Toxic Encephalopathy

Main Text

Preamble

The list of toxins and poisons that affect the CNS is long and continues to grow. Some agents are deliberately injected, inhaled, or ingested, whereas others are accidentally encountered or administered in a controlled medical setting. Some toxins accumulate slowly, so their clinical manifestations are subtle and onset insidious. Others cause profound, virtually immediate CNS toxicity with rapid onset of coma and death. Still, others—such as ethanol—have both acute and chronic effects.

Use of “street” drugs, opioids, synthetic “designer” drugs and the emergence of fentanyl are fueling a worldwide epidemic. Overdoses (ODs) are increasingly common. An accurate history is often difficult to obtain in patients with suspected OD, and clinical symptoms are frequently nonspecific. Presentation may also be confounded by “polydrug” abuse and secondary effects, such as hypoxia, that mask the underlying pathology.

The vast majority of toxins with CNS manifestations cause bilateral, relatively symmetric lesions. Symmetric abnormalities in the deep gray nuclei (basal ganglia, thalamus) with varying white matter (WM) involvement are suggestive of toxic-metabolic etiologies.

In this chapter, we first focus on the most common types of toxic encephalopathies, beginning with the acute and long-term effects of alcohol and similar substances on the brain together with a discussion of Wernicke encephalopathy (WE). We follow with a consideration of drug abuse. Inhaled gases and toxins (such as carbon monoxide and cyanide) and heavy metal poisoning are then considered. We conclude with a brief discussion of treatment-related disorders.

Alcohol and Related Disorders

Preamble

Alcohol [ethanol (EtOH)] is one of the most commonly abused substances in the world, estimated to affect 4% of the global population. The most recent Diagnostic and Statistical Manual of Mental Disorders (DSM5) estimates that in the USA, 36% of the male and 23% of the female population met the DSM criteria for alcohol use disorder (AUD) at least once during their lifetime.

AUD can affect more than 60 bodily systems, causing different effects on different organs. Although the gastrointestinal system is exposed to higher concentrations of alcohol than any other tissue, ethanol easily crosses the blood-brain barrier and is a potent neurotoxin. Both its short- and long-term effects on the CNS are profound.

We begin our discussion of alcohol and the brain by briefly considering the acute effects of alcohol poisoning. We then consider chronic alcoholic encephalopathy before turning to other complications of alcohol abuse, including alcohol-induced demyelination syndromes and Wernicke encephalopathy (WE).

We close this section with two less common forms of related abuse, i.e., methanol intoxication and ethylene glycol (antifreeze) ingestion.

Acute Alcohol Poisoning

Etiology

Acute EtOH exposure has deleterious effects on neuronal activity across the striatum, hippocampus, cerebellum, amygdala, substantia nigra, and ventral tegmental area. EtOH also drives changes in both GABAergic and glutamatergic signaling, leading to changes in long-term potentiation and depression across the entire CNS. Significant changes in neuronal networks and depression of glymphatic function, impaired normal immune cell function, increased inflammation, and aberrant microglia activation are also associated with acute EtOH exposure.

EtOH effects can be modulated by many factors, including age when drinking. The acute effects of binge drinking—and its complication, acute alcohol poisoning—are striking. EtOH inhibits Na+/K+ activity. Cellular swelling, life-threatening cytotoxic cerebral edema, and nonconvulsive status epilepticus may ensue (35-1). A blood alcohol concentration of 0.40% typically results in unconsciousness, and a level exceeding 0.50% is usually lethal.

Acute alcohol poisoning is a complication of binge drinking and is most common in adolescents and young adults. The adolescent brain is also still undergoing structural maturation and has a unique sensitivity to alcohol. Binge drinking-induced neurotoxicity damages the cortical and subcortical brain microstructure, especially in areas of the prefrontal and parietal regions that mediate reward-related motivation.

Co-use of ethanol with CNS depressant recreational drugs increases the adverse effects of both. Lower Glasgow Coma Scale (GCS) score, agitation/aggression, hypotension, and increased admission to intensive care units are significantly correlated with co-use of ethanol and recreational drug use.

