Leukoencephalopathy due to heroin use

INTRODUCTION — Although heroin use by inhalation ("chasing the dragon") can be traced back to the 1950s [1], the leukoencephalopathy and neurologic symptoms associated with this method of heroin abuse were initially described in 1982 in a report from the Netherlands [2]. Subsequent reports suggest that leukoencephalopathy can also develop with heroin injection or snorting [3,4].

This topic will discuss the pathogenesis, clinical features, diagnosis, and management of heroin leukoencephalopathy due to inhalation or other routes of intake.

Other aspects of heroin abuse are described separately. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment" and "Opioid use disorder: Treatment overview".)

TERMINOLOGY AND DESCRIPTION — "Chasing the dragon" is a method of heroin vapor inhalation that is distinct from smoking or sniffing heroin [1,5]. Other names for this process include "chinesing" and "Chinese blowing." A small amount of heroin powder is placed on aluminum foil, which is then heated by placing a match or lighter underneath. The white powder becomes a reddish-brown gelatinous substance that releases a thick, white smoke, which resembles a dragon's tail. The fumes are "chased" or inhaled through a straw or small tube [6].

PATHOGENESIS — Heroin and its metabolite, 6-monoacetylmorphine (6-MAM), are hydrolyzed to morphine, which is then conjugated to morphine-3-glucuronide and morphine-6-glucuronide. Plasma levels of heroin and its metabolites are detected after inhalation [7], and morphine and morphine-3-glucuronide are detectable in cerebrospinal fluid (CSF) after chronic systemic use [8]. Heroin and its metabolites cross the blood-brain barrier; however, the mechanism of neurologic injury related to heroin inhalation is unknown.

Since heroin leukoencephalopathy is observed less frequently among users who inject or snort heroin [3,4], it is possible that unknown toxins contained in the heroin pyrolysate (the product of chemical change caused by heating) are implicated in the condition [5]. However, the neuropathology was not replicated in rats exposed to this compound [2]. Triethyl tin (TET), a component of inorganic tin, was also suspected since TET poisoning results in vacuolar white matter edema [5,9], but an etiologic role for TET is unlikely, since the TET content in aluminum foil is negligible [5].

Aluminum toxicity has also been suspected as the etiology. However, when patients on dialysis were exposed to a contaminated water supply, the neurologic symptoms of aluminum toxicity differed from heroin leukoencephalopathy. Affected individuals presented with mental status changes and seizures, progressing, in some, to death [10]. An earlier pathology report of a fatal encephalopathy in dialysis patients linked the syndrome to aluminum accumulation in brain gray matter (unlike the white matter pathology seen in leukoencephalopathy) [11]. (See "Aluminum toxicity in chronic kidney disease", section on 'Acute encephalopathy'.)

Mitochondrial dysfunction may play a role in the development of heroin leukoencephalopathy, as suggested by mitochondrial changes in specimens from brain biopsy [2], by elevated lactate on magnetic resonance spectroscopy [5], and by the clinical improvement associated with antioxidant therapy that has been reported in a few patients [5]. (See 'Treatment' below.)

In this syndrome, parkinsonian symptoms may be caused by reversible inhibition of tetrahydrobiopterin metabolism; tetrahydrobiopterin is required for the conversion of tyrosine to levodopa, the precursor of dopamine, and for the conversion of tryptophan to serotonin [12].

EPIDEMIOLOGY — Despite the prevalence of heroin abuse, only 160 cases of leukoencephalopathy due to heroin inhalation (chasing the dragon) had been reported by the year 2018 [3]. However, inhaled heroin use may be on the rise. In a different review that identified 50 heroin abusers who developed leukoencephalopathy, the main route of use was inhalation (60 percent), but a substantial proportion used heroin by intravenous injection (30 percent) or snorting (10 percent) [4].

CLINICAL FEATURES — Heroin leukoencephalopathy has a variable clinical spectrum associated with a spongiform leukoencephalopathy.

Presentation and course — In a review of 50 patients with leukoencephalopathy associated with heroin use, cerebellar ataxia and dysarthria were the predominant symptoms in users who inhaled heroin, while altered mental status, mutism, and urinary or fecal incontinence were predominant in users who injected heroin [4].

