Stroke and Substance Abuse

Opioids

The most commonly abused opioid drugs are heroin (diacetylmorphine) and, prominently in the current worldwide opioid epidemic, prescription opioids (especially oxycodone), fentanyl and numerous fentanyl analogs, as well as novel “designer” opioids. Published reports of stroke have involved heroin, which can be injected, snorted, or smoked. Stroke affects heroin users via diverse mechanisms.

Injectors are at risk of infectious endocarditis and consequently both ischemic and hemorrhagic stroke. Infarction follows embolic vessel occlusion or, less often, bacterial or fungal meningitis. Cerebral or subarachnoid hemorrhage usually occurs after the rupture of a septic (mycotic) aneurysm, which can affect intracranial or cervical arteries. ^, Heroin users are also at risk for hemorrhagic stroke secondary to liver failure with deranged clotting and to heroin nephropathy with uremia or malignant hypertension.

In some heroin users, the drug itself appears to be more directly causal. Anecdotal reports describe young people without evident stroke risk factors whose ischemic strokes occurred temporally with heroin use. Some had angiographic changes suggestive of vasculitis, and some had immunologic changes suggestive of hypersensitivity. Opioid withdrawal symptoms and cerebral infarction were reported in two newborns whose mothers had used codeine during pregnancy. Intracerebral hemorrhage (ICH) has also followed heroin use. ^,

Heroin could cause stroke directly by a number of possible mechanisms. After heroin overdose, hypoventilation and hypotension can produce permanent brain damage. Delayed post-anoxic encephalopathy also occurs. Bilateral globus pallidus infarction is commonly observed at autopsy in heroin users, ^, and hemichorea and bilateral ballism are described in heroin users with pallidal infarction on imaging. ^{, ,} In some cases, an awkward position of the neck during overdose coma might have kinked the carotid artery and further decreased cerebral perfusion. Three days after injecting heroin, a young man developed hemiparesis, and angiography showed reversible bilateral segmental narrowing of the supraclinoid internal carotid, middle cerebral, and anterior cerebral arteries.

Direct toxic injury from either heroin or an adulterant is another possibility. Heroin has often been mixed with quinine and lactose or mannitol; other reported adulterants include talc, starch, curry powder, abrasive cleanser, caffeine, and strychnine. Quinine caused amblyopia in a heroin addict and might contribute to acute adverse reactions with pulmonary edema or sudden death after parenteral injection. However, there is no evidence linking quinine to stroke.

Embolization of foreign material to the brain has not been observed in parenteral heroin users (even though the jugular vein is commonly used, with occasional accidental arterial injection) but has been documented at autopsy in abusers of other opioids. ^, Probably because of restricted heroin supply, pentazocine (Talwin) and tripelennamine (Pyribenzamine; “Ts and blues”) were widely abused in American midwestern cities during the 1970s. Oral tablets were crushed, suspended in water, and injected intravenously, leading to microembolic cerebral infarcts and hemorrhages. Strokes were also reported following injection of paregoric, of pulverized meperidine tablets, and of hydromorphone suppositories.

Some heroin-related strokes follow the first injection after weeks or months of abstinence, and laboratory findings sometimes suggest an immunologic cause. Heroin nephropathy may be immunologically mediated; the C3 component of complement is reduced in patients with heroin pulmonary edema; and heroin addicts frequently have hypergammaglobulinemia, circulating immune complexes, antibodies to smooth muscle and lymphocyte membranes, false-positive serologic tests, and lymph node hypertrophy. Opium, morphine, codeine, and meperidine, moreover, have caused urticaria, angioneurotic edema, and anaphylaxis. Morphine binding by gamma globulin is reported in addicts and experimental animals.

Relevant to heroin stroke is heroin myelopathy. Acute paraparesis, sensory loss, and urinary retention occur shortly after injection, frequently after a period of abstinence. In some patients, symptoms are present on awakening from coma. Proprioception and vibratory sense are often preserved relative to loss of spinothalamic sensory modalities, suggesting infarction in the territory of the anterior spinal artery. ^, Possible mechanisms include “border-zone” infarction during a period of coma, hypoventilation, and hypotension, as well as hypersensitivity reaction. ^, A man using intravenous heroin for the first time in 2 years became comatose and apneic; after he received an opioid antagonist, quadriplegia, anarthria, dysphagia, and sensory loss consistent with a ventral pontine lesion developed over several hours.

Amphetamine and Related Agents

During the 1990s, methamphetamine became the fastest-growing illegal drug in North America and parts of Europe. Swallowed, injected, snorted, or smoked, methamphetamine is often taken with heroin, and samples contain a variety of pharmacologically active and inactive adulterants. Strokes common to any parenteral drug abuse are encountered. There are also strokes that may be unique to these agents.

In animals and humans, amphetamine overdose can cause severe hyperthermia, coagulopathy, and vascular collapse, with brain petechiae and neuronal degeneration. Intracranial hemorrhage is often a feature of heat stroke. ^, Amphetamine/methamphetamine users are also at risk for intracranial hemorrhage in the absence of hyperpyrexia and disturbed clotting.

