Exogenous Toxins and CNS Injuries
The interaction of numerous exogenous substances with the CNS may lead to toxic injuries. The CNS is more vulnerable to the effects of lipophilic compounds, and neurons are particularly susceptible due to their high lipid content and metabolic rates. Clinical neuroradiology plays an overall modest but, in some cases, very important role in the diagnosis of these disorders. Radiology techniques, primarily MRI and to some extent CT, can demonstrate toxic lesions at both early and delayed phases of disease, which may or may not match the severity of the neurological impairment, but in certain settings can predict the prognosis and clinical outcome. Toxic encephalopathies, along with hypoxic-ischemic brain injury, acquired metabolic disorders and inborn errors of metabolism, tend to produce a symmetric pattern of lesions often affecting cerebral deep grey matter. The white matter may also be involved with acute exposure to toxic agents, while neuroimaging in the chronic phase frequently reveals cortical and white matter abnormalities, including atrophy. Recognition of the specific imaging characteristics, presumably due to selective vulnerability, can often lead to the correct diagnosis, especially when combined with the clinical history and/or laboratory findings. However, some of the classic imaging presentations of certain poisonings are not necessarily very specific or sensitive, and neurological dysfunction may be caused by a combination of two or more toxic substances and/or other disorders. A few of the most common and important exogenous toxins will be covered in this chapter.
KeywordsCarbon monoxide Toxic alcohols Organic solvents Opioids Central stimulants Heavy metals Toxic encephalopathy Magnetic resonance imaging (MRI)
List of Abbreviations
Apparent diffusion coefficient map
Acute demyelinating encephalomyelitis
Central nervous system
Cytochrome P450 2A6
Delayed encephalopathy after acute carbon monoxide poisoning
Diffusion kurtosis imaging
Delayed neuropsychiatric sequelae
Delayed posthypoxic leukoencephalopathy
Diffusion tensor imaging
Ethylenediamine tetra-acetic acid
Fluid attenuated inversion recovery
Heroin-associated spongiform leukoencephalopathy
Hyperbaric oxygen therapy
Hepatitis C virus
Human immunodeficiency virus
Heroin-induced subacute leukoencephalopathy
Myelin basic protein
Middle cerebral artery
Magnetic resonance imaging
Magnetic resonance spectroscopy
Normobaric oxygen therapy
United States of America
Imaging Technique and Recommended Protocol
Standard Head CT and MRI protocols without intravenous contrast agent are recommended, including T1w, T2w, FLAIR, DWI/ADC, and T2∗ or SWI sequences on MRI. Pathologic contrast enhancement may sometimes be seen with certain toxic agents; however, this is not a helpful distinguishing feature.
In addition to apparent diffusion coefficient (ADC) measurements, MR spectroscopy (MRS), diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI) have been used to predict chronic morbidity and development of delayed neuropsychiatric sequelae (DNS) with carbon monoxide (CO) poisoning (Beppu 2014). MRS may also be helpful with some other toxic encephalopathies and can potentially distinguish delayed phases of poisoning from alternative causes. In patients with central stimulant (cocaine, amphetamines) intoxication, MR or CT angiography can reveal vascular irregularities, for which catheter angiograms may still be needed.
Carbon Monoxide Poisoning
Definition of Entity and Clinical Highlights
Carbon monoxide (CO) is a nonirritant, colorless, and odorless toxic gas produced by the incomplete combustion of hydrocarbons. It is contained in fumes from car engines, stoves, furnaces, and gas water heaters.
The clinical presentation of CO poisoning varies from nausea, headache, and dizziness to confusion, coma, and death, with a mortality rate in the range of 1–3%. The patients are often found unresponsive and any signs of possible CO exposure may be helpful for establishing the diagnosis. Management of these patients requires the identification of accompanying toxic exposures, especially in the setting of intentional poisoning and fire-related inhalational injuries. Therapy is limited to normobaric and hyperbaric oxygen. Surviving patients display 1 of 3 clinical types: approximately 70% present with various transient symptoms in the acute phase only; symptoms persist from the acute into the chronic phase in 20% of patients; and the remaining 10% exhibit delayed neuropsychiatric sequelae (DNS) with recurrent symptoms after an asymptomatic period (lucid interval) following apparent resolution of acute symptoms.
CO is the most common cause of human poisoning worldwide, both unintentional and deliberate, with no available antidotal therapy. The exposure comes from a variety of sources with incomplete combustion of carbon-containing fuels, such as poorly functioning heating systems (including defective exhaust tubes in old coal-heating facilities), indoor burning of charcoal briquettes, riding in the back of pick-up trucks, ice skating rinks using propane-powered resurfacing machines, and inappropriately located gasoline-powered generators. The World Health Organization suggests that levels greater than 6 ppm are potentially toxic over a longer period. Carboxyhemoglobin (COHb) levels of 2% or greater in nonsmokers and 10% or greater in smokers are considered abnormal and may produce symptoms.
