Disulfiram-Ethanol Reaction Causing Cortical Blindness

Ethanol dependence/alcohol use disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol drinking, loss of control of drinking, and a negative psychologic state when alcohol is not available. The pattern of alcohol use ranges from social drinking to alcohol dependence wherein sudden cessation of alcohol use results in physical and psychologic symptoms collectively called alcohol withdrawal syndrome.¹

Ethanol metabolism in humans requires sequential oxidation by alcohol dehydrogenase to form acetaldehyde, followed by oxidation of acetaldehyde by aldehyde dehydrogenase to form acetate, which then is broken down to water and carbon dioxide.² Disulfiram, a competitive inhibitor of the aldehyde dehydrogenase enzyme, is one of the 3 drugs approved by the Food and Drug Administration for the treatment of alcohol dependence. The individual taking disulfiram must be motivated to remain abstinent from ethanol.³ Coexistent use of ethanol with disulfiram leads to accumulation of acetaldehyde, causing disulfiram-ethanol reaction (DER), which results in a wide range of severe systemic symptoms, and serves as a deterrent to further alcohol consumption.⁴

In this case report, we present a severe manifestation of DER causing cortical blindness.

Case Presentation

RD, aged mid 40s, who had a 25-year history of AUD, had quit alcohol use and was on disulfiram 250 mg twice daily for 6 months. At a family event, RD drank alcoholic beverages late into the night. The following morning, after an interval of a few hours, RD fainted while at work. On regaining consciousness, RD had no perception of light bilaterally. Weakness of the left upper and lower limb, more on the upper limb, also was present. RD was brought to the hospital after 5 days and was admitted to the neurology service.

On examination, hemodynamic status was stable, and left hemiparesis with a power of 3/5 in the upper limb and 4+/5 in the lower limb was noted. Vision testing revealed only perception of light visual acuity. RD could not detect hand movements. Light reflex (pupillary reflex) was preserved, and no relative afferent pupillary defect was seen.

Detailed ophthalmologic evaluation revealed bilateral disc edema. Because the pupillary reaction was normal and no relative afferent pupillary defect was present, the optic disc edema was considered more likely to be attributable to papilledema than to papillitis. Brain MRI with contrast (Figure 1) showed diffusion restriction and contrast enhancement in the posterior cerebral artery territory, bilateral occipital cortices, and medial temporal lobe along with the right thalamus. There was residual edema of infarcted tissue causing narrowing of the cisternal spaces and compression of the lateral ventricles, suggesting intracranial pressure resulting in papilledema in the acute stage. Magnetic resonance angiogram (Figure 2) and venogram tested produced normal results. Subacute infarct with gyriform enhancement was noted (Figure 3) and cisternal cerebrospinal fluid spaces were reduced because of edema. Workup for connective tissue disorders (including antinuclear antibody and antineutrophil cytoplasmic antibody) was negative. EKG testing did not show any rhythm changes, and 2-dimensional echocardiography showed no structural abnormalities or clots. Workup for antiphospholipid antibodies was negative.

RD was managed conservatively with thiamine, antiplatelets, and statins. The weakness improved over a week, but there was no improvement in vision during the hospitalization. After a follow-up of 3 months, there was minimal visual improvement; although RD could detect hand movements and shapes of people, RD could only recognize people by their voices.

Discussion

Disulfiram, primarily used in alcohol rehabilitation centers, is an atypical pharmacologic agent that works by creating unpleasant physiologic symptoms when alcohol is consumed, providing negative reinforcement. Its active metabolite, S-methyl N,N-diethylthiocarbamate sulfoxide, irreversibly inhibits aldehyde dehydrogenase, which is involved in the metabolism of ethanol. Inhibition of aldehyde dehydrogenase causes accumulation of acetaldehyde and results in the DER. DER usually begins 15 minutes after ethanol consumption, and peak effects last for 30 to 60 minutes. Aldehyde dehydrogenase activity takes approximately 6 days to resolve after discontinuation of disulfiram.⁵

Disulfiram also is being repurposed into an anticancer drug. Its metabolite diethyldithiocarbamate binds to copper to form a complex, CuET (diethyldithiocarbamate-copper), which causes downstream effects. CuET inhibits the p97 segregase system, which assists the protein degradation system through the ubiquitin–proteasome pathway; by facilitating accumulation of toxic proteins, an unfolded protein response is induced in disulfiram-treated cells. Nuclear protein localization 4 (NPL4) acts as a cofactor for p97 segregase and CuET binds and immobilizes NPL4. The NPL4 aggregates induce a heat shock response by an HSF-1–dependent mechanism.⁶ The effectiveness of disulfiram as an anticancer drug has been tested in preclinical trials and breakthroughs have been reported in non-small cell lung cancer and glioblastoma multiforme.⁷

When taken along with alcohol, disulfiram is known to cause distressing symptoms, including palpitations, diaphoresis, facial flushing, nausea, vertigo, and hypotension—the constellation of symptoms known as DER.⁴ The severity of DER depends on the dosage of disulfiram taken and the amount of alcohol consumed.⁸ Usually DER occurs within minutes to an hour after alcohol consumption. However, delayed DER occurring several hours after alcohol consumption also has been reported. It may even occur several days after alcohol consumption, especially in those with disulfiram implants.^9,10

A DER can produce life-threatening effects; circulatory collapse, ST depression, stroke, myocardial ischemia, cardiogenic shock, cardiac arrhythmias, dyspnea, and bronchospasm have been reported.⁵ There have been case reports of prolonged and refractory hypotension necessitating the use of vasopressors in a person who consumed alcohol after disulfiram ingestion.¹¹ Even at lower doses, disulfiram, when taken with alcohol, can cause severe hypotension and tissue hypoperfusion (distributive shock) mimicking septic or anaphylactic shock.¹² There may be a predilection of posterior cerebral circulation to be involved in disulfiram toxicity, and the occurrence of posterior reversible encephalopathy syndrome with disulfiram toxicity has been reported.¹³

Cardiac arrhythmias, including atrial fibrillation and ventricular fibrillation, also may occur as a result of concomitant disulfiram and ethanol intake, resulting in embolic manifestations in addition to circulatory collapse. Poor hydration and nutritional status may aggravate the magnitude of circulatory collapse, especially in the tropics, where fluid losses may be high. In the case mentioned previously,¹² there was no evidence of thrombotic or embolic phenomena. Evaluation for hypercoagulable states had negative results. There was a strong temporal association between alcohol intake and the onset of symptoms. The authors noted that the individual exhibited “giddiness,” possibly attributable to hypotension.

Considering the widespread use of alcohol and the common use of disulfiram in India (despite the availability of first-line drugs naltrexone and acamprosate), the occurrence of severe adverse events likely is underreported. Awareness among rehabilitation therapists and users of disulfiram is crucial in avoiding serious complications with long-term effects. Counseling regarding strict abstinence from alcohol consumption needs to be reinforced during every clinic visit and awareness needs to be created that consumption of even a small amount of alcohol can lead to severe, potentially life-threatening side effects in a person taking disulfiram.

Conclusion

Disulfiram consumed with alcohol may result in severe systemic vasomotor changes (eg, vasodilatation) as well as cardiac arrhythmias resulting in circulatory collapse. This may precipitate cerebral infarcts because of hypoperfusion as a result of either distributive shock or an embolic phenomenon. Although the severity of DER is dose-dependent—based on both the disulfiram dose and amount of ethanol consumed—even small quantities of alcohol intake may precipitate significant hypotension. Therefore, caution must be exercised when prescribing disulfiram, and the necessity of strict alcohol abstinence must be reinforced.