Diamorphine (heroin)

Progressive spongiform leukoencephalopathy

A rare consequence of inhaling heated heroin (“chasing the dragon”) is a progressive spongiform leukoencephalopathy. The first cases of leukoencephalopathy due to inhalation of heroin pyrolysate were described in the Netherlands in 1982. The first three cases in the USA were reported in 1996 [ ].

The condition has three stages, progressing from cerebellar signs and motor restlessness to pyramidal and pseudobulbar signs and, in a minority of patients (about 25%), to a terminal stage characterized by spasms, hypotonic paresis, and ultimately death. Symmetrical spongiform degeneration occurs, particularly in the cerebral and cerebellar white matter and in corticospinal and solitary tracts. Involvement of the cerebellum and the posterior limb of the internal capsule, with sparing of the anterior limb, appear to be characteristic, helping to distinguish this condition from other causes of leukoencephalopathy. Neuroimaging techniques contribute significantly to the management of such patients, as is evident from recent cases.

• A 16-year-old man was found at home drowsy 36 hours after smoking heroin for the first time [ ]. He had a gaze paresis and sensorimotor hemiplegia on the left side. A CT scan showed bilateral hypodense lesions in the globus pallidus. An MRI scan 5 days later showed symmetrical hyperintense signals in the T2 weighted images, along with a massive diffusion disorder in the diffusion weighted images. This was predominantly in the deep white matter of the parieto-occipital cortex. There were also bilateral hyperintense T2 signals in the ventral globi pallidorum. MR spectroscopy suggested combined hypoxic and mitochondrial damage, resulting in axonal injury without demyelination. He was discharged 1 month later with no hemiplegia. A follow-up MRI scan 6 months later showed improvement. There were no signs of brain atrophy.

According to the authors, this is first reported MRI follow-up study of acute leukoencephalopathy after a single inhaled dose of heroin. It most likely involved a complex mechanism triggered by heroin, causing mitochondrial and hypoxic injury limited to specific areas of the white matter of the brain.

• A 21-year-old man became unconscious after smoking heroin at a rave party and developed an aspiration pneumonia, bilateral pyramidal signs, and spastic paresis [ ]. He was given clonidine and midazolam, but continued to have daily episodes of stretching spasms, hyperventilation, profuse sweating, pyrexia, and mydriasis. He was given ubidecarenone 300 mg qds on day 14. A CT scan showed diffuse hypodensities in the white matter indicative of spongiform leukoencephalopathy. On day 30, he began to improve and an MRI scan showed diffuse abnormal lesions in the white matter. He gradually recovered and an MRI scan on day 59 showed less extensive lesions. At 7 months he had regained all functions but had a residual gait ataxia. A follow-up MRI scan showed recovery of the white matter, but some necrosis.

Another report has provided more details from physical assessments and laboratory and radiological (MRI and MRS) data, and more information about the course of this heroin-related effect [ ]. The three cases showed raised concentrations of intracerebral lactate (reflecting mitochondrial dysfunction), which suggests a conversion of aerobic to anaerobic metabolism seen in hypoxic-ischemic conditions, including stroke. One patient recovered quite well after antioxidant therapy, supporting a metabolic effect of the heroin-related toxin; a similar response to co-enzyme Q has been found in other mitochondrial disorders with a high CSF lactate. Thus, the authors recommended that although the role of antioxidant therapy in this condition is unclear, it may be prudent to administer oral co-enzyme Q supplemented with vitamins C and E to patients with this syndrome.

Intravenous administration of pure heroin did not cause a leukoencephalopathy in a patient in whom inhalation had caused it [ ], and toxicity in these cases may have been due to the heating of the heroin. This might have implications for young heroin users who, because of the known increased risk of HIV infection, prefer to “chase” (smoke) the drug, rather than to inject it intravenously.

• A 23-year-old pregnant woman at 39 weeks of gestation developed tonic-clonic seizures and hypothermia after taking excessive heroin intravenously [ ]. She developed Cheyne-Stokes respiration needing intubation and a cesarean section was performed, after which she developed inappropriate secretion of antidiuretic hormone and acute renal insufficiency. She made a complete recovery.

The mechanism of heroin-induced spongiform leukoencephalopathy is not known and the disease is not reproducible in animals. Suspicions have been raised about potential contaminants, such as strychnine, caffeine, phenacetin, quinine, and procaine. This man started inhaling heroin 2 weeks before the onset of the disease, but he used it in large amounts, raising the possibility that the severity of the disease is dose-related. In the two cases discussed above, the onset was abrupt, which is not usual. Antioxidant therapy, such as the use of ubidecarenone (coenzyme Q), is supported by its efficacy in previous cases and also because mitochondrial swelling has been reported in patients with such lesions. The authors stressed that there was a favorable outcome with prolonged and supportive care and the use of ubidecarenone, especially in a patient who developed stretching spasms, a feature that has been associated with a very high mortality rate. Because cases occur in clusters, even though many others who inhale heroin do not get this effect, there is suspicion about the possible role of contaminants of small batches of drug by an unknown substance. In addition, some have suggested that heating could be important, since leukoencephalopathy has not been reported with other means of heroin use (until this year, as reported in the next case). The authors of the report postulated that there might be a relation between the amount of heroin inhaled and the severity of the illness. Once symptoms develop, progression continues, usually for 2–3 weeks, but in some individuals it progresses for up to 6 months after exposure. “Coasting,” or the phenomenon of symptom progression after cessation of exposure to toxins, has been observed with other toxins, and it is proposed to result from the storage of toxin in lipid-rich neural or non-neural body tissues, with subsequent release into the bloodstream. Although the “toxin” involved in this condition is unknown, progression could be due to “coasting.” Alternatively, oxidative damage could be initiated by the toxin and produce persistent metabolic changes in the affected white matter. Whatever the mechanism, the illness is extremely grave, with no known treatment and with progression to akinetic mutism and death in about 20% of reported cases.