The largest study, a 2018 review of the literature of patients with confirmed acute heroin inhalation leukoencephalopathy, identified 88 cases [3]. These were divided into three levels of clinical severity (mild, moderate, or severe [13]):

●A mild syndrome, characterized by inattentiveness, confusion, ataxia, and psychomotor symptoms, in 21 percent

●A moderate syndrome, characterized by corticospinal or extrapyramidal involvement and severe confusion or delirium, in 52 percent

●A severe syndrome, characterized by generalized motor impairment, apathy/abulia without language disorders or apraxia, and impaired alertness, in 27 percent; death ensued in two-thirds of these cases (see 'Prognosis' below)

In the initial cohort of 47 heroin vapor inhalers from the Netherlands, the leukoencephalopathy occurred in three stages [2]. In the first stage, the initial symptoms (in order of decreasing frequency) were:

●Soft/pseudobulbar speech

●Cerebellar ataxia

●Motor restlessness

●Apathy/abulia/bradyphrenia

After two to four weeks, approximately half of the patients progressed to the second (intermediate) stage, which was characterized by rapid worsening of cerebellar symptoms and additional features [2]:

●Pyramidal tract signs

●Hyperactive reflexes

●Spastic hemiplegia or quadriplegia

●Tremor and myoclonus

●Chorea and athetosis

A few weeks later, one-fourth of the initial cohort entered the terminal stage and developed the following symptoms before death ensued [2]:

●"Stretching spasms"

●Hypotonic/areflexic paresis

●Akinetic mutism

●Central pyrexia

Various features of parkinsonism, in some cases reversible, may be seen as early or late manifestations of heroin leukoencephalopathy [2,5,12]. These include bradykinesia, tremor, chorea, short festinating steps, masked facies, soft speech, cogwheel rigidity, and loss of postural reflexes.

Communicating and obstructive hydrocephalus, requiring neurosurgical intervention, have been described as complications of heroin inhalation in case reports [14,15].

Once symptoms develop, progression of disease can continue for a few weeks up to six months in the absence of continued exposure [2,5,16], a phenomenon called "coasting" [17].

While most individuals have had a subacute presentation, three patients presented with acute change in mental status requiring intubation (for airway protection) despite normal respirations [18]. The diagnosis of heroin-induced inhalation leukoencephalopathy was confirmed through history, laboratory testing, and imaging.

Neuroimaging — Brain MRI (image 1) shows diffuse, symmetrical white matter hyperintensities on T2 and fluid-attenuated inversion recovery (FLAIR) sequences in the cerebellum, posterior cerebrum, and posterior limbs of the internal capsule. There can be additional signal abnormalities in the splenium of the corpus callosum, the corticospinal tracts, the lemniscal pathway in the brainstem, and the hippocampus [5,19-22]. Increased signal in periventricular white matter may be present on diffusion-weighted images with corresponding low signal on apparent diffusion coefficient (ADC) maps [23], perhaps due to vacuolization rather than infarction. Most patients demonstrate T2 shine-through with increased ADC signal [24].

With heroin inhalation, a posterior-anterior gradient is typically seen in the supratentorial white matter, and the frontal lobes are therefore relatively spared [4,5]. However, with significant heroin abuse, there may be frontal lobe involvement.

Heroin inhalation by other modalities (ie, sniffing, snorting, or smoking) and intravenous heroin use may cause symmetric, confluent T2 and FLAIR hyperintense lesions on brain MRI in the frontoparietal white matter (often involving the subcortical U-fibers), centrum semiovale, and genu of the internal capsule [4,25-27]. The brainstem and cerebellum are often spared, distinguishing these abnormalities from the imaging characteristics observed in chasing the dragon.

Magnetic resonance spectroscopy abnormalities in three patients with heroin leukoencephalopathy included abnormally elevated lactate, suggesting mitochondrial dysfunction in the affected white matter and decreased levels of N-acetyl aspartate and choline in the white matter, gray matter, and cerebellum [5,22].

Laboratory — Electroencephalography in two severely affected patients showed moderate diffuse slowing with excess delta, consistent with a global encephalopathy [5].

Neuropathology — Pathologic data from autopsy cases as well as brain biopsies reveal spongiform degeneration of white matter with relative sparing of subcortical U-fibers, and vacuole formation in oligodendroglia and myelin sheaths visible with electron microscopy. Axons are typically spared, and demyelination is not a prominent feature. The deep white matter is edematous, but inflammation is absent. Mitochondria are also abnormal [5].

