Selected References

Toxic Encephalopathy

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.

Many illicit "street" drugs and synthetic "designer" CNS stimulants with innocent-sounding names such as "pink" and "bath salts" can have serious adverse impacts on the CNS. Dosage is highly variable and notoriously unreliable. Adulterated drugs are common, and contaminants may have additional adverse effects on their own.

A more recent development is the growth of so-called "legal high" drugs. Use of painkillers, "pep pills," and other legitimate pharmaceuticals for illicit or recreational purposes is becoming an epidemic, and 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. Acute effects on chronic underlying disease in abusers also contributes to the difficulty in sorting out which clinical and imaging findings can be attributed to specific drugs.

The vast majority of toxins with CNS manifestations cause bilateral, relatively symmetric lesions. Abnormalities in the deep gray nuclei (basal ganglia, thalamus) with varying white matter involvement are suggestive of toxicmetabolic causes.

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

Alcohol and Related Disorders

Alcohol [ethanol (EtOH)] is one of the most commonly abused substances in the world. EtOH has multiorgan effects, resulting in a wide range of diseases and disorders. EtOH causes different effects on different organs. Although the gastrointestinal system is exposed to higher concentrations of alcohol

(30-1) Autopsy of acute EtOH poisoning shows brain swelling with necrosis in subcortical/deep white matter , especially marked in the corpus callosum . Basal ganglia/thalami are swollen, pale, infarcted . (Courtesy R. Hewlett, MD.)

than any other tissue, ethanol easily crosses the blood-brain barrier and is a potent neurotoxin. Both its shortand longterm effects on the central nervous system are profound.

Excessive alcohol consumption can result in chronic brain changes as well as acute, life-threatening neurologic disorders. Comorbid diseases such as malnutrition with vitamin deficiencies may lead to Wernicke encephalopathy. Altered serum osmolarity associated with alcohol abuse can cause acute demyelinating disorders.

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 alcoholinduced demyelination syndromes and Wernicke encephalopathy. We close the section with two less common forms of related abuse, i.e., methanol intoxication and ethylene glycol (antifreeze) ingestion.

Acute Alcohol Poisoning

Etiology

The acute effects of binge drinking are striking. EtOH inhibits Na /K activity. Cellular swelling, life-threatening cytotoxic cerebral edema, and nonconvulsive status epilepticus may ensue (30-1). 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 undergoing structural maturation and has a unique sensitivity to alcohol. Adolescent binge drinking

(30-2) T2WI in a comatose patient who drank 1 gallon of vodka or whisky daily for a full week shows diffuse brain swelling, hyperintense white matter , bithalamic lesions . This is acute alcohol poisoning.

reduces adult neurotransmitter gene expression, reduces basal forebrain function, and decreases the density of cholinergic neurons.

Binge drinkers are especially vulnerable to alcohol neurotoxicity. Binge drinkers represent a model for endophenotypic risk factors for alcohol misuse and early exposure to repeated binge cycles.

Imaging

Imaging findings in patients with acute alcohol poisoning include diffuse brain swelling and confluent hyperintensity in the supratentorial subcortical and deep white matter on T2/FLAIR (30-2). Seizure-induced changes in the cortex, with gyral hyperintensity and diffusion restriction, may also be associated. DTI can detect brain changes after acute alcohol consumption that are not visible on conventional MR.

Chronic Alcoholic Encephalopathy

The long-term adverse effects of ethanol on the brain are much more common than those of acute alcohol poisoning. The effects are even more pronounced in immature brains. Recent fMR studies on alcohol use disorders (AUDs) have shown that even moderate repeated alcohol consumption can adversely affect the intrinsic functional architecture of adolescent brains.

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 effects, which are mostly related to the sequelae of liver disease, malnutrition, malabsorption, and electrolyte disturbances.

(30-3) Sagittal graphic shows generalized and superior vermian atrophy and corpus callosum necrosis related to alcoholic toxicity. Mammillary body and periaqueductal gray necrosisis seen with Wernicke encephalopathy.

Etiology

Alcohol is readily absorbed through the gastric and small intestinal mucosae. A normally functioning liver breaks down nearly 90% of alcohol.

