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Encephalopathies are commonly encountered in the intensive care unit (ICU) and portend worse outcomes. This chapter presents a case study of a 54-year-old man with a history of alcohol abuse and cirrhosis who was admitted to the neurologic ICU after drainage of a large right-sided subdural hematoma. His mental status returned to baseline after treatment with lactulose and neomycin. A general physical examination should search for evidence of trauma or intoxication. Meningismus should be evaluated. A fundoscopic examination may reveal papilledema. Electroencephalographic monitoring during administration of flumazenil can be used to determine if an occasional subclinical seizure can be detected. Inflammatory mediators have also been implicated in the etiology of hepatic encephalopathy. Ruling out physiologic, pharmacologic, and neurologic etiologies requires a thorough history, careful physical examination, and the appropriate use of laboratory and imaging tests. Treatment should be tailored to the underlying etiology of the encephalopathy.