Imaging

Imaging findings in patients with acute alcohol poisoning include diffuse brain swelling and confluent hyperintensity in supratentorial subcortical and deep WM on T2/FLAIR (35-2). Seizure-induced changes in cortex with gyral hyperintensity and diffusion restriction may also be associated.

Chronic Alcoholic Encephalopathy

The long-term adverse effects of ethanol on the brain are much more common than those of acute alcohol poisoning. These effects are even more pronounced in immature brains. Even moderate repeated alcohol consumption can adversely affect the developing functional architecture of adolescent brains.

AUD in adults causes increased apoptosis, dysregulated synaptic connectivity, and widespread volume loss throughout the brain, especially in the middle frontal, cingulate, superior temporal and cerebellar cortices.

Chronic alcohol-related brain damage can be divided into primary and secondary effects. We begin our discussion with the effects of EtOH itself on the brain and then consider secondary remote effects, which are mostly related to the sequelae of liver disease, malnutrition, malabsorption, and electrolyte disturbances.

Etiology

As ethanol readily crosses the blood-brain barrier, both direct and indirect neurotoxicity may ensue. Upregulation and expression of inflammatory factors contribute to CNS hyperexcitability and aberrant excitotoxicity. Longer-term neurotoxic effects include neuronal loss and reduction of WM volume.

Pathology

Chronic excessive EtOH consumption causes brain atrophy, evidenced by enlarged ventricles and sulci (35-6). Alcohol-induced cerebellar degeneration is also common. The folia of the rostral vermis and anterosuperior aspects of the cerebellar hemispheres are atrophic, seen as widened interfolial sulci.

Imaging

CT Findings

NECT scans show generalized ventricular and sulcal enlargement (35-3A). The great horizontal fissure of the cerebellum and the superior vermian folia are unusually prominent relative to the patient’s age (35-3) (35-4).

MR Findings

Overall brain volume loss, especially in the prefrontal cortex, is common as is more focal atrophy of the superior vermis (35-5). Volumetric studies show selective frontal, parietal, and temporal gyri are affected along with the insula, cingulate cortex, hippocampus, thalamus, and pallidum. Focal and confluent cerebral WM hyperintensities on T2/FLAIR sequences are frequently present.

DTI may demonstrate low fractional anisotropy (FA) and increased mean diffusivity, reflecting compromised fiber tract integrity. The frontal and superior tracts are most affected with relative sparing of posterior and inferior tracts.

MRS may show reduced NAA:tCr and Cho:tCr ratios in the frontal and medial temporal lobes, cerebellum, and thalami. Metabolic changes associated with AUD may normalize with discontinuation of alcohol consumption.

Chronic liver failure secondary to cirrhosis may cause basal ganglia hyperintensity on T1WI, probably secondary to manganese accumulation. Increased iron deposition in the basal ganglia and dentate nuclei may also occur.

Marchiafava-Bignami Disease

Marchiafava-Bignami disease (MBD) is a rare disorder characterized by osmotic demyelination (and later necrosis) of the corpus callosum (35-7). MBD is seen most frequently in patients with a history of severe alcohol abuse but can also occur in nonalcoholic patients with malnourishment, poorly controlled diabetes mellitus, or osmotic stresses.

Terminology

MBD is also (incorrectly) known as “red wine drinkers’ encephalopathy.”

Etiology

Alcohol-induced neurotoxicity is the most common associated condition. Vitamin B complex deficiency (i.e., all eight B vitamins, in contrast to the more specific B1 deficiency of WE) has been reported in nonalcoholic patients.

Pathology

Myelinolysis with selective involvement of the middle layers of the corpus callosum along its entire length is strongly suggestive of MBD (35-9). Cases with extracallosal extension into the hemispheric WM, basal ganglia, internal capsule, and middle cerebellar peduncles have been reported.

Clinical Issues

MBD is rare. Most reported cases are found in middle-aged men (40-60 years old). A history of malnutrition and alcohol dependence with neuropsychiatric symptoms is common.