Chronic or harmful alchohol use leads to neurochemical, structural, and morphologic neuroplastic changes. EtOH readily crosses the blood-brain barrier, causing both direct and indirect neurotoxicity.

Direct brain toxicity is caused by upregulation of NMDA receptors, resulting in increased susceptibility to glutamatemediated excitotoxicity. Other direct effects include the toxicity of acetaldehyde and related lipid peroxidation products, which can bind to brain tissue and initiate upregulation and expression of inflammatory factors. The resultant membrane injury, neuronal loss, and reduction of white matter volume reflect the indirect effects of alcohol neurotoxicity.

Repeated binge drinking damages the cortical and subcortical microstructure of the brain. Disturbed dendritic complexity occurs in areas of the prefrontal and parietal regions that mediate reward-related motivation.

Chronic EtOH abuse also dysregulates synaptic connectivity, causes increased apoptosis, and decreases expression of myelin protein-encoding genes in the frontal cortex, hippocampus, and cerebellum.

Pathology

Gross Pathology. The brain reflects the gross long-term effects of cumulative EtOH consumption (30-3). Cerebral atrophy is evidenced by enlarged ventricles and sulci,

(30-4) Sagittal T1WI in chronic alcoholic encephalopathy and Marchiafava-Bignami disease shows hypointensity in the entire middle corpus callosum . Mammillary bodies and superior vermis are atrophic. (Courtesy A. Datir, MD.)

particularly in the frontal lobes, and is due predominantly to reduced white matter volume.

Alcohol-induced cerebellar degeneration is also common. The folia of the rostral vermis and anterosuperior aspects of the cerebellar hemispheres are atrophic, separated by widened interfolial sulci.

Microscopic Features. Histologic changes in the cerebral hemispheres are nonspecific. Purkinje cell loss in the cerebellum, together with patchy loss of granular cells and molecular layer atrophy, reflects the alcohol-induced cerebellar degeneration.

Clinical Issues

The mechanisms that underlie alcohol's rewarding effects, the neuroadaptations from chronic exposure that contribute to tolerance and withdrawal, and the changes in fronto-striatal circuits that lead to loss of control and enhanced motivation to drink are complex and interdependent. Significant alterations in dopamine and serotonin-mediated neurotransmission also contribute to compulsive alcohol taking, dysphoria/depression, and other AUD-related disorders.

Imaging

General Features. A characteristic pattern of progressive brain volume loss is seen with chronic alcoholic encephalopathy. Initially, the superior vermis atrophies and the cerebellar fissures become prominent (30-4) (30-5) (30- 6). In later stages, the frontal white matter becomes involved, reflected by widened sulci and enlarged lateral ventricles. In the final stages, global volume loss is present (30-7).

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CT Findings. NECT scans show generalized ventricular and sulcal enlargement. The cerebral white matter is often abnormally hypodense and reduced in volume. The great horizontal fissure of the cerebellum and the superior vermian folia are unusually prominent relative to the patient's age.

MR Findings. Brain volume loss, especially in the prefrontal cortex, is common as is more focal atrophy of the superior vermis. Focal and confluent cerebral white matter hyperintensities on T2/FLAIR sequences are frequently present.

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 occur.

ACUTE/CHRONIC ALCOHOLIC ENCEPHALOPATHY

Acute Alcohol Poisoning

•Rare; caused by binge drinking

•Imaging

○Diffuse cerebral edema

○Acute demyelination

Chronic Alcoholic Encephalopathy

•Primary toxic effect on neurons

•Secondary effects related to liver, GI disease

○Hepatic encephalopathy

○Malnutrition, malabsorption, electrolyte imbalance

•Imaging

○Atrophy (superior vermis, cerebellum, generalized)

○White matter myelinolysis

Wernicke Encephalopathy

Terminology

Wernicke encephalopathy (WE) is also known as WernickeKorsakoff syndrome. Both alcohol-related and non-alcohol- related Wernicke encephalopathy can occur.

Etiology

General Concepts. Common sequelae of chronic AUD include nutritional deficiencies, most notably thiamine (B1) deficiency. Thiamine is required to maintain membrane integrity and osmotic gradients across cell membranes. Inadequate thiamine results in lactic acidosis with intraand extracellular edema.