DIAGNOSIS — The diagnosis of heroin inhalation leukoencephalopathy is clinical and should be suspected in patients with a history of heroin use, especially if by inhalation, who present with acute or subacute onset of neurologic abnormalities. These may include one or more of the following features [2,5,19]:

●Cerebellar, pyramidal, or extrapyramidal signs

●Neurobehavioral changes, including confusion, apathy/abulia, or motor restlessness

●Mutism and/or incontinence

The diagnosis is supported by the characteristic neuroimaging findings (see 'Neuroimaging' above). A positive urine test for morphine is supportive of heroin use in the preceding 48 to 96 hours. The presence of the metabolite 6-monoacetylmorphine (6-MAM) is specific for heroin. However, 6-MAM is detectable for only two to eight hours after heroin use. Therefore, the absence of 6-MAM in urine that is positive for opioids does not rule out the use of heroin [3].

Diagnostic uncertainty is increased when the method of heroin abuse or history of exposure is unknown.

Proposed diagnostic criteria for heroin leukoencephalopathy due to inhalation (chasing the dragon) consist of the following [3]:

●Inclusion criteria:

•1) Presence of a clinical syndrome suggestive of leukoencephalopathy

•2) Positive heroin toxicology testing

•3) Heroin use confirmed by the patient, his or her next of kin, or a witness

•4) Supportive neuroimaging

•5) Neuropathology findings consistent with spongiform leukoencephalopathy

●Exclusion criteria:

•Confirmed history of acute intoxication or exposure to a toxin other than heroin that can cause a chasing the dragon-like outcome

•Overt clinical picture suggesting an infectious, demyelinating, vascular, or paraneoplastic cause

•Neuroimaging consistent with predominantly cortical involvement along with sparing of subcortical areas and posterior fossa

The diagnosis of chasing the dragon is considered definite if the patient fulfills all of the inclusion criteria; probable if the patient fulfills inclusion criteria 1 through 4, and possible if only inclusion criteria 1 through 3 are met, or if criteria 1 through 4 are met but are accompanied by confirmed polysubstance abuse or heroin abuse by multiple routes [3]. While postmortem neuropathology remains the gold standard for diagnosis, brain biopsy is discouraged in clinical practice.

DIFFERENTIAL DIAGNOSIS — Heroin addiction has been associated with a number of neurologic conditions [28], including brain abscess [29], transverse myelitis [30,31], neuropathy [32,33], and rhabdomyolysis with myoglobinuria [31,34,35]. However, these disorders are not likely to be confused with leukoencephalopathy.

Leukoencephalopathy — Leukoencephalopathy may occur after global anoxic-ischemic injury or after toxic exposure to a variety of agents, including the following [13,36]:

●Antineoplastic agents (cranial irradiation, methotrexate, carmustine, cisplatin, cytarabine, fluorouracil, levamisole, fludarabine, thiotepa, interleukin-2, interferon alfa)

●Immunosuppressive drugs (cyclosporine, tacrolimus)

●Antimicrobial agents (amphotericin B, hexachlorophene)

●Drugs of abuse (toluene, ethanol, cocaine, 3,4-methylenedioxymethamphetamine, intravenous heroin, inhaled heroin pyrolysate, psilocybin, benzodiazepines)

●Environmental toxins (carbon monoxide, arsenic, carbon tetrachloride)

The acronym "CHOICES" has been proposed as an aid to remembering the causes of acute toxic leukoencephalopathy [37]:

●C – Chemotherapy

●H – Heroin-induced

●O – Opioid analog use

●I – Immunosuppressant or imidazole medications

●C – "Crack" cocaine abuse

●E – Environmental (carbon monoxide) and ethanol-related

●S – Splenial lesions associated with use of antiseizure, chemotherapy, and immunosuppressant medications

Anoxic-ischemic injury — Global anoxia or ischemia, which can be precipitated by drug overdose or cardiopulmonary arrest, typically affects the gray matter in the cerebral cortex and various subcortical structures, such as the globus pallidus, with the cerebellum less frequently involved [38-40].

Cerebral white matter damage may occur with anoxic-ischemic injury, particularly after prolonged hypoxia and hypotension [39]. The radiologic appearance of white matter damage may be delayed [40]. Nevertheless, there are reports of early preferential involvement of white matter after anoxic-ischemic injury [41,42]. In addition, drug overdose from intravenous heroin use has been reported as a cause of anoxic-ischemic leukoencephalopathy [39].