Spongiform leukoencephalopathy has been described in a 26-year-old after inhalation of heroin [ ]. The diagnosis was confirmed by MRI scan.

A cluster of five cases of toxic leukoencephalopathy over a span of 5 weeks after inhalation of heroin vapor has been reported, with details of three [ ].

• A 27-year-old man was found at home in a low state of consciousness after smoking heroin. He developed aphasia and spastic quadriparesis. A CT scan showed symmetrical white matter hypodensity in the cerebellum and symmetrical white matter hypoattenuation in the posterior limb of the internal capsule and optic radiations. An MRI scan showed white matter hypointensity in the cerebellum, with sparing of the cortex and dentate nuclei. There were also hyperintensities in the medial lemnisci and spinothalamic tracts. He died after a seizure 6 weeks later. An autopsy showed spongiform degeneration of the white matter that coincided with the MRI scans.

• A 39-year-old man developed bradykinesia and ataxia after smoking heroin. A brain MRI scan showed symmetrically increased signals in the white matter of the cerebellum, the peduncles, and the pons, with sparing of the dentate nuclei. There were abnormal signals in the posterior limb of the internal capsule and optic radiations. The signal abnormalities in this patient were not as pronounced as the previous one, who ultimately died. This patient was also taking methadone in a maintenance program.

• A 32-year-old man in a methadone program developed dysarthria, bradykinesia, and ataxia after smoking heroin. CT scans showed symmetric hypodensities in the cerebellum with sparing of the dentate nuclei. There were abnormal signals in the internal capsule and optic radiations., although not as extensive as in those who died.

These cases were typical of toxic leukoencephalopathy secondary to heroin inhalation. Moreover, they had symptoms involving both cerebellum and non-cerebellar structures.

In two reports from China 10 cases (nine men and one woman) of heroin-induced spongiform leukoencephalopathy have been reviewed. The first report discussed six cases with cerebellar signs and symptoms, with symmetrical lesions on neuroimaging in the white matter of the cerebellum, basal ganglia, posterior crus of the internal capsule, and the semi-oval center [ ]. The second report, described four cases that occurred during the abstinence period and showed improvement after 4 weeks of comprehensive treatment [ ].

Two cases of possible toxic leukoencephalopathy following probable inhalation of heroin vapor have been reported [ ].

• A 55-year-old man developed confusion, behavioral change, aggression, poor attention, disorientation in time, and impaired short-term memory. He had full ocular movements with no nystagmus, brisk deep tendon reflexes, and bilateral extensor plantar responses. He became progressively drowsy with myoclonic jerks and died 2 weeks later.

• A 36-year-old man with a history of substance abuse became unresponsive, with his eyes in mid-position gaze, with pinpoint pupils, brisk deep tendon reflexes, and bilateral extensor plantar responses. On day 9 he spontaneously opened his eyes. However, he died 1 month later with persistent pyrexia from methicillin resistant Staphylococcus aureus .

Neuroimaging and neuropathology in both cases showed diffuse symmetrical degeneration of white matter, with sparing of subcortical U fibers, cerebellum, and brain stem. Toxicology was negative, but was done some time after the report of substance use. In these case reports heroin use could not be confirmed. Although the findings suggested the possibility of heroin toxicity due to inhalation, sparing of the cerebellum and brain stem, frontal predominance of degeneration, and the more prominent axonal involvement are not typical of heroin toxicity, throwing speculation on an unidentified impurity.

• A 37-year-old male cocaine abuser was admitted with intoxication, mutism, and substupor [ ]. His toxicological screening was positive for heroin and cocaine. There was spasticity of all limbs and Babinski reflexes. The CSF contained some erythrocytes. The electroencephalogram showed generalized slowing, and a CT scan showed bifrontal confluent hypodensities in the deep white matter. The cranial MRI scan showed diffuse bihemispheric white matter lesions dominantly in the frontal lobe on T2-weighted images. There were abnormal hyperintense lesions in the pyramidal tracts and the corpus callosum. He gradually improved and made a complete recovery within 6 months, as confirmed by neurological and neuropsychological examination.

The findings of toxic leukoencephalopathy in this patient’s brain-imaging studies were similar to those reported in patients who have inhaled impure heroin. However, he had used intravenous heroin and cocaine. This is therefore the first case report of leukoencephalopathy after intravenous use of these drugs. However, it should be noted that the authors did not indicate how the route of drug use was confirmed. They noted that lipophilic substances, such as hexachlorophene or triethylthin, were likely impurities in the abused substances.

