2020 NPA-07

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 37-year-old man presented to the hospital with a two-week history of decreasing alertness, headache, and new-onset ataxic gait. He was somnolent and minimally responsive to commands. He had a three-year history of substance abuse that began with prescription opioid abuse and evolved to inhalation of heroin vapors. Head CT showed a diffuse hypodense pattern in the cerebellar and cerebral white matter with symmetric involvement of the posterior limbs of the internal capsule. MRI demonstrated T1-hypointense, T2-hyperintense white matter lesions, and additionally noted involvement of white matter tracts in the pontine corticospinal tracts. Infectious etiologies including HIV, Lyme, JC virus, and herpes simplex virus were ruled out. Cerebrospinal fluid analysis including cytology, cultures, and immunologic testing were normal. His neurologic status declined to comatose, and death was pronounced five days after hospital arrival.

Tissue Site
Brain

The diagnosis is toxic “chasing the dragon” heroin leukoencephalopathy, or CTD heroin leukoencephalopathy. The brain weighed 1,400 grams and displayed moderate to marked generalized edema with herniation of bilateral uncinate processes and cerebellar tonsils. Sectioning showed symmetric white matter lesions with soft, chalky texture and areas of cavitation in the cerebrum (Image A and Image B) and cerebellum (Image C). Microscopic examination revealed cerebral and cerebellar white matter vacuolization, perivascular rarefaction, and hypoxic-ischemic changes (Image D and Image E) with sparing of subcortical U fibers and preservation of cerebellar folia and the dentate nucleus (Image F). Higher magnification views revealed mild lymphohistiocytic inflammatory infiltrates (Image G), with macrophages and activated microglia highlighted by CD68 IHC (Image H). Luxol fast blue-periodic acid Schiff (LFB-PAS) staining highlighted white matter demyelination and sparing of subcortical U fibers (Image I). Bielschowsky silver stain showed mild-to-moderate loss of axons, with occasional axonal swellings (Image J).

Opioid deaths in the United States have risen precipitously in recent years, with increases in deaths due to overdoses of both prescription and illicit opioids. Heroin was first synthesized in the late 1800’s and is produced by processing of the opium poppy, Papaver somniferum. Heroin, or diacetylmorphine, is rapidly metabolized in vivo to active compounds 6-monoacetylmorphine, morphine, morphine-3-glucuronide, and morphine-6-glucuronide. Heroin metabolites readily cross the blood-brain barrier (BBB) to bind with opioid receptors and therefore modulate pain sensation. Activation of opioid receptors also causes respiratory depression, sedation, and euphoria.

Heroin is primarily solubilized and injected intravenously but may also be injected into skeletal muscle or subcutaneous soft tissues, snorted in powder form, administered orally or rectally, or heroin powder can be heated on aluminum foil and the pyrolysate vapors inhaled. Inhalation of heroin vapors, or “chasing the dragon,” emerged as a popular form of heroin intake in the 1950s and has become more prevalent in recent years presumably due in part to a lower risk of infectious disease transmission than injection methods and greater ease of use. CTD heroin leukoencephalopathy was first described in 1982 and is a rare, aggressive, progressive, toxic spongiform leukoencephalopathy with an estimated mortality rate of approximately 23%. The pathophysiologic mechanisms of CTD heroin leukoencephalopathy are largely unknown but are thought to involve direct oligodendroglial and/or astroglial toxicity resulting in demyelination and increased BBB permeability. Patients may present with mild symptoms including inattentiveness or confusion, headache, dysarthria, and/or cerebellar ataxia or with more severe symptoms including profound altered mental status, generalized motor impairment, coma, or death. Patients may also present with acute hydrocephalus due to changes in BBB permeability, a surgical emergency requiring immediate intervention.

CT imaging in patients with CTD heroin leukoencephalopathy typically reveals nonenhancing, hypodense, symmetric lesions, predominantly in the cerebellar white matter and brainstem, with additional lesions extending anteriorly in the periventricular cerebral hemispheric white matter and in posterior limbs of the internal capsule. MR imaging typically shows bilateral, symmetric, periventricular white matter diffusion restriction; lesions are T1-hypointense and T2-hyperintense. Histopathologic changes include spongiform degeneration of cerebellar and cerebral white matter with reduced oligodendrocytes, active demyelination, and axonal degeneration. Subcortical U fibers are spared, as are the anterior limbs of the internal capsule.

Disparate symptoms and CNS changes are seen in patients with heroin intake by other methods; for example, intravenous injection of heroin tends to result in lesions involving subcortical U fibers and the genu of internal capsules, and the cerebellum and brainstem are typically uninvolved. Patients who inject heroin are more likely to present with mutism, bladder/bowel incontinence, and overdose due to respiratory suppression. Overdose by injected heroin can result in generalized anoxic-ischemic changes due to hypotension and poor brain perfusion if the patient is resuscitated and survives. Intravenous injection of heroin is also more likely to be associated with CNS infections, vasculitis, and delayed-onset encephalopathy weeks after initial symptomatic acute intoxication presentation and recovery.