The clinical diagnosis of MBD is difficult and often confused with WE, so diagnosis is mainly based on imaging manifestations.

Three clinical subtypes of MBD based on acuteness of onset and disease progression have been described. Acute-onset MBD presents with sudden loss of consciousness, seizures, and rapid progression to coma. Subacute forms have varying prodromes ranging from depression to ataxia or spasticity. Chronic MBD presents as a progressive dementia with behavior abnormalities, hallucinations, and delusions.

Imaging

General Features

Imaging findings vary with disease stage. The early stages of MBD are characterized by diffuse edema and swelling of the corpus callosum. The subacute and chronic stages are characterized by diffuse volume loss and selective necrosis of the middle layers of the corpus callosum spreading from the genu through the body to the splenium.

CT Findings

CT may be normal in acute MBD. Chronic MBD shows linear hypodensity in the corpus callosum that, in the setting of chronic AUD, is highly suggestive of the diagnosis (35-8A).

MR Findings

Imaging findings vary with disease stage. The early stages of MBD are characterized by diffuse callosal swelling with T1 hypo- and T2 hyperintensity. Acute MBD is best seen on sagittal FLAIR. Hyperintensity in the genu and frontoparietal cortex appear first and are followed by extension into the splenium. Involvement of the adjacent hemispheric WM and basal ganglia occurs but is less common.

Acute lesions of the corpus callosum and adjacent deep WM may exhibit petechial hemorrhages, restrict on DWI, and enhance on T1 C+(35-10). Both solid and ring-enhancing patterns have been reported (35-11).

Chronic MBD with frank callosal necrosis is seen as thinning of the corpus callosum on sagittal T1WI with linear hypointensities in the middle layers (35-8B). T2* GRE or SWI sequences may demonstrate multiple microbleeds in the cortical-subcortical WM and corpus callosum. DTI shows a substantial decrease in fibers crossing through the corpus callosum. Other changes associated with chronic alcohol abuse, such as cortical, cerebellar, and mammillary body atrophy, are common.

Differential Diagnosis

The main differential diagnosis of acute MBD is WE. WE and acute MBD may coexist. Involvement of the medial thalami and periaqueductal gray matter as well as the mammillary bodies is more common in WE. In the setting of AUD, volume loss with necrosis of the middle layers of the corpus callosum is highly suggestive of chronic MBD.

Other diseases that may affect the corpus callosum include multiple sclerosis and other demyelinating disorders, traumatic axonal injury, and lacunar infarction (rare because of rich blood supply). All have patchy, discontinuous lesions and rarely involve the entire length of the corpus callosum.

Methanol Intoxication

Methanol (MtOH) is a strong CNS depressant. Patients are often comatose, and an accurate history may be impossible to obtain. Moreover, few hospitals include methanol in their standard toxicology screens. Therefore, delayed diagnosis is common, and morbidity and mortality remain high.

Etiology

MtOH intoxication typically occurs as accidental ingestion of adultered illicit spirits (“moonshine”) containing methanol. Rumored efficacy of ingesting alcohol, disinfectants, or sanitizers in an attempt to prevent or cure infection during the COVID-19 epidemic resulted in a worldwide spate of cases with methanol poisoning.

Methanol is metabolized to formic and lactic acid, causing high anion gap severe metabolic acidosis and end-organ damage with arterial pHs ranging from 6.8 to 7.1. Formic acid inhibits cytochrome oxidase and disrupts oxidative phosphorylation.

Pathology

Hemorrhagic and nonhemorrhagic bilateral basal ganglia necrosis is the most characteristic feature of MtOH poisoning. Selective putamina involvement with relative sparing of the globi pallidi is common (35-12). Diffuse necrosis of the subinsular and subcortical WM as well as the cerebellum and optic nerves may occur in severe cases. Hemorrhagic transformation is variable and can occur immediately or as a delayed phenomenon.

