Four acutely agitated patients with diagnoses of mania were treated with a combined regimen of lithium carbonate and high doses of haloperidol—a form of therapy that had been used previously in Metropolitan Hospital without reported adverse effects. In these four, severe encephalopathic syndromes developed. Symptoms consisted of lethargy, fever, tremulousness, confusion, and extrapyramidal and cerebellar dysfunction, accompanied by leukocytosis and elevated levels of serum enzymes, blood urea nitrogen, and fasting blood glucose. Two patients suffered widespread, devastating, irreversible brain damage. Two others were left with persistent dyskinesias. Causal factors have not been identified. (JAMA 230:1283-1287, 1974)