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Letters   |    
Myoclonus Associated With Disulfiram
Kongasseri Sreejayan, M.B.B.S., M.D.; Samir Kumar Praharaj, M.B.B.S., M.D., D.P.M.
The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:E37-E39. doi:10.1176/appi.neuropsych.12030073
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Dept, of Psychiatry, Kasturba Medical College, Manipal, Karnataka, India

Correspondence: Dr. Sreejayan K., M.B.B.S., M.D.; e-mail: sreejayan.k@gmail.com

Copyright © 2013 American Psychiatric Association

To the Editor: Disulfiram, an inhibitor of acetaldehyde dehydrogenase, has been used in the management of alcohol dependence as a deterrent agent. The major adverse events with disulfiram include hepatic, neurologic, psychiatric, and dermatologic reactions. There are few reports of seizures associated with disulfiram.

Disulfiram 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.1 It inhibits acetaldehyde dehydrogenase, leading to accumulation of acetaldehyde after consumption of alcohol, which in turn results in distressing symptoms such as flushing, palpitations, fall in blood pressure and syncope, nausea, and vomiting.2 The major adverse events with disulfiram include hepatic, neurologic, psychiatric and dermatologic reactions; among them the neurologic adverse effects constitute up to 28%, making the nervous system the most affected organ system.3 The neuropsychiatric adverse effects reported are optic neuritis, headache, ataxia, paresthesias, delirium, convulsions, dysarthria, frontal release signs, anxiety, impaired memory, decreased concentration, depression, and psychosis.4 We report on a case where the patient developed myoclonic seizures while on disulfiram.

“Mr. P,” a 30-year-old single man diagnosed with alcohol dependence for the past 12 years presented with uncomplicated withdrawal symptoms. Detoxification was done using benzodiazepines in tapering dose, and vitamin supplementation was initiated. Nonpharmacological interventions, including cognitive-behavioral strategies, were done for relapse-prevention. Investigations, including complete blood count, blood sugar, liver, and renal function tests were within normal limits. After he gave written informed consent, disulfiram was started at a dose of 250 mg at bedtime as an aversive agent. He was also receiving amitriptyline 50 mg at bedtime for chronic daily headache. His birth and developmental history was unremarkable. There was no past or family history of major medical or psychiatric illness. Premorbidly, he had impulsive traits.

He had been on regular medications under the supervision of a family member and abstinent from alcohol after discharge from the hospital. After 1 month, he presented with a 4-day history of sudden jerky movements of the body with increasing frequency. The number of such movements increased over the 4 days, and, on the 4th day, he had fallen down and was unconscious for a few seconds. There were no tonic or clonic movements of the body. He was admitted for observation. Electroencephalography (EEG) done on the 5th day showed generalized spike and wave discharges (Figure 1). He was diagnosed with myoclonic seizures possibly related to disulfiram, and all his medications were discontinued. The Naranjo Adverse Drug Reaction (ADR) probability scale5 score was 6, which suggests a probable association. From the next day onward, the frequency of the myoclonic jerks gradually decreased, and, on the 8th day, he did not have any such episodes. He was discharged on the 9th day and started on acamprosate as anticarving agent and amitriptyline. At follow-up, after 2½ months, there was no recurrence of such episodes. He had stopped medications after 1 month and had restarted consuming alcohol for 2 weeks. A repeat EEG done at this time was normal.

 
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FIGURE 1.Electroencephalogram Showing Generalized Spike-Wave Discharge

In this patient, disulfiram was considered the cause of his myoclonic seizures since he did not have any history of seizures in his family or in the past. The episodes started 1 month after starting disulfiram and stopped after the drug was withdrawn. Amitriptyline can also cause seizures, but it is usually related to higher doses and in predisposed individuals.6 Furthermore, there was no recurrence of seizures after reintroducing amitriptyline; this implicates disulfiram as the causal agent. This pattern of appearance of adverse effects with increase in duration of drug exposure has been described in the nervous system.3 There are rare case reports of seizures associated with disulfiram. In three reports, the patients had generalized convulsions,79 and another case had drop attacks.10 To our knowledge, there are no reports of myoclonic seizures associated with disulfiram.

The mechanism of seizures associated with disulfiram is not known. The most important toxic metabolites are disulfiramarediethyldithiocarbamate (DDC), and its metabolite, carbon disulfide (CS2).11 DDC chelates copper, thus impairing the activity of dopamine betahydroxylase.2 Studies have found that disulfiram and DDC increase the release of glutamate from striato-cortical synaptic vesicles, both in vitro and in rats, suggesting a possible mechanism for DDC-mediated neuronal damage and development of seizures.12,13 Another possible mechanism could be exposure to CS2,14,15 acute exposure to which causes rapid onset of headache, confusion, nausea, hallucinations, delirium, seizures, coma, and, potentially, death.8,9 Noradrenergic transmission has been implicated in the modulation of seizure activity. Norepinephrine depletion with disulfiram exacerbates seizures and facilitates seizure kindling.10

Although the frequency of seizures associated with disulfiram appears to be low, caution needs to be taken when prescribing this medication in those with risk factors for seizure. Also, myoclonic seizures could be another possible manifestation of disulfiram toxicity, in addition to generalized convulsions and drop attacks. Nevertheless, larger studies are required to document the association of seizures with disulfiram therapy.