Clinical Issues

The triad of visual impairment, gastrointestinal symptoms, and metabolic acidosis occur in 6-24 hours following methanol ingestion. Increased anion and osmolar gaps are important laboratory clues to the presence of MtOH toxicity. Approximately 25% of cases are comatose at presentation and may not be able to provide a suggestive history of MtOH intoxication.

Imaging

CT Findings

The initial NECT scan is often normal in many patients with MtOH poisoning. Most patients who survive for more than 24 hours demonstrate bilateral symmetric hypodense lesions in the putamina, globi pallidi, and sometimes the subcortical and deep cerebral WM (35-14A). Hemorrhagic putaminal necrosis is seen in 15-45% of cases. If the patient survives, cystic cavities may form within the putamina, representing the chronic sequelae of MtOH poisoning (35-16).

MR Findings

Bilateral putaminal and basal ganglia necrosis with variable WM involvement is present. T2/FLAIR hyperintensity is seen (35-14B). Up to 25% of patients exhibit “blooming” hemorrhagic foci on T2* GRE or susceptibility imaging (35-13).

DWI shows restricted diffusion in the acute stage of MtOH poisoning. MRS shows reduced NAA and markedly elevated lactate (35-15).

Differential Diagnosis

Bilateral symmetric putaminal lesions are not specific for MtOH and can be seen in Wilson disease and the mitochondrial encephalopathies. Hypoxic-ischemic encephalopathy involves the caudate and other deep gray nuclei in addition to the putamina. Acute cyanide poisoning is rare but can resemble MtOH encephalopathy. Carbon monoxide poisoning generally affects the globi pallidi rather than the putamina.

Ethylene Glycol Poisoning

Ethylene glycol is the third most common chemical responsible for deaths by nonpharmaceutical poisoning (following ethanol and carbon monoxide).

Ethylene glycol is a poisonous form of alcohol that is a common ingredient in many household products, such as antifreeze, deicing solutions, and windshield wiper fluids. It can be accidentally ingested by children and animals. Intake of even a small volume can be lethal.

Imaging findings of acute ethylene glycol toxicity include symmetric edema in the basal ganglia, thalami, midbrain, and upper pons. Symmetric hyperintensity in these areas on coronal T2/FLAIR scans has been likened to an Olympic torch (35-17).

Wernicke Encephalopathy

Terminology

Wernicke encephalopathy (WE) is also known as Wernicke-Korsakoff syndrome. WE is a neuropsychiatric syndrome caused by thiamine deficiency.

Etiology

Both alcohol-related and nonalcoholic WE can occur! WE is caused by thiamine (vitamin B1) deficiency. Approximately 50% of WE cases are AUD-related nutritional deficiencies with inadequate thiamine intake, decreased gastrointestinal absorption, &/or poor intracellular thiamine utilization.

Nonalcoholic WE may occur with hyperemesis (pregnancy- or chemotherapy-related vomiting), eating disorders, bariatric surgery, and prolonged hyperalimentation. A WE-like encephalopathy has also been reported with some drugs, including antineoplastic agents.

Pathology

The mammillary bodies, hypothalamus, medial thalamic nuclei (adjacent to the third ventricle), tectal plate, and periaqueductal gray matter are most commonly affected (35-18). Less commonly involved areas include the cerebellum (especially the dentate nuclei), red nuclei, corpus callosum splenium, and cerebral cortex.

Demyelination and petechial hemorrhages are common in the acute stage of WE. Callosal necrosis, WM rarefaction with brain volume loss, and mammillary body atrophy can be seen in chronic WE.

Clinical Issues

Alcohol abuse is the most common cause of WE. However, almost 1/2 of all WE cases occur in nonalcoholics. Although nonalcoholic WE is generally more common in adults, it can and does occur in children.

The underlying pathophysiology of nonalcoholic WE is identical to that of alcoholic WE, but the etiology is different. Malnutrition secondary to hyperemesis gravidarum (pregnancy-related vomiting), eating disorders, parenteral therapy, or bariatric surgery with drastically reduced thiamine intake is typical. Hyperemesis (e.g., pregnancy, chemotherapy) and prolonged hyperalimentation are other common causes of nonalcoholic WE.