Wernicke encephalopathy is caused by thiamine deficiency. Self-neglect and poor diet together with repeated vomiting may accompany alcoholism. Malnutrition with inadequate thiamine intake, decreased gastrointestinal absorption, and poor intracellular thiamine utilization may all contribute to the onset of alcoholic WE.

The underlying pathophysiology of nonalcoholic WE is identical to that of alcoholic WE, but the etiology is different.

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(30-8) Autopsy specimens are from a patient with Wernicke encephalopathy. (Upper left) Coronal section through the mammillary bodies shows hemorrhagic mammillary body necrosis . The inset below the pathologic section shows normal mammillary bodies for comparison. (Upper right) Section through the third ventricle shows bithalamic necrosis around walls of the third ventricle. (Lower left and right) Sections through the midbrain and upper pons show necrosis in periaqueductal gray matterand the bottom of the tectum . (Courtesy R. Hewlett, MD.)

Malnutrition secondary to hyperemesis gravidarum (pregnancy-related vomiting), eating disorders, 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.

A WE-like encephalopathy has also been reported with some drugs including antineoplastic agents such as ifosfamide. Toxicity is likely mediated through its metabolite chloroacetaldehyde, which may impair thiamine function.

Pathology

Location. The mammillary bodies, hypothalamus, medial thalamic nuclei (adjacent to the third ventricle), tectal plate, and periaqueductal gray matter are most commonly affected (30-8). Less commonly involved areas include the cerebellum (especially the dentate nuclei), red nuclei, corpus callosum splenium, and cerebral cortex.

Gross Pathology. If WE occurs in the setting of chronic alcoholism, generalized brain atrophy (especially of the cerebellar vermis and frontal lobes) is present. Demyelination and petechial hemorrhages are common in the acute stage of

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WE. Callosal necrosis, white matter rarefaction, and mammillary body atrophy can be seen in chronic WE.

Clinical Issues

Demographics. Alcohol dependence occurs in all countries and all socioeconomic groups. In the developed world, AUD is the most common cause of WE. Alcohol-related WE is dose dependent and occurs without sex or ethnicity predilection.

Almost half of all WE cases occur in nonalcoholics. Although WE is generally more common in adults, it can and does occur in children!

Presentation. Only 30% of patients demonstrate the classic WE clinical triad of (1) ocular dysfunction (e.g., nystagmus, conjugate gaze palsies, ophthalmoplegia), (2) ataxia, and (3) altered mental status (confusion). The majority of patients have polyneuropathy.

Natural History. Mortality of untreated WE is high. Rapid intravenous thiamine replacement is imperative to prevent the most severe sequelae of WE. Some survivors develop Korsakoff psychosis with severe retrograde amnesia, memory loss, and confabulation.

Imaging

Imaging—especially MR—is playing an increasingly important role in the early diagnosis of WE.

CT Findings. CT has a low sensitivity for the detection of WE and is generally unhelpful. NECT scans in acute WE are often normal. Subtle findings may include bilateral hypodensities around the third ventricle and midbrain. CECT may show subtle enhancement in the affected areas.

MR Findings. MR is much more sensitive than CT and is the procedure of choice in evaluating patients with possible WE. 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 (30-9). Bilateral symmetric lesions in the putamina and medial thalami around the third ventricle are present in 85% of cases. The tectal plate and periaqueductal gray matter are involved in nearly two-thirds of cases. T2/FLAIR hyperintensity in the mammillary bodies is seen in 50-60% of cases.

Less commonly, the dorsal medulla is affected (30-10). Cerebellar and symmetric cranial nerve involvement have been reported. Bilateral but asymmetric cortical hyperintensities can be present, and some cases show an isolated focus in the corpus callosum splenium (30-10E).

DWI shows corresponding restricted diffusion in the affected areas (30-9E). Some cases show an isolated focus of diffusion restriction in the corpus callosum splenium (30-10F).

In about half 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 (30-9F). 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 the spectrum of neuromyelitis optica (NMO). Therefore, measurement of aquaporin 4 antibodies should be considered if no obvious cause for thiamine deficiency is present.

