Robinson Artworkby Michelle C. Liu, BA; Amir Garakani, MD; Katherine A. Krauskopf, MD, MPH; and Jessica Robinson-Papp, MD
Ms. Liu is from the Icahn School of Medicine at Mount Sinai, New York, New York; Dr. Garakani is from Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, and Silver Hill Hospital, New Canaan, Connecticut; Dr. Krauskopf is from Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and Dr. Robinson-Papp is from Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.

Innov Clin Neurosci. 2013;10(9–10):26–29

Funding: There was no funding for the interviews, development, and writing of this article.

Financial Disclosures: The authors do not have conflicts of interest relevant to the content of this article.

Key Words: Mothballs, leukoencephalopathy, paradichlorobenzene, PDB, cocaine abuse, HIV Infection, HAND

Mothball ingestion has been previously cited to induce toxic-leukoencephalopathy, secondary to the destructive effects of paradichlorobenzene on central nervous system white matter. This case presents a 37-year-old woman who experienced a neuropsychiatric syndrome consistent with paradichlorobenzene-induced toxic leukoencephalopathy after two decades of mothball abuse. Her clinical presentation was insidious, involving fluctuating cognitive decline, depression, and psychosis. This was further complicated by a human immunodeficiency virus infection and concomitant cocaine abuse. Ultimately, her clinical findings were attributed to a reversible toxic-leukoencephalopathy from mothball ingestion, and her magnetic resonance imaging findings were consistent with symmetric leukoencephalopathy and atrophy. Though leukoencephalopathy in human immunodeficiency virus has numerous potential etiologies, a patient with a history of substance abuse warrants consideration of toxin-induced leukoencephalopathy, and further inquiry regarding abuse of other substances is appropriate.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the most common neurologic complications of HIV. HAND typically presents insidiously with cognitive impairment, affective disturbances (depression, apathy) and motor abnormalities resembling parkinsonism. Magnetic resonance imaging (MRI) features include symmetric leukoencephalopathy and atrophy.1 HAND is highly prevalent and is often the initial diagnostic consideration in an HIV-infected patient with neuropsychiatric symptoms and leukoencephalopathy on MRI. Differential diagnosis includes other infectious etiologies such as progressive multifocal leukoencephalopathy (PML) and toxic leukoencephalopathy secondary to environmental exposure or substance abuse.[2] These toxic causes can be particularly important, as clinical improvement relies on removal of the offending agent.[3] Alternatively, no cure exists for HAND, although some patients improve with combined antiretroviral therapy (cART).

Toxic leukoencephalopathy is associated with exposure to various substances, including antineoplastic agents, antimicrobial agents, environmental toxins such as carbon monoxide, and substances of abuse (e.g., alcohol, heroin, “crack”/cocaine, inhalants).[4] Amphetamines, such as methylenedioxy-methamphetamine (MDMA), have produced cases of central nervous system (CNS) white matter toxicity and neuropsychiatric manifestations.5 Aromatic hydrocarbons, such as para-dichlorobenzene (PDB), found commonly in household items (e.g., pesticides, toilet bowl deodorizers, and mothballs) may also cause toxic leukoencephalopathy. These substances are abused via inhalation or ingestion, which produces a euphoric effect.[6,7] Clinical features of PDB-induced leukoencephalopathy include psychiatric symptoms (e.g., psychosis, depression), cognitive decline, and neurologic deficits (e.g., ataxia, dysarthria, hyperreflexia, spasticity, bradykinesia, weakness).[8,9] Dermatologic and medical manifestations may also occur with PDB toxicity, including refractory pruritus, anemia, and abnormal electrolytes and liver function tests.[7,10,11] PDB has also been implicated as a possible carcinogen.[5]

We report a case of an HIV-infected patient who presented with a complicated neuropsychiatric syndrome originally attributed to a combination of HAND, major depression with psychotic features, and cocaine abuse, but ultimately was found to have a component of reversible toxic leukoencephalopathy due to mothball abuse.

Case Report
The patient was a 37-year-old woman who had been diagnosed with HIV six years prior. She was adherent to her antiretroviral regimen since diagnosis (emtricitabine-tenofovir, ritonavir, and atanazavir). Her viral load was undetectable and her CD4+ count ranged from 211 to 636, with a nadir of 51. The patient had a diagnosis of major depressive disorder, severe, recurrent, with psychotic features, which pre-dated her HIV diagnosis. She intermittently experienced both auditory and visual hallucinations, and had been psychiatrically hospitalized several times for suicide attempts and command auditory hallucinations to commit suicide. The patient’s poor adherence to her psychiatric medications had resulted in numerous medication trials. She was ultimately stabilized on venlafaxine, quetiapine, and trazodone, with which she reported full adherence. Other psychiatric history included habitual cocaine use for six years, with periods of daily crack-cocaine use in between months of successful abstinence. She carried a six-year history of anemia most consistent with anemia of chronic disease. Six years after her HIV diagnosis, she was found to have lobular carcinoma-in-situ (LCIS) of the breast, and subsequently underwent lumpectomy. Post-operative follow-up remained negative for recurrent malignancy.

