-glutamyl transferase 217 U/L). The urine toxicology test was positive for benzodiazepines and negative for opiates, amphetamines, cannabinoids and cocaine.The positive result for benzodiazepines was explained by the administration of diazepam in the emergency department before urine test because of the presence of abstinence symptoms. Other parameters or tests were within normal range

By the time the patient was admitted for treatment, he had about 180 g of alcohol per day and used to show morning abstinence symptoms, including tremors and sweating.

At admission, the psychiatric assessment showed the patient was alert, cooperative with the interviewer and oriented in all references. His mood was depressed, and affects were congruent with his mood. The patient reported anhedonia, headaches, insomnia, diminished libido and decreased concentration as well as memory deficits. He had lost about 4 kg (3% of usual weight lost) due to decreased appetite. He denied suicidal ideation. His global functioning was severely impaired, as he had been unemployed for almost 5 years.

On admission, a fixed dose of benzodiazepines was prescribed and later adjusted according to clinical evaluation and hospitalisation length. Treatment for detoxification and prevention of alcoholic abstinence syndrome included oxazepam 15 mg qid; oxazepam 50 mg qd; vitamin B₁ 200 mg qd (intramuscular for 4 days and then oral); folic acid 5 mg qd; lactulose bid. The detoxification process was well tolerated without evidence of either abstinence symptoms, or changes of mental state (ie, altered level of consciousness) during medical evaluation. There were no clinical intercurrences, the patient remained haemodynamically stable, normotensive, apyretic and without gastrointestinal changes.

Since the patient was highly motivated to maintain abstinence, and considering his comprehensive history of failed attempts in maintaining abstinence, a second-line treatment with DSF was proposed. The prescription of DSF requires a signed informed consent by the patient, in which he is informed of its potential risks and confirms that he is willing to abstain from alcohol. At the 11th day of hospitalisation, DSF 250 mg bid was initiated, adding to the previous prescription given on admission, except for oxazepam that had been adjusted on the 8th day to 95 mg/day (15 mg tid and 50 mg qd).

After approximately 9 hours of DSF first administration, the patient had one episode of generalised tonic-clonic seizure, and 10 mg of intramuscular diazepam were promptly administered with resolution of seizures. This episode lasted for about 90 s and it was characterised by loss of consciousness, with loss of sphincter control, followed by a post-ictal phase on recovery. He was later transferred to the emergency department, where a second convulsive episode with similar characteristics was observed.

At the emergency department, physical examination was unremarkable, and after neurological examination by a neurology consultant, also unremarkable, organic causes of seizures were excluded. DSF was discontinued and benzodiazepine dosage increased, with no additional convulsive episodes.

Investigations

Blood tests in the emergency room revealed normocytic normochromic anaemia (9.8×10 g/L), thrombocytopenia (114×10⁹/L), mild increase of creatine kinase (491 U/L) and myoglobin (544.2 ng/mL). Other parameters such as urea, creatinine, serum electrolytes, hepatic transaminases, ammonia, glucose, urinalysis, thyroid function and uric acid levels were all within normal limits, ruling out other causes of seizures.

A CT scan of the brain obtained without the administration of contrast material revealed no significant abnormalities, except for mild cortical and subcortical atrophy.

An EEG performed after 4 days of DSF discontinuation was normal.

Treatment

Treatment included prompt discontinuation of DSF and titration of benzodiazepines, with gradual discontinuation in the following days.

Outcome and follow-up

After discontinuation of disulfiram there were no additional convulsive episodes. There was global improvement of the patient psychopathological state, with no other occurrences related to his clinical condition. He was discharged after 26 days of hospitalisation with the following therapeutical scheme: trazodone 150 mg qd, propranolol 10 mg tid, furosemide 20 mg qd, spironolactone 200 mg qd and pantoprazole 20 mg id. He was referred to a reevaluation appointment after 2 weeks, and was also attending a group for alcohol-relapse prevention.