WERNICKE ENCEPHALOPATHY

Etiology

•Thiamine (vitamin B1) deficiency

•Alcohol related (50%), nonalcoholic (50%)

Pathology

•Acute = petechial hemorrhages (especially mammillary bodies), demyelination

•Chronic = callosal necrosis, mammillary atrophy

Clinical Issues

•Classic triad = ocular dysfunction, ataxia, altered mental status

•Can occur in children!

•Intravenous thiamine imperative

Imaging

•MR > > CT (usually unhelpful)

•T2/FLAIR hyperintensity, DWI restriction

○Common = medial thalami (85%), periaqueductal gray matter (65%), mammillary bodies (60%), tectum (30%)

○Less common = dorsal medulla (8%), cerebellum/cranial nerve nuclei (1%), corpus callosum splenium

•SWI may show microhemorrhages

•Enhancement varies

○More common in alcoholic WE

○Mammillary body enhancement pathognomonic

Differential Diagnosis

•Artery of Percheron infarct, deep cerebral vein thrombosis

•Viral infection (e.g., influenza A, West Nile virus)

•Neuromyelitis optica

Marchiafava-Bignami Disease

Marchiafava-Bignami disease (MBD) is a rare disorder characterized by osmotic demyelination—and later necrosis—of the corpus callosum.

(30-11) Autopsy specimen from a patient with MarchiafavaBignami disease shows necrosis in the middle layers of the corpus callosum , the classic pathology in this disorder. (Courtesy R. Hewlett, MD.)

Terminology

MBD is also (incorrectly) known as "red wine drinkers' encephalopathy."

Etiology

MBD is primarily associated with chronic EtOH abuse. There is an anecdotal (but unproven) association with red wine. Rare cases of MBD in nonalcoholic patients have been reported. Most investigators attribute MBD to vitamin B complex deficiency (i.e., all eight B vitamins, in contrast to the more specific B1 deficiency of WE).

Pathology

Location. The imaging diagnosis of MBD is based on the presence of callosal lesions. Selective involvement of the middle layers along the entire length of the corpus callosum is highly suggestive of MBD (30-11).

Extracallosal lesions do occur with MBD. Extension into the hemispheric white matter as well as internal capsule and middle cerebellar peduncle lesions have been reported. In addition, a specific type of cerebral cortical lesion, known as Morel laminar sclerosis, can be seen in the frontolateral cortex.

Gross Pathology. Corpus callosum degeneration is the hallmark of MBD and varies from demyelination to frank cystic necrosis with cavitation of the middle layers.

Clinical Issues

Epidemiology. MBD is rare. Most cases are found in middleaged men.

(30-12) CECT scan in an alcoholic patient with MarchiafavaBignami disease shows generalized cerebral atrophy and striking hypodensity in the corpus callosum genu and the adjacent white matter . (Courtesy A. Datir, MD.)

Presentation. The clinical diagnosis of MBD is difficult and often confused with WE. Some investigators report that both diseases often occur together.

MBD presents in two major clinical forms. In acute MBD, rapid decline with impaired consciousness, seizures, muscular rigidity, and death within several days is typical. In the chronic form, interhemispheric disconnection syndrome (e.g., apraxia, hemialexia, dementia) can be seen and lasts from months to several years.

Natural History. Most patients who survive MBD have severe neurologic sequelae although a few cases with favorable outcome have been reported.

Treatment Options. If instituted quickly, intravenous vitamin B complex and methylprednisolone therapy may reverse the course of acute MBD.

Imaging

General Features. Selective involvement of the middle layers of the corpus callosum is typical. As with other alcohol-related disorders, MBD can also be accompanied by other alcoholrelated pathologies. Chronic alcoholic encephalopathy with generalized brain volume loss is common. Electrolyte disturbances may cause osmotic demyelination.

CT Findings. CT may be normal in the acute stage of MBD. Chronic MBD shows linear hypodensity in the corpus callosum genu that, in the setting of chronic alcohol abuse, is highly suggestive of the diagnosis (30-12).

MR Findings. The initial changes of acute MBD are best seen on sagittal FLAIR. Hyperintensity in the corpus callosum genu and frontoparietal cortex appears first, followed by splenial

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lesions. During the acute phase, the entire corpus callosum may appear swollen and hyperintense.