Hemorrhagic stroke in abusers of amphetamine or methamphetamine has followed oral, intravenous, nasal, and inhalational routes of administration. Most were chronic users, but in some, stroke followed a first exposure. The dose was usually unknown but, in one case, was as low as 80 mg. In addition to amphetamine or methamphetamine, some patients also took methylphenidate, lysergic acid diethylamide (LSD), dimethoxymethylamphetamine (“STP”), cocaine, heroin, or barbiturates. Severe headaches usually occurred within minutes of drug use. Blood pressure was elevated in the majority of patients in whom it was recorded, with diastolic pressure as high as 120 mm Hg. Hemorrhagic stroke was fatal in a third of cases. Computed tomography (CT) variably showed ICH (frequently lobar) or subarachnoid hemorrhage. In some patients, angiography revealed irregular narrowing (beading) of distal cerebral arteries, suggesting (but not pathognomonic for) vasculitis. Angiography also showed vascular malformation or saccular aneurysm. In one series, a ruptured aneurysm was present in a third of 37 cases of hemorrhagic stroke.

Thus some of these amphetamine/methamphetamine-induced intracranial hemorrhages seem to have been secondary to acute hypertension, some to cerebral vasculitis, and some to a combination of the two; however, in others neither feature was apparent. A case report described cerebral vasculitis at autopsy after methamphetamine-associated ICH. Another autopsy report of methamphetamine-associated ICH found no evidence of vasculitis. Although acute hypertension secondary to amphetamine could be causal, it might have been a transient result of the stroke in some patients. Conversely, in other patients, fleeting blood pressure elevations could have been missed.

Amphetamine and methamphetamine-associated ischemic strokes have been less frequently reported.

Two epidemiologic studies addressed the association of amphetamine/methamphetamine and stroke. In a population-based case-control study of women aged 15–44 years, amphetamine/methamphetamine was a risk factor for combined hemorrhagic and ischemic stroke (odds ratio [OR], 3.8). Some women in that study used both cocaine and amphetamine/methamphetamine, and drug use was based on self-report at a later interview; claims did not always match what was recorded in the medical record, including positive results on urine drug screening. Hospitalized control subjects, moreover, did not undergo drug screening, and if they were even less likely than case patients to report drug use, the risk of stroke might be exaggerated. A case-control study using a cross-sectional design based on more than 3 million patients discharged from Texas hospitals over a 3-year period found that amphetamine/methamphetamine increased the risk of hemorrhagic stroke (OR, 4.95) but not ischemic stroke.

Amphetamine-induced cerebral vasculitis appears to be of more than one type. Necrotizing angiitis, sometimes affecting the nervous system, occurred in 14 Los Angeles polydrug abusers. All but two patients used intravenous methamphetamine, and one used it exclusively. Systemic symptoms included fever, skin rash, pulmonary edema, renal failure, pancreatitis, gastrointestinal hemorrhage, peripheral neuropathy, anemia, leukocytosis, and hemolysis. One patient had “progressive encephalopathy” and, at autopsy, vasculitis affecting pontine arterioles. Another had cerebral and pontine infarction, cerebellar hemorrhage, and vasculitis in the cerebrum, cerebellum, and brain stem. Vessel lesions were considered typical for polyarteritis nodosa and different from hypersensitivity angiitis, which involves small arteries, capillaries, and venules. ^,

Although such brain lesions have been found pathologically in other amphetamine/methamphetamine abusers, ^, in some, cerebral arteritis has been presumed on the basis of cerebral angiography, ^a and sometimes the relation to amphetamine abuse has been tenuous. In a report of thalamic infarction following intranasal methamphetamine use, angiography was not performed.

a References 74, 75, 79, 89, 99, 127–130.

A radiographic study of 19 young drug abusers, most taking intravenous methamphetamine and hospitalized for coma or stroke, revealed widespread segmental constrictions of large and medium-sized cerebral arteries and stenosis or occlusion of many penetrating arterioles (beading). Such a finding could reflect multiple emboli, vasculitis, or spontaneous segmental vasoconstriction. The same researchers gave rhesus monkeys intravenous methamphetamine, 1.5 mg/kg (considered the lower limit of dosage for most abusers). Cerebral angiography showed an irregularly decreased caliber of small cerebral vessels, and postmortem examination revealed subarachnoid hemorrhage in some animals, with numerous brain petechial hemorrhages, infarcts, edema, microaneurysms, and perivascular white-blood-cell cuffing. ^,

In rats receiving 2 weeks of intravenous methamphetamine, electron microscopy showed that brain capillaries had abnormal “budding” from the luminal walls of endothelial cells and vesicles within the endothelial cell cytoplasm. These changes affected vessels smaller than 100 μm and thus would be missed on angiography. (The vulnerability of small vessels might be related to their separate innervation; large cerebral vessels are innervated by the peripheral sympathetic nervous system, but nerve terminals on smaller arteries appear to be from central noradrenergic neurons. )

These lesions are different from those of polyarteritis nodosa, in which elastic arteries, capillaries, and veins are spared. Whether the lesions in methamphetamine users are the result of direct toxicity or hypersensitivity is unclear, nor can the possibility be excluded that the early angiographic findings are secondary to subarachnoid hemorrhage (although beading of distal pial arteries in subarachnoid hemorrhage is rare). Possibly contributing to methamphetamine-related vasculitis is the formation of circulating “advanced glycation end products” with proinflammatory immunoreactive properties.

In an adolescent amphetamine abuser with mononeuritis multiplex, sural nerve biopsy showed apparent hypersensitivity angiitis of medium and small muscular arteries, arterioles, venules, and veins. The central nervous system, however, was clinically unaffected.

In two reported series of methamphetamine-associated stroke, cerebral vasculitis was notably absent. ^,

A study using single-photon emission CT (SPECT) found reduced cerebral blood flow in the cingulate cortex of both long-term and short-term abstinent methamphetamine users.

In mice, pretreatment with methamphetamine exacerbated damage after middle cerebral artery ligation.

Amphetamines cause direct myocardial toxicity with contraction band necrosis, and arrhythmia and thrombosis can cause cardioembolic stroke.