WE can be challenging to diagnose clinically or biochemically. Only 30% of patients demonstrate the classic WE clinical triad of (1) oculomotor dysfunction (e.g., nystagmus, conjugate gaze palsies, ophthalmoplegia), (2) cerebellar dysfunction (ataxia), and (3) altered sensorium. Nearly 20% of confirmed WE cases do not display any of these symptoms. In some cases, seizure may be the main manifestation, especially in nonalcoholic WE.

Mortality of untreated WE is high. Untreated, undiagnosed WE can lead to permanent neurologic damage, psychiatric sequelae, and death. Rapid high-dose intravenous thiamine administration is imperative to prevent the most severe sequelae of WE.

Imaging

MR is the procedure of choice in evaluating patients with possible WE, although up to 1/3 of reported cases have normal initial studies on admission.

T1WI may show hypointensity around the third ventricle and cerebral aqueduct. In severe cases, petechial hemorrhages are present and may cause T1 hyperintensities in the medial thalami and mammillary bodies. T2* SWI sequences may be helpful in detecting microhemorrhages in the affected areas.

During the acute phase, T2/FLAIR hyperintensity can be seen in the affected areas (35-19). Bilateral symmetric lesions in the putamina and medial thalami around the third ventricle are present in up to 85% of confirmed cases (35-20). The tectal plate and periaqueductal gray matter are involved in nearly 2/3 of cases. T2/FLAIR hyperintensity in the mammillary bodies is seen in 50-60% of cases (35-19A).

Less commonly, the dorsal medulla is affected (35-20A). Bilateral but asymmetric cortical hyperintensities (“ribboning”) can be present (35-19C) (35-20C).

DWI shows corresponding restricted diffusion in the affected areas. Some cases show an isolated transient focus of diffusion restriction (“cytotoxic lesion”) in the corpus callosum splenium.

In ~ 1/2 of all alcoholic WE cases, postcontrast scans demonstrate enhancement of the periventricular and periaqueductal lesions. Strong uniform enhancement of the mammillary bodies is seen in up to 80% of acute cases and is considered pathognomonic of WE. With chronic WE, mammillary body atrophy ensues.

Differential Diagnosis

The medial thalami and midbrain can be symmetrically involved in artery of Percheron (AOP) infarct and deep cerebral vein thrombosis (CVT). Viral infections, such as influenza A and West Nile virus meningoencephalitis, cause symmetric medial thalamic and midbrain lesions that may mimic WE. Mammillary bodies are usually not involved.

A rare but reported imaging differential diagnosis is demyelination in neuromyelitis optica spectrum disorder (NMOSD). Therefore, measurement of aquaporin-4 antibodies should be considered if no obvious cause for thiamine deficiency is present.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, autosomal recessive, pan-ethnic treatable metabolic disorder of childhood (age 3-10 years) associated with biallelic pathogenic variations in SLC19A3. Bilateral symmetric lesions in the caudate nuclei, putamen, and medial thalami with variable extension into the brainstem, cortex, and cerebellum are typical. Sparing of the mammillary bodies and more extensive cortical involvement is helpful in distinguishing BTBGD from nonalcoholic WE. Treatment with high-dose biotin and thiamine is given orally as early in the disease course as possible and is continued lifelong.

Medication-Related Toxic Encephalopathies

Preamble

A number of common medications may exert toxicity in the CNS. While a detailed discussion of drug side effects on the CNS is beyond the scope of this text, we focus on identifying some common recognizable medication-related MR patterns that present acutely (metronidazole, acetaminophen, and antiepileptics).

Metronidazole-Induced Encephalopathy

Metronidazole is an antibiotic commonly used in the treatment of some parasitic and microbial infections (e.g., amebiasis and Clostridium difficile). The drug is usually well tolerated, but patients occasionally develop serious neurologic impairment, including peripheral neuropathy, cerebellar dysfunction, vestibular &/or cochlear toxicity, ataxia, dysarthria, nystagmus, seizures, and sometimes severely altered mental status.