DWI is initially negative, suggesting that the FLAIR changes probably reflect intramyelinic vasogenic (not cytotoxic) edema. Restriction subsequently develops in the corpus callosum splenium.

Acute white matter lesions may also enhance (30-13). Both peripheral (rim) or solid confluent patterns have been reported.

Chronic MBD with frank callosal necrosis is seen as thinning of the corpus callosum on sagittal T1WI with linear hypointensities in the middle layers (30-4). In patients with chronic MBD, T2* susceptibility-weighted imaging may demonstrate multiple microbleeds in the cortical-subcortical regions and corpus callosum. Other changes associated with chronic alcohol abuse, such as cortical, cerebellar, and mammillary body atrophy, are common.

For inpatients with chronic MBD, DTI with fiber tracking discloses a substantial decrease in fibers crossing through the splenium.

Differential Diagnosis

In the setting of EtOH abuse, callosal lesions are highly suggestive of MBD. Other diseases that may affect the corpus callosum include multiple sclerosis, axonal stretch injuries, and lacunar infarction. All have patchy discontinuous lesions that 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. Imaging

may provide important clues to the diagnosis of possible MtOH toxicity.

Terminology

MtOH intoxication or poisoning is also known as methanol encephalopathy.

Etiology

MtOH is a common component of solvents, varnishes, perfumes, paint removers, antifreeze, and gasoline mixtures. It can be accidentally or intentionally ingested, inhaled, or absorbed transdermally. Some cases of MtOH poisoning result from the intake of illicit spirits ("moonshine").

MtOH is metabolized to formic and lactic acid, causing severe metabolic acidosis with arterial pHs ranging from 6.8 to 7.1. Increased anion and osmolar gaps are important laboratory clues to the presence of MtOH toxicity.

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Pathology

Location. Bilateral basal ganglia necrosis is the most characteristic imaging feature of MtOH poisoning. Selective putamina involvement with relative sparing of the globi pallidi is common. Diffuse necrosis of the subinsular and subcortical white matter occurs in severe cases (30-14).

There is no consistent relationship between clinical outcome and the extent of imaging abnormalities.

Clinical Issues

Epidemiology. Compared with ethanol-induced encephalopathy, MtOH poisoning is rare.

Demographics. Patients are overwhelmingly male. Peak age is between the third and fourth decades.

Presentation. A peculiarity of MtOH poisoning is the latent period between ingestion and the appearance of clinical

(30-14) Autopsy specimen from a patient with fatal methanol toxicity shows hemorrhagic necrosis in both putamina and subinsular white matter. (Courtesy R. Hewlett, MD.) (30-15) Axial NECT in acute methanol poisoning shows confluent, symmetric hypointensities in the basal ganglia and internal capsules.

(30-16) NECT scan in a patient with subacute methanol poisoning shows confluent and patchyhemorrhagic putaminal necrosis. (Courtesy R. Ramakantan, MD.) (30-17) NECT scan in a patient who survived acute methanol poisoning shows shrunken, hypodense putamina and bilateral symmetric hypodensities in the subcortical white matter.

(30-18) Single-voxel MRS through the basal ganglia in a patient with methanol-induced putaminal necrosis shows reduced NAA and a huge lactate doublet .

(30-19) Sagittal T1WI shows pons and midbrain hypointensity, which is better seen as hyperintensity on coronal FLAIR . Patchy enhancement is seen on T1 C+ .

symptoms. Symptom onset is variable and often delayed, especially if ethanol is ingested simultaneously, as this slows MtOH metabolism. Between 85-90% of patients present with visual disturbances. Three-quarters of all patients have nonspecific gastrointestinal symptoms such as nausea and vomiting. Approximately 25% are comatose on admission.

Natural History. Ingestion of 30 mL of pure MtOH usually results in death. As little as 4 mL can result in blindness. Blood MtOH levels above 200 mg/L are considered toxic, and levels above 1,500 mg/L are potentially fatal.

Although the latency in symptom onset is variable, symptom progression may be rapid. Respiratory arrest and death can occur within a few hours.

