DSS 2013-Case 2 Declan McGuone, Jeremy Schmahmann, MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL DSS 2013-Case 2 Declan McGuone, Jeremy Schmahmann, E. Tessa Hedley-Whyte, Matthew P. Frosch

Disclosures NONE MASSACHUSETTS HARVARD MEDICAL SCHOOL GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL NONE Disclosures

Clinical History 69 yo pain & stiffness 2 days after neck lipectomy MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Clinical History 69 yo pain & stiffness 2 days after neck lipectomy No sx of infection or neurologic symptoms Hydromorphone (1.5mg + 1mg) & diphenhydramine (25+25 mg) Admitted. Next AM unresponsive, hypotensive & hypoxic. Resuscitated and receives Narcan Discharged home at baseline 3 days later

Clinical History, cont. 3 WKS : MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Clinical History, cont. 3 WKS : Behavioral, memory & attention deficits appeared. Over next 72 hrs rapid decline in mental status with progressive akinesia, mutism & rigidity Lab investigations Unremarkable T2/FLAIR

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Clinical History 3 MOS : she was alert, responsive, followed simple commands. 6-9 MOS: fluent speech, paranoid & delusional with impaired visuo-spatial, memory encoding, exec. & behavioral functions. Death 2 years following presentation

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL 1300g

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

Discussion MASSACHUSETTS HARVARD MEDICAL SCHOOL GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Discussion

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Neurofilament GFAP

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL CD45 CD68 CD45

Diagnosis Delayed post-hypoxic leukoencephalopathy MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Diagnosis Delayed post-hypoxic leukoencephalopathy

Delayed post-hypoxic leukoencephalopathy MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Delayed post-hypoxic leukoencephalopathy A rare complication of prolonged cerebral hypoxia The classic clinical presentation is biphasic – patients recover within 24hours of a prolonged hypoxic injury and return to baseline before developing a sudden onset neuropsychiatric syndrome within 1-3 weeks Exact incidence is not known Etiology of insults reported to cause DPHL is heterogeneous (e.g. anoxic anoxia, anemic anoxia and ischemic anoxia)

Delayed post-hypoxic leukoencephalopathy MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Delayed post-hypoxic leukoencephalopathy Two clinical phenotypes: Parkinsonism Rigidity, tremor, masked facies. dystonic posturing, agitation, apathy, hallucinations, odd behavior, impaired cognition, emotional lability Akinetic mutism Apathy, functional incontinence, pathologic laughter or crying, Examination: Frontal release signs CST signs (hyperreflexia, Babinski) Frontal-executive dysfunction

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Neuropathology Severe diffuse hemispheric demyelination (sparing of U-fibers) Morphologically normal oligodendroglia No vacuolar change (as sometimes seen with inhaled heroin) Preserved neocortical and hippocampal architecture Elevated CSF myelin basic protein (marker of acute widespread demyelination) Plum and Posner, Archives internal medicine, 1962

Mechanism Unknown but likely multifactorial MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL Mechanism Unknown but likely multifactorial ? Mitochondrial dysfunction DPHL can be reproduced in animals using potassium cyanide to impair cytochrome c (Shprecher D, Mehta L, et al. Neurorehabilitation, 2010) ? Reduced cerebral blood flow (DPHL more prevalent and more severe in older patients with cerebrovascular disease) ? Pseudodeficiency of Arylsulfatase A (Gottfried JA, Mayer SA et al. Neurology 1997) ? Delayed oligodendroglial apoptosis (Chu K, Jung KH et al. Eur Neurol 2004)

MASSACHUSETTS GENERAL HOSPITAL PATHOLOGY HARVARD MEDICAL SCHOOL References [1] Plum F, Posner JB, et al. Delayed neurological deterioration after anoxia. Arch Intern Med, 1962 [2] Shprecher D, Mehta L. The syndrome of delayed post-hypoxic leukoencephalopathy. Neurorehabilitation, 2010. [3] Shprecher D, Flanigan K et al. Clinical and diagnostic features of delayed hypoxic leukeoncephalopathy. J Neuropsychitary Clin Neurosci, 2008 [4] Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol, 1983 [5] Gottfried JA, et al. Delayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy. Neurology 1997.