MR shows symmetrical T2/FLAIR hyperintensity in the dentate nuclei of the cerebellum and dorsal midbrain in > 90% of cases (35-21). Involvement of the dorsal medulla, cerebellar peduncles, olivary nuclei, corpus callosum splenium, internal capsules, thalami, globi pallidi, and cerebral WM have also been reported in some cases. Imaging findings usually resolve after metronidazole discontinuation.

Acute Acetaminophen Intoxication

Acetaminophen (APAP), a.k.a. paracetamol in Europe, is one of the most common nonprescription medications for pain and fever reduction. In the USA, more than 25 billion doses are sold yearly as 325-mg and 500-mg immediate-release tablets, and high-dose (650-mg) extended release tablets are often used for the treatment of arthritis.

If used in proper therapeutic doses, APAP has an excellent safety profile. Because APAP is metabolized in the liver, acute hepatotoxicity can occur after accidental or intentional overdose (OD). APAP poisoning is the most common cause of acute liver failure in the USA. Nearly 1/2 of all ODs are unintentional. APAP OD can occur at any age, including infants and children.

APAP OD breaches the blood-bile barrier, causing massive oxidative stress and hepatocyte death. Only one drug, N-acetylcysteine, is approved for the treatment of APAP OD and must be given within 8 hours after ingestion.

Imaging findings are those of acute liver failure with hyperammonemia (acute hyperammonemic encephalopathy). Symmetrical, extensive cortical T2/FLAIR hyperintensity involving the insular, cingulate, and frontoparietal cortices (cortical ribbon sign) with sparing of the occipital and perirolandic areas is typical. Both thalami are often affected. Affected areas show restricted diffusion (35-22).

Reversible Splenial Lesions

Terminology

Reversible splenial lesions (RSLs) are also known as cytotoxic lesions of the corpus callosum (CLCCs). These are acquired, usually transient or reversible lesions that are associated with a number of different entities and often characterized by a nonspecific encephalopathy.

Etiology

While RSLs/CLCCs have been associated with a number of conditions, most are related to seizures, withdrawal of antiepileptic or psychotropic medications, metabolic derangements, and infections, such as viral encephalitis.

Clinical Issues

RSLs/CLCCs themselves are usually asymptomatic and discovered incidentally on imaging studies. Most resolve spontaneously and disappear.

Imaging

RSLs are most often round, ovoid, or boomerang-shaped lesions (35-24)centered on the middle of the corpus callosum splenium (35-23). Rarely, CLCCs extend anteriorly from the splenium into the corpus callosum body. Mass effect is absent or minimal.

RSLs/CLCCs are iso- to mildly hypointense on T1WI, homogeneously hyperintense on T2/FLAIR, and do not enhance following contrast administration (35-23). Most demonstrate restricted diffusion (35-23D). Lesions typically resolve completely within a few days or weeks, and follow-up imaging studies are normal.

Differential Diagnosis

The differential diagnosis is limited. Glioblastoma and primary CNS lymphoma may involve the corpus callosum splenium but cause mass effect and typically enhance strongly on T1 C+.

Amphetamines and Derivatives

Preamble

CNS stimulants include cocaine, amphetamine, methamphetamine (MA), methylenedioxymethamphetamine (MDMA), and methylphenidate. Although not a classic CNS stimulant, nicotine is a prototypic drug that is avidly self-administered and has some stimulating properties. All of these drugs have a high human abuse liability.

Most addictive drugs are excitotoxic and cause two major types of pathologies: Vascular events (e.g., ischemia, hemorrhage) and leukoencephalopathy.

Methamphetamine

Methamphetamine (MA or “meth”) is a highly addictive psychostimulant drug. “Crystal” MA abuse has been steadily increasing over the past decade. Even a single acute exposure to MA can result in profound changes in cerebral blood flow. Both hemorrhagic (35-25)and ischemic strokes (35-26)occur.