Putaminal hemorrhage and insular subcortical white matter necrosis are associated with poor clinical outcome.

Treatment Options. MtOH is effectively treated with alkali to combat acidosis, antidotes (ethanol or fomepizole) to block production of formic acid, and hemodialysis to remove MtOH and formate.

Imaging

CT Findings. Initial NECT scan is 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 deep cerebral white matter (30-15). Hemorrhagic putaminal necrosis is seen in 15-25% of cases (30-16). Enhancement is variable, ranging from none to peripheral enhancement of the putaminal lesions.

If the patient survives, cystic cavities form within the putamina, representing the chronic sequelae of MtOH poisoning (30-17).

MR Findings. Bilateral putaminal and basal ganglia necrosis with variable white matter involvement is present. T2/FLAIR hyperintensity is seen with 25% exhibiting "blooming" foci on T2*. DWI shows restricted diffusion in the acute stage of methanol poisoning. MRS shows reduced NAA and markedly elevated lactate (30-18).

Surviving patients have symmetric T2/FLAIR hyperintense lesions in the putamina with variable involvement of the subcortical white matter.

Differential Diagnosis

Bilateral symmetric putaminal lesions are not specific for MtOH and can be seen in Wilson disease and mitochondrial encephalopathies (e.g., Kearns-Sayre, Leigh). Hypoxicischemic 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

Recent reports from the American Association of Poison Control Centers indicate that ethylene glycol is the third most common chemical responsible for deaths by nonpharmaceutical poisoning (following ethanol and carbon monoxide).

(30-20A) NECT scan shows a 32y man with amphetamine abuse, energy drink bingeing who presented with left hemiparesis and facial droop. Note focal acute hemorrhage in the right basal ganglia and posterior limb of the internal capsule .

Ethylene glycol is a colorless, odorless, sweet-tasting, but poisonous form of alcohol that is a common component found in many household products such as antifreeze, deicing solutions, and windshield wiper fluids. It may be ingested by alcoholics or, because of its sweet taste and the ease of access, it is often accidentally ingested by children and animals. Intake of even a small volume can prove lethal.

When ingested, ethylene glycol causes metabolic acidosis and can damage the brain, liver, kidneys, and lungs. The toxicity of ethylene glycol is mediated by its metabolites, mainly glycolic acid and oxalate. Glycolic acid is responsible for the metabolic acidosis. Glycolate is then metabolized to oxalate, which precipitates with calcium as calcium oxalate and is deposited in various tissues. The high anion gap of metabolic acidosis and osmolar gap resolve within 24 to 72 hours.

Early treatment with bicarbonate and ethanol or the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP, fomepizole) is very effective. Emergent hemodialysis is appropriate if the ethylene glycol level is more than 50 mg/dL and can be life saving.

Imaging findings of acute ethylene glycol toxicity include edema in the basal ganglia, thalami, midbrain, and upper pons (30-19). Hemorrhagic putaminal necrosis, similar to that observed in methanol intoxication, can be seen in subacute and chronic cases.

(30-20B) AP DSA in the same case obtained 24 hours later shows striking irregularity and beading of the medial and lateral lenticulostriate arteries . This was drug-induced vasculitis.

Amphetamines and

Derivatives

The "hedonic" and addictive properties of drugs of abuse—particularly amphetamines and cocaine—are at least in part related to increased dopamine levels in the synapses of monoaminergic neurons although multiple other neurotransmitter systems (e.g., serotonergic, GABAergic and glutamatergic circuits) are clearly involved in stimulant pharmacology.

CNS stimulants include cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine (MDMA), and methylphenidate. Although not a classic CNS stimulant, nicotine is a prototypic drug that is avidly selfadministered and has some stimulating properties. All 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.

Functional neuroimaging studies have also demonstrated that drugs of abuse are associated with dysfunctions in a range of overlapping brain regions. Working memory, inhibitory control, attention, and decision-making are all negatively impacted, the degree of which correlates with the severity and chronicity of abuse. In addition, CNS mitosis, migration, and cell survival in the fetus of a pregnant, substance-abusing woman are adversely affected.