Most fatalities result from fires, malfunctioning stoves, exhaust systems, and heaters, as well as suicide attempts. An abrupt increase in suicide rates by CO in several countries over the past decade or so has been associated with Internet searches for sites where “how-to” information is available. Populations at risk of death from CO poisoning are those over the age of 75, individuals with underlying cardiopulmonary disorders, neonates (because of the persistence of fetal hemoglobin), and the fetus in utero. A chronic low-level CO exposure may cause memory deficits, vertigo, neuropathy, chronic fatigue, abdominal pain, and diarrhea. The neurological and cognitive deficits that may occur from such exposure do not resolve after removal from the CO source, suggesting neurological damage even at low levels of environmental CO. Prevention and diagnosis of CO poisoning is hampered by the lack of awareness of CO as a cause of illness, among both the general public and healthcare professionals (Rose et al. 2017).
Once CO is inhaled, it crosses the alveolar capillary membrane and binds strongly to heme-containing compounds. The affinity of hemoglobin for carbon monoxide is approximately 250 times greater than its affinity for oxygen and it binds with CO to form COHb, with a consequent substantial reduction in oxygen-carrying capacity, which in turn leads to hypoxia in tissues. A shift in the oxyhemoglobin dissociation curve to the left inhibits release of oxygen (the dissociation of CO from carboxyhemoglobin is over 3000 times slower than that of oxygen), thereby further exacerbating tissue hypoxia. If loss of consciousness is accompanied by hypotension, it adds to hypoxia, and the hypoxic-hypotension process leads to ischemic changes in the arterial border zones of the brain. Brain hypoxia increases the level of excitatory amino acids with subsequent injuries to the cortex and causes apoptosis as well as inflammation. Mechanisms other than hypoxia also play a role. By binding to cytochrome a3, CO decreases the levels of cytochrome c oxidase, inhibiting mitochondrial metabolism and leading to cellular respiratory dysfunction, similar to the effects of cyanide. CO is also involved in the formation of free radicals, including its binding to platelet heme proteins that causes the release of nitric oxide. Additionally, CO is responsible for platelet-to-neutrophil aggregation, which starts a cascade of events that eventually alter the structure of myelin basic protein (MBP), trigger lymphocytic immunologic responses, and increase microglia activation, which in turn lead to progressive demyelination with ongoing inflammation (Beppu 2014; Rose et al. 2017). So, the damage to the brain results not only from tissue hypoxia but a combination of various direct and indirect toxic effects of CO.
At autopsy, cherry red discoloration, primarily affecting globi pallidi and cerebral white matter is seen following fatal CO poisoning. Bilateral necrosis of globus pallidus (GP) and demyelination of white matter tracts are found in chronic cases. On histology, there are sharply demarcated foci of ischemic or hemorrhagic necrosis in GP and perivascular foci of demyelination in deep white matter with sparing of arcuate fibers. Two reasons for selective damage to the GP have been proposed: its poor anastomotic blood supply and/or direct binding of CO to heme iron in the GP which is a brain region with the highest iron content. Neurons in gray matter may tolerate pure hypoxia for longer than ischemia, which may explain relative sparing of the cortex. Areas of necrosis may also be seen in pars reticulata of substantia nigra (another region with high iron content), caudate nucleus, cerebellum, and hippocampus (Beppu 2014).
However, a recent publication from a single institution found that none of 27 cases with bilateral basal ganglia lesions on autopsy were associated with CO poisoning, while there was no evidence of GP necrosis in any of the known CO poisoning cases. These findings may suggest that GP lesions are not necessarily characteristic of CO poisoning.
Clinical Scenario and Indications for Imaging
The presence of a clinical triad ideally leads to diagnosis in the acute setting: symptoms consistent with CO poisoning, history of recent CO exposure, and elevated COHb levels. The symptoms and the severity of the disease do not necessarily correlate with presenting COHb levels, in part because the plasma levels rapidly reduce upon removal of the source and are not a reliable biomarker of exposure and tissue damage. Neither the initial severity nor the clinical improvement directly correlates with the blood COHb level or COHb clearance (Beppu 2014; Rose et al. 2017). Mild poisoning may present as a viral infection in the absence of fever, including fatigue and subtle cognitive deficits. While headache, nausea, and vomiting are the common presenting symptoms in children and adults, the most frequent symptom in infants is disturbance of consciousness. If the history of CO exposure is not known or suspected, it may be mistaken for other, more benign diagnoses. Patients with more severe intoxication usually demonstrate neurological signs, particularly impaired gait and balance, less commonly sensory deficits such as cortical blindness and deafness. Approximately, a third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Transient loss of consciousness is a common presentation; however, persistent loss of consciousness, even after oxygen administration, suggests severe intoxication. Characteristics associated with high short-term mortality are fire as a source of CO, loss of consciousness, pH values less than 7.20, high COHb level (above 40%), and need for endotracheal intubation during hyperbaric oxygen therapy (HBOT) (Rose et al. 2017).
As altered mental status is a common presenting symptom, head CT and/or MRI is performed in many patients, including those without clinical suspicion for CO poisoning. The presence of acute brain lesions on DWI was found to be significantly associated with the development of delayed neurological sequelae in a recent study (Jeon et al. 2018).