Following her HIV diagnosis, initial cognitive assessment revealed cognitive impairment, including perseveration, poor set-shifting, poor executive functioning, and impaired short-term memory. These deficits were attributed to HAND. Repeat assessment after one year showed improvement in the setting of antiretroviral use and abstinence from cocaine. Two years later, after a cocaine relapse, cognitive assessment revealed declines in visual-spatial processing, speed of information processing, concentration, and short-term memory. MRI of the brain demonstrated extensive, symmetric high T2 signal in the periventricular white matter bilaterally that was not present on MRI at the time of her HIV diagnosis.

During a routine visit with her psychiatrist, six years after her HIV diagnosis, the patient admitted to periodically inhaling and ingesting mothballs beginning at the age of fifteen, a practice she kept a secret due to embarrassment. She used mothballs even during periods of abstinence from cocaine. After watching a documentary that featured a woman with a mothball addiction who later developed cancer, our patient grew increasingly fearful that her own mothball habit had caused her breast cancer, and revealed this concern to her psychiatrist. The patient expressed regret toward her past mothball abuse, and vowed to completely abstain from mothball use in the future.

Three months following this visit, the patient presented to the clinic severely depressed and anxious, and endorsed command auditory hallucinations telling her to commit suicide. At this time, her urine toxicology was positive for cocaine, and she admitted to relapsing on cocaine. She reported complete abstinence from mothballs since her last appointment. She was subsequently hospitalized in our inpatient psychiatry unit and stabilized clinically with an increase in her antidepressant medication, venlafaxine.

After four months of abstinence from mothballs, the patient demonstrated improvement in several clinical realms. Her anemia had improved; her hemoglobin rose to 11.6 from 9.5g/dL, and her prior microcytosis had disappeared. On repeat cognitive testing, the patient continued to display attention and delayed recall deficits, but her prior visuospatial and executive functioning deficits had resolved. She reported an improved mood since her discharge from the inpatient psychiatric unit, and denied auditory or visual hallucinations. Her HIV viral load remained undetectable and her CD4+ T cell count was stable at 540. Other labs, including electrolytes and liver function tests, revealed no abnormalities. She denied recent cocaine use and subsequent random urine drug screens were negative.

Leukoencephalopathy is a clinical syndrome involving neurologic deficits and altered mental status, secondary to structural alteration of cerebral white matter and myelin damage. Toxin-induced leukoencephalopathy may be due to exposure to various substances, including carbon monoxide, heroin vapor, cocaine, and aromatic hydrocarbons. Toxic leukoencephalopathy classically presents after exposure to environmental hazards or substances of abuse. Delayed leukoencephalopathy of carbon monoxide toxicity is a demyelinating syndrome that occurs after prolonged periods of inadequate cerebral oxygenation. Clinical manifestations appear after complete or near-complete recovery from the acute event, often days to weeks later. Patients demonstrate memory and cognitive deficits, apathy, and mutism, as well as urinary incontinence and gait disturbances.[12] Heroin-inhalation leukoencephalopathy, secondary to the practice of “chasing the dragon” (inhaling the vapor [pyrolysate] of heated heroin) was first reported in the 1980s.[4] Heroin inhalation produced a progressive spongiform encephalopathy, characterized by three stages: first, cerebellar dysfunction including gait and limb ataxia, speech deficits, apathy, and akathisia; next, myoclonus and choreoathetoid movements; and lastly, hyperpyrexia, hypotonic paresis, and akinetic mutism.[12] Cocaine-induced toxic leukoencephalopathy has been described in literature, though infrequently.[13] Clinical presentations vary widely; some cases report altered levels of consciousness, spasticity, and rigidity, while others report focal neurologic deficits and cognitive deficits that improve with discontinuation of cocaine.[4] Excessive exposure to household products, such as mothballs, toilet bowl deodorizers, or pesticides, may cause toxic encephalopathy due to PDB. While mothball toxicity has historically been associated with naphthalene-induced hemolytic anemia, hepatotoxicity, and nephrotoxicity, PDB has recently replaced naphthalene as the primary constituent of mothballs.[7] A highly lipophilic compound, PDB enters the nervous system, accumulates in white matter and causes widespread myelin damage. Toxicity often presents in a delayed manner, termed coasting. Coasting refers to clinical deterioration despite cessation of PDB ingestion, due to the continued release of PDB from adipose stores. Alternatively, acute intoxication may cause sudden clinical deterioration. Both acute intoxication and coasting may present with neurologic dysfunction and psychiatric symptoms including muscle weakness, hyperrreflexia, spasticity, rigidity, and ataxia, cognitive changes that range from mild deficits to catatonia, disturbed speech, dysphoria, and depression.[6,8,9,11] MRI of the brain reveals increased T2 signal in the periventricular white matter, splenium of the corpus callosum, and cerebellum, consistent with diffuse demyelination.[1,3] Medical complications of PDB toxicity include abnormal electrolytes (low sodium, low potassium), elevated liver enzymes (AST, ALT, alkaline phosphatase, bilirubin), decreased albumin, and low hemoglobin.[7]