Methamphetamine (MA or "meth") is a highly addictive psychostimulant drug. "Crystal" methamphetamine 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 and ischemic strokes occur (30-20) (30-21) (30-22).

MR in chronic adult MA users demonstrates lower gray matter volumes on T1WI, especially in the frontal lobes, and more white matter 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 fractional anisotropy in the frontal lobes and higher ADC values in the basal ganglia.

(30-21) A 32y female methamphetamine abuser had sudden severe headache and coma. NECT shows diffuse subarachnoid, intraventricular hemorrhage and focal interhemispheric hematoma surrounding an ACoA aneurysm . (30-22) Axial NECT in a 35y female methamphetamine abuser shows a large basal ganglionic hemorrhage that has dissected into the lateral ventricle .

3-,4-Methylenedioxymethamphetamine is also known as MDMA or ecstasy. Popular as a party drug, MDMA induces euphoria and sensory disturbances secondary to rapid release of potent vasoconstrictors from serotonergic synapses. 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 (30-23).

Acute hippocampal necrosis with subsequent atrophy has been reported in chronic ecstasy users.

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 overdose has been associated with hypoxicischemic encephalopathy (30-24), hemorrhagic ischemic strokes (30-25), 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.

Etiology

Regardless of the route of administration, the adverse impact of cocaine on the brain is largely related to its vascular effects.

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Systemic hypertension can be extreme, causing spontaneous hemorrhagic strokes.

Rupture of a preexisting aneurysm or underlying vascular malformation accounts for nearly half of all cocaine-related hemorrhagic strokes (30-28). Cocaine also facilitates platelet aggregation and may lead to thrombotic vascular occlusion.

Acute cerebral vasoconstriction and/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.

Pathology

Macroscopic hemorrhages, particularly in the putamen and external capsule, are the most common gross pathologic findings and are twice as common as ischemic strokes.

(30-24) A 60y depressed woman was found unconscious after overdose with benzodiazepines and opioids. Imaging shows bilateral symmetric globi pallidi lesions. (30-25) MR scans in a 45y bipolar woman with toxicology positive for opiates and benzodiazepines show globi pallidi and cortical infarcts. She also had symmetric hemorrhagic cerebellar infarcts (not shown).

(30-26) NECT shows acute hypertensive hemorrhage with putamen/external capsule hemorrhage in a patient who abused cocaine. (30-27) NECT scan in a patient with cocaine abuse shows diffuse brain swelling and multifocal ischemic infarcts .

(30-28) (Upper L) NECT in polydrug abuse shows occipital hematoma . (Upper R) T2WI 3 days later shows early subacute hematoma . (Lower L, R) SWIs show multiple microbleeds . Unmasking of multiple cavernous malformations is shown.

Microscopically, cocaine arteriopathy is characterized by inflammatory changes and necrosis.

Clinical Issues

Epidemiology. Nearly one-third 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 6 hours after drug use.

Presentation. Headache, seizure, and focal neurologic deficits are the most common symptoms.

Natural History. The onset of cocaine-related stroke may be immediate if hypertensive or subarachnoid hemorrhage occurs. Cocaine-induced vasculopathy with ischemic infarcts may occur up to a week after use.

Imaging

Strokes—both ischemic and hemorrhagic—are the major manifestations of cocaine-induced brain damage (30-26). The hemorrhages can be parenchymal (secondary to hypertension or vascular malformation) (30-28) or subarachnoid (aneurysm rupture). Hypertensive bleeds are usually centered in the external capsule/putamen or in the thalamus.

Ischemic strokes can be caused by vasospasm, cocaineinduced vasoconstriction, vasculitis, or thrombosis (30-27). Bilateral globus pallidus infarction has also been reported as a stroke subtype in cocaine abuse.

Acute cocaine-induced strokes are positive on DWI (30-29). MRA, CTA, or DSA may show focal areas of arterial narrowing and irregularity.

(30-29) Axial FLAIR scan (L) and DWI (R) in a 35y male cocaine abuser show ischemic infarcts in the left basal ganglia .

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 middleaged 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

•Methamphetamine

○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

•Acute hypertensive encephalopathy

○Posterior reversible encephalopathy syndrome (PRES)

○Vasogenic edema (typically bioccipital)