The differential diagnosis of a toxic leukoencephalopathy like CTD heroin leukoencephalopathy is broad and includes a variety of infections, demyelinating diseases, leukodystrophies, paraneoplastic syndromes, vascular diseases, and leukoencephalopathies associated with other toxins (Table 1). The clinical history and circumstances surrounding initial presentation are critical in guiding diagnostic algorithms as many of these entities may have overlapping neuroradiologic and histopathologic findings. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in the NOTCH3 gene on chromosome 19; it is the most common heritable stroke disorder. The most common clinical presentation is ischemic cerebral infarct at a mean age of approximately 45 years. Gross findings typically include multiple cavitary lesions of variable age in periventricular white matter and lacunar infarcts in deep gray nuclei. Microscopic examination reveals characteristic PAS-positive basophilic granules in the media of arterioles in the brain and skin which appear as granular osmiophilic material on electron microscopy. Globoid cell leukodystrophy, also known as Krabbe disease, is an autosomal recessive lysosomal storage disease of infancy that is rarely seen in adults; it is caused by mutations in the GALC gene on chromosome 14, resulting in a deficiency of galactocerebroside beta-galactosidase. Neuropathologic findings include diffuse white matter demyelination with sparing of subcortical U fibers, marked loss of oligodendroglia, and pathognomonic epithelioid and globose multinucleated PAS-positive macrophages, often clustered around blood vessels. Subacute sclerosing panencephalitis (SSPE) is a chronic viral encephalitis resulting from persistent measles (Rubeola virus) infection, a member of the paramyxoviridae family. SSPE is most commonly seen in children and adolescents who were exposed to measles before the age of two years. CSF typically shows an elevated viral antibody titer, and the brain shows massive white matter demyelination, severe cortical atrophy, perivascular and intraparenchymal lymphohistiocytic inflammatory infiltrates, characteristic eosinophilic intranuclear neuronal inclusions, and neurofibrillary tangles. Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by JC virus, a member of the polyomaviridae family. PML is typically seen in immunocompromised patients and causes confusion, disorganization/incoordination, ataxia and possible seizures. The brain shows multifocal white matter demyelination, often occurring at the gray-white junction, and characteristic oligodendroglial viral inclusions, demonstrable by IHC or in situ hybridization methods.

Antioxidative and symptomatic treatments may benefit patients with CTD heroin leukoencephalopathy and lead to lower mortality. Patients presenting with milder clinical symptoms are more likely to survive and recover, while patients presenting with more severe symptoms typically have a higher mortality.

Table 1: Causes of leukoencephalopathy.

References

1. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med. 2001;345(6):425-32.
2. Filley CM, McConnell BV, Anderson CA. The expanding prominence of toxic leukoencephalopathy. J Neuropsychiatry Clin Neurosci. 2017;29:308-18.

• Toxic heroin leukoencephalopathy shows distinct neuropathologic features dependent on the method of heroin intake.
• CTD heroin leukoencephalopathy characteristically manifests with symmetric spongiform degeneration of cerebellar and cerebral white matter, posterior limbs of internal capsules, and white matter tracts in the brainstem with associated reduced oligodendrocytes, active demyelination, and axonal degeneration. Subcortical U fibers are spared, as are the anterior limbs of the internal capsule.
• The differential diagnosis of a toxic leukoencephalopathy like CTD heroin leukoencephalopathy is broad and includes a variety of infections, demyelinating diseases, leukodystrophies, paraneoplastic syndromes, vascular diseases, and leukoencephalopathies associated with other toxins. The clinical history and circumstances surrounding initial presentation are critical in guiding diagnostic algorithms as many of these entities may have overlapping neuroradiologic and histopathologic findings.
• Antioxidative and symptomatic treatments may benefit CTD heroin leukoencephalopathy patients and lead to lower mortality.

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2. Cheng MY, Chin SC, Chang YC, et al. Different routes of heroin intake cause various heroin-induced leukoencephalopathies. J Neurol. 2019;266:316-29.
3. Ellison D, Love S, Chimelli L, et al. Neuropathology: A reference text of CNS pathology. 3rd ed. Edinburgh: Mosby Elsevier; 2013.
4. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med. 2001;345(6):425-32.
5. Filley CM, McConnell BV, Anderson CA. The expanding prominence of toxic leukoencephalopathy. J Neuropsychiatry Clin Neurosci. 2017;29:308-18.
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8. Wolters EC, van Wijngaarden GK, Stam FC, et al. Leucoencephalopathy after inhaling “heroin” pyrolysate. Lancet. 1982;2(8310):1233.