Hughes  JC;  Cook  CC:  The efficacy of disulfiram: a review of outcome studies.  Addiction 1997; 92:381–395
[CrossRef] | [PubMed]
 
Schuckit  MA:  Drug and Alcohol Abuse , 5th Edition.  New York,  Kluwer, 2000
 
EnghusenPoulsen  H;  Loft  S;  Andersen  JR  et al: EnghusenPoulsen H:  Disulfiram therapy: adverse drug reactions and interactions.  Acta Psychiatr Scand Suppl 1992; 369:59–65, discussion 65–66
[PubMed]
 
Basu  D;  Sharma  A;  Nebhinani  N:  Disulfiram-induced delirium: diagnostic dilemma.  Journal of Mental Health and Human Behavior 2009; 14:105–107
 
Naranjo  CA;  Busto  U;  Sellers  EM  et al:  A method for estimating the probability of adverse drug reactions.  Clin Pharmacol Ther 1981; 30:239–245
[CrossRef] | [PubMed]
 
Rosenstein  DL;  Nelson  JC;  Jacobs  SC:  Seizures associated with antidepressants: a review.  J Clin Psychiatry 1993; 54:289–299
[PubMed]
 
Price  TR;  Silberfarb  PM:  Disulfiram-induced convulsions without challenge by alcohol.  J Stud Alcohol 1976; 37:980–982
[PubMed]
 
McConchie  RD;  Panitz  DR;  Sauber  SR  et al:  Disulfiram-induced de novo seizures in the absence of ethanol challenge.  J Stud Alcohol 1983; 44:739–743
[PubMed]
 
Daniel  DG;  Swallows  A;  Wolff  F:  Capgras delusion and seizures in association with therapeutic dosages of disulfiram.  South Med J 1987; 80:1577–1579
[CrossRef] | [PubMed]
 
Akai  J;  Ishii  N;  Muramatsu  T  et al:  [Disulfiram-induced drop attack].  Arukoru Kenkyuto Yakubutsu Ison 1985; 20:143–149
[PubMed]
 
Johansson  B:  A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.  Acta Psychiatr Scand Suppl 1992; 369:15–26
[CrossRef] | [PubMed]
 
Vaccari  A;  Saba  PL;  Ruiu  S  et al:  Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine.  Toxicol Appl Pharmacol 1996; 139:102–108
[CrossRef] | [PubMed]
 
Vaccari  A;  Ferraro  L;  Saba  P  et al:  Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate.  J Pharmacol Exp Ther 1998; 285:961–967
[PubMed]
 
Kane  FJ  Jr;  Kane  JR:  Carbon disulfide intoxication from overdosage of disulfiram.  Am J Psychiatry 1970; 127:690–694
[PubMed]
 
Rainey  JM  Jr:  Disulfiram toxicity and carbon disulfide poisoning.  Am J Psychiatry 1977; 134:371–378
[PubMed]
 
References Container

FIGURE 1. Electroencephalogram Showing Generalized Spike-Wave Discharge
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References

Hughes  JC;  Cook  CC:  The efficacy of disulfiram: a review of outcome studies.  Addiction 1997; 92:381–395
[CrossRef] | [PubMed]
 
Schuckit  MA:  Drug and Alcohol Abuse , 5th Edition.  New York,  Kluwer, 2000
 
EnghusenPoulsen  H;  Loft  S;  Andersen  JR  et al: EnghusenPoulsen H:  Disulfiram therapy: adverse drug reactions and interactions.  Acta Psychiatr Scand Suppl 1992; 369:59–65, discussion 65–66
[PubMed]
 
Basu  D;  Sharma  A;  Nebhinani  N:  Disulfiram-induced delirium: diagnostic dilemma.  Journal of Mental Health and Human Behavior 2009; 14:105–107
 
Naranjo  CA;  Busto  U;  Sellers  EM  et al:  A method for estimating the probability of adverse drug reactions.  Clin Pharmacol Ther 1981; 30:239–245
[CrossRef] | [PubMed]
 
Rosenstein  DL;  Nelson  JC;  Jacobs  SC:  Seizures associated with antidepressants: a review.  J Clin Psychiatry 1993; 54:289–299
[PubMed]
 
Price  TR;  Silberfarb  PM:  Disulfiram-induced convulsions without challenge by alcohol.  J Stud Alcohol 1976; 37:980–982
[PubMed]
 
McConchie  RD;  Panitz  DR;  Sauber  SR  et al:  Disulfiram-induced de novo seizures in the absence of ethanol challenge.  J Stud Alcohol 1983; 44:739–743
[PubMed]
 
Daniel  DG;  Swallows  A;  Wolff  F:  Capgras delusion and seizures in association with therapeutic dosages of disulfiram.  South Med J 1987; 80:1577–1579
[CrossRef] | [PubMed]
 
Akai  J;  Ishii  N;  Muramatsu  T  et al:  [Disulfiram-induced drop attack].  Arukoru Kenkyuto Yakubutsu Ison 1985; 20:143–149
[PubMed]
 
Johansson  B:  A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.  Acta Psychiatr Scand Suppl 1992; 369:15–26
[CrossRef] | [PubMed]
 
Vaccari  A;  Saba  PL;  Ruiu  S  et al:  Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine.  Toxicol Appl Pharmacol 1996; 139:102–108
[CrossRef] | [PubMed]
 
Vaccari  A;  Ferraro  L;  Saba  P  et al:  Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate.  J Pharmacol Exp Ther 1998; 285:961–967
[PubMed]
 
Kane  FJ  Jr;  Kane  JR:  Carbon disulfide intoxication from overdosage of disulfiram.  Am J Psychiatry 1970; 127:690–694
[PubMed]
 
Rainey  JM  Jr:  Disulfiram toxicity and carbon disulfide poisoning.  Am J Psychiatry 1977; 134:371–378
[PubMed]
 
References Container
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