MR in chronic adult MA users demonstrates lower gray matter volumes on T1WI, especially in the frontal lobes, and more WM hyperintensities on T2/FLAIR scans than are appropriate for the patient’s age. MRS shows increased choline and myoinositol levels in the frontal lobes. DTI shows lower FA in the frontal lobes and higher ADC values in the basal ganglia.

MDMA (“Ecstasy”)

3-,4-Methylenedioxymethamphetamine is also known as MDMA or ecstasy. MDMA can cause arterial constriction, vasculitis, or prolonged vasospasm with acute ischemic infarcts. MDMA-induced ischemia is most pronounced in serotonin-rich brain areas, such as the globus pallidus and occipital cortex, which are especially vulnerable.

Benzodiazepines

Benzodiazepines, sometimes called “benzo, “are psychoactive drugs used to treat anxiety, insomnia, seizures, muscle spasms, and alcohol withdrawal. Benzodiazepines, such as temazepam and midazolam, act selectively on GABA-A receptors in the brain, inhibiting or reducing the activity of neurons.

Benzodiazepine OD has been associated with hypoxic-ischemic encephalopathy (35-27) (35-28), hemorrhagic ischemic strokes, and delayed toxic leukoencephalopathy.

Cocaine

Cocaine can be sniffed/snorted, smoked, or injected. In its most common form (cocaine hydrochloride), it is ingested via the nasal mucosa. “Crack,” the alkaloidal freebase form of cocaine hydrochloride, can also be smoked.

Regardless of the route of administration, the adverse impact of cocaine on the brain is largely related to its vascular effects. Systemic hypertension can be extreme, causing spontaneous hemorrhagic strokes.

Etiology

Nearly 1/3 of strokes in patients younger than 45 years old are drug related with 80-90% occurring in the fourth and fifth decades. Stroke risk is highest within the first six hours after drug use.

Rupture of a preexisting aneurysm or underlying vascular malformation accounts for nearly 1/2 of all cocaine-related hemorrhagic strokes. Cocaine also facilitates platelet aggregation and may lead to thrombotic vascular occlusion.

Acute cerebral vasoconstriction &/or cocaine-induced vasculopathy may lead to ischemic strokes. Snorted cocaine causes severe vasoconstriction in the vascular plexus of the nasal septal mucosa (Kiesselbach plexus). Chronic abuse may lead to septal necrosis and perforation.

Imaging

Strokes—both ischemic and hemorrhagic—are the major manifestations of cocaine-induced brain damage (35-28). The hemorrhages can be parenchymal (secondary to hypertension or vascular malformation) or subarachnoid (aneurysm rupture) (35-32). Hypertensive bleeds are usually centered in the external capsule/putamen or in the thalamus.

Ischemic strokes can be caused by vasospasm, cocaine-induced vasoconstriction, vasculitis, or thrombosis. Bilateral globus pallidus infarction has also been reported as a stroke subtype in cocaine abuse.

Acute cocaine-induced strokes are positive on DWI. MRA, CTA, or DSA may show focal areas of arterial narrowing and irregularity.

Acute hypertensive encephalopathy with posterior reversible encephalopathy (PRES-like syndrome) can also occur. Vasogenic edema in the occipital lobes is the most common finding.

Differential Diagnosis

Unexplained parenchymal hemorrhage in young and middle-aged adults should prompt evaluation for possible drug abuse. Embolic infarcts as well as vasculitis may appear identical to cocaine vasculopathy.

COCAINE AND AMPHETAMINE EFFECTS ON THE BRAIN

Amphetamines

• MA (“meth”)

Hemorrhagic, ischemic strokes

• MDMA (“ecstasy”)

Vasospasm, infarcts

 Location: Occipital cortex, globus pallidus

• Benzodiazepines

Delayed toxic leukoencephalopathy

Cocaine

• Intracranial hemorrhage

 Hypertensive intracranial hemorrhage (50%)

 “Unmasked” aneurysm or arteriovenous malformation (50%)

• Ischemic stroke

Vasospasm, vasculitis

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