A 57-year-old male presented with severely altered mental status (AMS) and respiratory failure, requiring intubation. The hypoxic event was suspected to be secondary to cocaine and benzodiazepine intoxication, confirmed on urine drug screen. Within days, he returned to baseline mental status, was extubated, and discharged. Two weeks later, he re-presented with AMS, agitation, insomnia, hallucinations, and akinetic mutism without focal neurological deficits. Continuous EEG showed diffuse slowing without epileptiform discharges or lateralizing features. Brain CT showed diffuse abnormalities of the supratentorial white matter while MRI showed diffuse leukoencephalopathy, sparing the subcortical U-fibers. Infectious, metabolic, paraneoplastic, autoimmune, and lumbar puncture workups were unremarkable. The patient rapidly deteriorated with decreased cognition, increased agitation, and myoclonic movements. Despite intravenous steroids and antioxidants, he became aphasic with worsening limb contractures and progression to death two days later. Autopsy neuropathological findings were those of a diffuse symmetric vacuolar leukoencephalopathy, predominantly cerebral hemispheric, with extensive demyelination. This clinical course strongly indicated a diagnosis of DPHL.