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Toxic Injury


Toxic Leukoencephalopathy

Definition

  • General term used here to describe a white matter demyelinating/destructive process caused by innumerable therapeutic and toxic agents

Clinical Features

Epidemiology

  • May affect all ages, overall prevalence unknown

  • Abused substances

    • Inhalants (glue, spray paint, etc.)

    • Cocaine, heroin, “ecstasy”

    • Heroin vapor inhalation (“chasing the dragon”)

    • Ethanol: greater white matter loss than nonabusers over time

  • Chemotherapy (especially intrathecal methotrexate)

  • Whole brain irradiation (up to 28% affected)

  • Immunosuppressive therapy

  • Antimicrobials (amphotericin B)

  • Carbon monoxide

  • Arsenic

  • Herbal remedies (“phytomedicine”)

  • Occupational (e.g., organic solvents)

Presentation

  • Onset sometimes delayed (weeks/months)

  • Initial presentation: alterations in executive functioning (common)

  • Psychiatric, focal neurologic deficits

  • Severe toxicity: dementia, spasticity, mutism, apathy, coma

Prognosis and Treatment

  • Prognosis varies, exposure parameter dependent

  • Mild cases potentially reversible

  • Corticosteroids, leucovorin (methotrexate), chelation (arsenic), anticoagulants

Pathology

Gross

  • Diffuse edema; necrosis and discoloration of the white matter

Histology

  • Patchy to widespread white matter edema with extensive macrophage infiltrates

  • Demyelination, relative axon preservation

  • Subcortical U-fiber sparing

  • Severe cases: axonal injury (spheroids/varicosities/oligodendroglial loss/necrosis)

  • Ethanol

    • Marchiafava-Bignami disease: necrosis of corpus callosum

  • Heroin

    • Intravenous: brain stem, cerebellum sometimes spared

    • Inhalation (“chasing the dragon”): severe spongiform change (symmetrical), axonal loss, multivacuolated oligodendroglia

  • Solvent inhalation

    • Hydrocephalus ex vacuo, white matter pallor, macrophages: periodic acid-Schiff (PAS)+/birefringent inclusions

Immunopathology/Special Stains

  • Amyloid precursor protein (axonal spheroids)

  • Luxol fast blue (LFB)/PAS

Main Differential Diagnoses

  • Genetic leukodystrophies

  • Demyelinating diseases (e.g., multiple sclerosis [MS])

  • Infections

  • Metabolic

  • Vascular (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Binswanger disease)

  • Delayed post-hypoxic leukoencephalopathy

Fig 1, Toxic leukoencephalopathy. There is bilateral necrosis and discoloration of the deep white matter in this patient who died after a substance abuse “binge.”

Fig 2, Toxic leukoencephalopathy. At low magnification there is extensive white matter pallor due to widespread necrosis. Note that a band of subcortical white matter (“U-fibers”) ( upper center and left ) is relatively spared. (The cerebral cortex is at the upper left of this image. )

Fig 3, Toxic leukoencephalopathy. Higher magnification shows a sharply demarcated area of white matter necrosis with abundant macrophages ( left side of image ).

Carbon Monoxide

Definition

  • Encephalopathy due to toxic exposure to carbon monoxide (CO) gas

Clinical Features

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