Disulfiram Ethanol Reaction with Ischemic Stroke

Disulfiram (tetraethylthiuram disulfide) has been used since decades in the treatment of alcohol addiction. It causes aversive behaviour towards alcohol due to Disulfiram Ethanol Reaction (DER). The classical DER includes flushing, sweating, tremors, nausea, vomiting, tachycardia, hypotension and restlessness. Complete recovery is the usual outcome in clinical settings. Life threatening reactions are rare but sometimes occur. Rare complications include shock, myocardial ischemia, hypertension, bronchospasm and methemoglobinemia. We present here a very rare case of ischemic stroke in a hemodynamically stable patient, which developed secondary to disulfiram–ethanol reaction. To the best of our knowledge, this is the first such reported case in literature.


INTRODUCTION
Disulfiram was first used for the treatment of alcohol dependency in 1940.The effectiveness of disulfiram in discouraging alcohol consumption is aversive in nature as it is dependent on the patient's fear of developing a disulfiram -ethanol reaction and does not produce central nervous system effects that alter an alcoholic's drinking behaviour (1).

CASE
A 35 year old man who was a chronic alcoholic and smoker was on treatment with T.Disulfiram 250mg once daily for about 3 months.He was not a known diabetic or hypertensive.On the occasion of a festival, the patient drank about 150 ml of whisky.10 to 15 minutes after the alcoholic drink, patient became unwell with sweating, giddiness, disturbed vision and tremors of extremities.Later he developed drowsiness and lost consciousness.There was paucity of movements of the left half of the body.He was admitted to our hospital for further evaluation and management.On admission, patient was afebrile and comatose.His blood pressure was 110/80 mmHg, pulse 80 beats per min, regular.Neurological examination revealed presence of left sided hemiplegia.Pupils were equal on both sides with preserved pupillary reaction, papilledema was present.There were no signs of meningeal irritation.Cardiovascular, respiratory and per abdomen examination were within normal limits.On investigations, complete hemogram, biochemical parameters like blood sugar, blood urea, serum creatinine, liver function tests, lipid profile, serum calcium, magnesium, electrolytes and ABG were within normal limits.ECG and ECHO were normal.CT scan of head showed a large, hypodense lesion involving the right parietal, temporal, frontal and parieto-occipital lobes with mass effect suggestive of acute infarction in the right middle cerebral artery territory and adjacent watershed zones (Figure 1).Doppler study of both carotid arteries was normal.HIV and VDRL tests were both negative.ANA, IgM antiphospholipid antibody, lupus anticoagulant, protein C, protein S, antithrombin III, serum homocysteine levels were within normal limits.A final diagnosis of chronic alcoholism with disulfiram -ethanol reaction with ischemic stroke was made.Patient was treated with mannitol, glycerol, antiplatelet drugs, statins, folic acid and vitamin B complex supplements.Patient recovered consciousness one week after admission.MR Cerebral angiogram done at one week of stroke showed normal cerebral vessels.There was haemorrhagic conversion of the infarct with increased intracerebral edema with midline shift (Figure 2).At one month of follow up, patient's orientation was normal and the power of the affected limbs had improved to 4/5.CT scan of head done at one month of follow up showed resolving features of old infarction in right middle cerebral artery territory and adjacent watershed zones (Figure 3).

DISCUSSION
Therapeutic doses of disulfiram used as a part of a comprehensive treatment program typically range from 125-500 mg/day.Disulfiram and its metabolites impair both cytosolic aldehyde dehydrogenase-1 (ALDH1) and mitochondrial aldehyde dehydrogenase-2 (ALDH2).The inhibition by disulfiram of ALDH2 leads to a rise of acetaldehyde levels 5 to 10 times above baseline levels and a few days of treatment with disulfiram can reduce

Figure 3. CT scan of head done at one month of follow up showing resolving features of old infarction in right middle cerebral artery territory and adjacent watershed zones.
baseline aldehyde dehydrogense activity by 50% Most patients taking disulfiram who are exposed to ethanol develop symptoms of DER within 15 minutes (2).The symptoms gradually peak within 30 minutes to 1 hour and then gradually subside over the next few hours.DER is due to increased serum acetaldehyde concentration generated by the metabolism of ethanol since disulfiram is a powerful inhibitor of the enzyme acetaldehyde dehydrogenase that degrades it.The accumulation of acetaldehyde that is normally metabolized rapidly by acetaldehyde dehydrogenase is responsible for many of the symptoms produced by DER (3).Signs and symptoms of DER include flushing, sweating, conjunctival injection, pruritus, light headedness, vertigo, headache, nausea, vomiting, palpitations, breathlessness, tachycardia and hypotension.Rare complications include shock, myocardial infarction, hypertension, bronchospasm and methemoglobinemia (4)(5)(6).Esophagal rupture and intracranial haemorrhage secondary to profound vomiting may occur (7,8).Symptomatic and supportive care is the mainstay of treatment.
Ischemic stroke following DER has been reported in just one case in the literature which was attributed to severe hypotension that developed following DER (9).In the present case, patient was normotensive during the development of ischemic stroke.The cerebral infarction can be attributed to the spasm of the cerebral vessel.It is well known that acetaldehyde releases catecholamines from the sympathetic nerve terminals of the blood vessels and result in vasoconstriction (10).Acute myocardial infarction(AMI) associated with DER in a young man with normal coronary arteries has been reported in the literature (11).The incidence of AMI in patients with normal or near normal coronary arteries ranges from 1% to 12% and mainly affects young people and is distinctly rare in patients older than 50 years (12).The mechanism leading to AMI in these patients remain unknown.It has been hypothesized that the probable mechanism may be temporary occlusion of the infarct related vessel by spasm or thrombus or a combination of both.In the present case, patient showed improvement in one week of treatment in the form of recovery of consciousness and at one month of follow up showed improvement in the power of the affected limbs (13)(14)(15).
To conclude, there is significant inter individual and intra individual variation in the intensity and duration of a disulfiram ethanol reaction.Though complete recovery is the usual outcome in clinical settings, life threatening complications can occur.Disulfiram is helpful is creating aversion to alcohol but it should be used in patients who comply with the strongly advised restriction to alcohol consumption when on disulfiram therapy.

Figure 1 .
Figure 1.CT scan of head showed a large, hypodense lesion involving the right parietal, temporal, frontal and parieto-occipital lobes with mass effect suggestive of acute infarction in the right middle cerebral artery territory and adjacent watershed zones.