• A 53-year-old man with a 7-year history of heroin abuse presented with confused speech and unsteady gait [ ]. A CT scan showed low attenuation in the white matter tracts and an MRI scan showed increased signal intensity in the white matter tracts extending from the centrum semiovale, corpus callosum, corona radiata, posterior limbs of the internal capsules, cerebral and cerebellar peduncles, and pyramidal tracts, suggestive of spongiform demyelination. He became bed-bound and tetraplegic and died of a chest infection.

• A 37-year-old man, with a short history of heroin and cocaine use, presented with spasticity of all limbs, a confusional state, and mutism [ ]. The electroencephalogram, CT scan, and MRI scan showed predominantly positive frontal pathology, with other lesions in the pyramidal tracts and corpus callosum. The diagnosis was leukoencephalopathy. The symptoms gradually abated after 4 weeks, and repeat tests after 6 months shown to be normal.

Three cases of toxic and progressive spongiform leukoencephalopathy have also been reported as a result of vapor inhalation of heroin [ ]. There were generalized white matter abnormalities and pathology in the cerebellum, internal capsule, corpus callosum, and brain stem.

Heroin-induced leuckoencephalopathy has been misdiagnosed as psychiatric illness [ ].

• A 47-year-old woman, with a history of amphetamine abuse, depression, and paranoia, smoked heroin for 4 weeks after stopping amphetamines, and 10 days later became drowsy and confused with increased paranoia and depression. She was disoriented and restless. Her speech was garbled. She had frequent non-purposeful movements and an unsteady gait. A CT brain scan was normal. She was given chlorpromazine, doxepin, and diazepam, but her ataxia and incontinence worsened, her speech and all her movements slowed, with increased tone in all limbs and cogwheel rigidity. Her power and sensation were normal. Truncal ataxia impaired walking. An MRI brain scan showed diffuse high-intensity signals in both cerebral hemispheres, and review of the CT scan showed hypodensities in the same regions. She was treated with co-enzyme Q and regained mobility and continence, but with no improvement in cognitive impairment.

Progressive myelopathy

Another form of brain injury, progressive myelopathy, has been reported after inhalation of heroin vapor [ ].

• A 46-year-old man chronically abused heroin through inhalation and developed a gait disorder with paresthesia of the legs, incontinence, and impotence. MRI scans showed bilateral subcortical lesions and bilateral signal abnormalities in the corticospinal tract and posterior columns. Motor evoked potentials were slow, with prolonged F wave latency, which is evidence of peripheral nerve disease. Multivitamins and high doses of prednisone did not produce benefit.

This condition was diagnosed as progressive myelopathy affecting only the corticospinal tract and posterior columns, the characteristics of which differ from acute leukoencephalopathy significantly, although both are serious consequences of heroin inhalation. Progressive myelopathy has been reported after heroin insufflation but never after inhalation of vapors. The authors favored an immune mechanism.

Cerebellar lesions

Symmetrical deep cerebellar lesions have been associated with heroin smoking [ ].

• A 40-year-old man presented to the emergency room after smoking heroin on 2 consecutive days. He complained of unsteadiness and clumsiness. While speaking to a nurse, his condition dramatically worsened, and he became severely ataxic, dysarthric, and clumsy and was unable to stand. An MRI scan showed symmetric bilateral “C-shaped” lesions in the white matter and dentate nuclei of the cerebellum. The diagnosis was toxic leukoencephalopathy secondary to inhaled heroin. Six months later, his cerebellar dysfunction was unchanged.

Because of clustering of cases, it was thought that an additive in the heroin had brought on the symptoms.

Parkinsonism

Reversible Parkinsonism from heroin vapor inhalation has been reported [ ].

• A 38-year-old Caucasian woman, who had taken heroin vapor 2 weeks before, developed confusion, ataxia, and urinary incontinence. She was afebrile and spoke with a slow low-volume monotonous voice. She had marked truncal ataxia with absent postural reflexes, cogwheel rigidity in her limbs, and marked bradykinesia. She had used non-prescription amfetamine up to 4 g/day intermittently for 8 years. After a bout of depression, she came under the care of a psychiatrist and stopped taking amfetamine after she was given chlorpromazine and diazepam. She then started using heroin. In the CSF, protein was raised with normal glucose and lactate; homovanillic acid, a dopamine metabolite, was markedly reduced and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was mildly reduced. Tetrahydrobiopterin was just detectable. She was given co-enzyme Q 30 mg tds and became more alert and began to move and talk. She had recovered fully 1 month later.

According to the authors tetrahydrobiopterin has a range of co-factor roles, including being required for the activity of tyrosine and tryptophan hydroxylase, enzymes that are essential for dopamine and serotonin synthesis. They speculated that something present in the heroin pyrolysate, a product formed when heroin is heated to 250 °C, inhaled by the patient, acted as a reversible inhibitor of tetrahydrobiopterin metabolism, providing a biochemical explanation for impairment of dopamine metabolism and Parkinsonism in this case.