Although a history of toxin exposure with congruous clinical and radiologic findings suggests toxic leukoencephalopathy, other leukoencephalopathies should be considered including acute disseminated encephalomyelitis and multiple sclerosis.[12] Leukoencephalopathy in the setting of HIV raises additional diagnostic possibilities. HIV itself can cause leukoencephalopathy as part of HAND. HAND remains a common complication of HIV, even under adequate therapy on cART and successful suppression of viral RNA. Behavioral manifestations, such as apathy and depression, are commonly seen in HAND. In addition to white matter changes, MRI of the brain may demonstrate subcortical atrophy and reduced cortical thickness. Progressive multifocal leukoencephalopathy (PML) is caused by a CNS infection from the JC virus. The virus destroys oligodendrocytes and myelin resulting in focal neurologic deficits, ataxia, and cognitive deficits. Concurrent changes on MRI demonstrate hyperintense white matter lesions that reflect demyelination. Rarer causes of leukoencephalopathy in HIV include HIV-related acute inflammatory leukoencephalopathy (characterized by the sudden onset of symptoms, including cognitive deficits, hemiparesis, dysphagia), leukoencephalopathy of undetermined origin in HIV (disabling cognitive and motor deficits, diffuse cerebral white matter damage), and HIV-associated cerebellar leukoencephalopathy.[14,15]

We report a patient who experienced the effects of PDB-induced toxic leukoencephalopathy secondary to a longstanding history of mothball abuse, whose clinical presentation was complicated by HIV infection and concomitant cocaine abuse. Her initial cognitive deficits were detected shortly after her HIV diagnosis, and were attributed to a combination of HAND and her cocaine use, an impression that was supported by clinical stabilization with anti-retroviral treatment and cessation of cocaine use. Concurrent with a later cocaine relapse, the patient again demonstrated cognitive deterioration. While cocaine abuse and HAND may explain our patient’s fluctuating cognitive performance, PDB-induced toxic leukoencephalopathy inarguably contributed to her clinical presentation. Shortly after the patient ceased mothball use, her performance on cognitive reassessment improved significantly. Perhaps our patient’s several unexplained medical issues, including cancer at an early age, anemia, and intermittent electrolyte abnormalities, should have prompted a search for etiologies beyond HAND and cocaine abuse. The patient’s extensive psychiatric history was another potential clue. Our patient’s depression and psychosis predated her HIV diagnosis by many years, and could have been related to chronic PBD-induced leukoencephalopathy. Of note, after she ceased mothball use, she presented with a transient exacerbation of her psychiatric symptoms, which could reflect the coasting effect of delayed toxic leukoencephalopathy; however, it is difficult to untangle her complex psychiatric history of substance abuse and major depression from the toxin-mediated effects of PDB.

In summary, this case underscores the importance of maintaining a broad differential diagnosis for neurocognitive decline and leukoencephalopathy, particularly in HIV-infected populations who have high rates of substance abuse and are also at risk for neurotoxic infections. Clinicians should consider all potential etiologies of leukoencephalopathy, including toxic, metabolic, and infectious etiologies, even if the clinical presentation is consistent with HAND. Toxic leukoencephalopathy can often be reversed upon cessation of exposure of the toxin; likewise, metabolic or infectious etiologies can be corrected via appropriate medical therapy. In many cases, leukoencephalopathy is multifactorial, and therefore identifying and addressing those elements that can be reversed may improve a patient’s clinical status and quality of life.

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