Drugs of abuse — Varying degrees of white matter injury may be found in chronic abusers of heroin, alcohol, and toluene [13].

●Chronic alcohol abuse is associated with white matter damage. Alcohol abusers, including those with liver disease and Wernicke encephalopathy, lose a disproportionate amount of subcortical white matter compared with cortical gray matter. Marchiafava-Bignami disease is a rare disorder of demyelination or necrosis of the corpus callosum and adjacent subcortical white matter that occurs predominantly in malnourished individuals with alcohol use disorder. (See "Overview of the chronic neurologic complications of alcohol", section on 'Marchiafava-Bignami disease'.)

●Chronic toluene abuse from inhalation of vapor in glue ("glue sniffing"), paint, and paint thinner is associated with neurologic impairment, including dementia and selective white matter injury [43]. Widespread white matter hyperintensity is seen on brain MRI in severely affected patients with toluene leukoencephalopathy. (See "Inhalant misuse in children and adolescents".)

A case report described a severe diffuse leukoencephalopathy that followed methylenedioxymethamphetamine (MDMA, also called ecstasy) use and respiratory insufficiency [44]. However, the relative contribution of anoxic-ischemic injury compared with the leukoencephalopathy is unclear.

TREATMENT — There is no proven treatment for heroin leukoencephalopathy.

Empiric antioxidant therapy (with either coenzyme Q10 [300 mg four times a day] alone, or coenzyme Q10 in combination with vitamin E [2000 mg daily] and vitamin C [2000 mg daily]) has been used to treat nine patients with heroin inhalation leukoencephalopathy [5,19,45-48], with varying improvement in five and deterioration or no change in four [5,49].

Given these data, the absence of proven treatment, and the low likelihood of serious side effects, we suggest antioxidant therapy with the combination of coenzyme Q10, vitamin C, and vitamin E for patients with heroin leukoencephalopathy.

PROGNOSIS — The severity of disease probably depends on the duration and cumulative amount of heroin inhaled, as well as presence of comorbidities, including other substance abuse.

In the 2018 systematic review of heroin inhalation, with outcome data for 83 cases, 17 patients (20 percent) died; details of the cause of death were often unreported [3]. Nearly all the deaths occurred among the 24 patients with severe symptoms, where 16 (67 percent) died. Among 42 patients with moderate symptoms, only one patient (2 percent) died. There were no deaths among the 17 patients with mild symptoms.

Patients who survive often require physical and drug rehabilitation.

SUMMARY AND RECOMMENDATIONS

●"Chasing the dragon" is a method of heroin vapor inhalation that is distinct from smoking or sniffing heroin and is associated with leukoencephalopathy. (See 'Terminology and description' above.)

●The mechanism of neurologic injury related to heroin use is unknown. (See 'Pathogenesis' above.)

●Initial symptoms of heroin leukoencephalopathy include soft speech, ataxia, motor restlessness, bradyphrenia, and apathy/abulia. Some patients develop progressive disease with later occurrence of pyramidal signs, hyperactive reflexes, pseudobulbar palsy, spastic paresis, tremor, myoclonus, chorea, and athetosis. Severe disease is characterized by fever, akinetic mutism, spasms, hypotonia, areflexia, and death. (See 'Clinical features' above.)

●Brain magnetic resonance imaging (MRI) (image 1) shows diffuse, symmetrical white matter hyperintensities on T2 and fluid-attenuated inversion recovery (FLAIR) sequences with a posterior to anterior gradient of involvement; the frontal lobes may be relatively spared. (See 'Neuroimaging' above.)

●Neuropathology reveals spongiform degeneration; demyelination is not a prominent feature. (See 'Neuropathology' above.)

●The diagnosis of heroin inhalation leukoencephalopathy is clinical, and is supported by the characteristic neuroimaging findings. The differential diagnosis includes leukoencephalopathy following global anoxic-ischemic injury or exposure to other drugs of abuse. (See 'Diagnosis' above.)

●Although there is no proven treatment for heroin leukoencephalopathy, we suggest antioxidant therapy (Grade 2C). The suggested regimen is coenzyme Q10 (300 mg four times a day), vitamin E (2000 mg daily), and vitamin C (2000 mg daily). (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alan Percy, MD, who contributed to earlier versions of this topic review.