Following resolution of acute symptoms, there may be a lucid interval of 2–40 days (mean duration of about 3 weeks) before the development of DNS (various other generally similar names have been used in the literature, including “delayed encephalopathy after acute carbon monoxide poisoning” – DEACMP and “delayed posthypoxic leukoencephalopathy” – DPHL). Clinical symptoms and signs include the triad of mental deterioration, urinary incontinence, and gait disturbance, as well as other neuropsychiatric manifestations. The course of DNS ranges from full recovery to a progressive deterioration ending in coma or death. The patients can improve over up to 1 year after the exposure, and approximately 75% of patients with DNS ultimately recover. Delayed encephalopathy can even occur in patients with mild symptoms of acute CO poisoning and a significant number suffer from long-term neuropsychiatric sequelae including parkinsonism or other motor impairments, cognitive dysfunction, akinetic mutism, mood disorder, and personality change (Beppu 2014; Jeon et al. 2018). These deficits likely result from the multiple various effects of CO rather than just direct anoxic damage, with markedly elevated levels of MBP in the CSF preceding the clinical manifestations. Poor outcomes have been associated with advanced age and earlier onset and the levels of MBP in the CSF may serve as a predictor of both the development and outcomes of DNS.
The cornerstone for treatment of CO poisoning is 100% normobaric oxygen using a tight-fitting mask for greater than 6 h (NBOT). NBOT and HBOT at 2.5–3 atmospheres remove CO at a faster rate from the blood by increasing the partial pressure of oxygen. The only study to meet all Consolidated Standards of Reporting Trials criteria and measure 1-year outcome did show a significant improvement in long-term neurocognitive dysfunction with HBOT. Recent practice recommendations by experts in the hyperbaric medicine field do recommend HBOT use and it should be considered for all cases of serious acute CO poisoning, including loss of consciousness, ischemic cardiac changes, neurological deficits, significant metabolic acidosis, or COHb greater than 25% (Rose et al. 2017).
Despite clear effectiveness of HBOT in minimizing DNS, a substantial portion of survivors suffer long-term morbidity, including permanent severe cognitive, affective, and/or physical sequelae. The combined application of dexamethasone and HBOT as well as treatment with acetylcholinesterase inhibitors appear to show promising results that remain to be evaluated in clinical trials.
It needs to be mentioned that DNS is not limited to CO poisoning, as similar postanoxic delayed encephalopathies may also be seen in the settings of respiratory arrest, exposure to drugs, and other toxins, anaphylaxis, seizures, or anesthesia. This is discussed in the chapter “Imaging of Diffuse Mechanisms of Brain Ischaemia”.
Although bilateral GP lesions have been considered the classic manifestation of acute CO poisoning on neuroimaging, other patterns of brain injury have been described, and GP is not necessarily the most common site of abnormalities. The lesions occasionally involve the putamen, caudate nucleus, thalamus, hippocampus, and cerebellum, as well as the substantia nigra, where the alterations are less conspicuous. Isolated involvement of cerebellar hemispheres without any supratentorial lesions have been described in a few young patients. The most common MRI finding in CO-poisoned patients may actually be the cerebral white matter signal alterations, while basal ganglia abnormalities, including lesions of the GP, may be less common than generally considered and previously reported (Rose et al. 2017; Jeon et al. 2018). On the other hand, isolated bilateral GP lesions have been described in a number of patients with methanol intoxication.
Pathologic changes progress in the brain from the time of CO inhalation to several years later. The timing of imaging studies will thus have a major effect on the findings, which may be broken down into the consecutive phases: hyperacute within the first 24 h, acute at 24 h to 7 days, subacute at 8 days to 3 weeks, and chronic 22 days and thereafter (Beppu 2014).
Fractional anisotropy (FA) in the centrum semiovale may offer a quantitative indicator of the extent of demyelination during the subacute phase in CO-poisoned patients. FA decreases before the appearance of DNS and roughly correlates with MBP concentration in the CSF. Low FA values might continue until 3 months after poisoning and improvement in FA has correlated with improvement of DNS (Beppu 2014). The finding of lower NAA/Cr ratios, likely reflecting decreased neuroaxonal viability, within 1 week after CO intoxication on MRS in the centrum semiovale appears useful for predicting DNS development. Increased Cho/Cr ratio in the subacute phase, likely representing inflammation with progressive demyelination, may predict chronic neurological symptoms. The MRS abnormalities correlate with the elevation of MBP in CSF, and presence of lactate peak is a predictor of a poor long-term outcome.
A dedicated GM-suppressed IR MR sequence detected increased normalized signal ratio in the middle and lateral segments of the substantia nigra in patients with delayed parkinsonism after CO intoxication and further research may provide additional clinically relevant information (Kao et al. 2012).
It needs to be mentioned that normal MRI and MRS studies do not exclude neuropsychologic abnormalities from chronic CO exposure.
In addition to the most widely known CO poisoning, reported hemorrhagic and necrotic lesions selective for injuring the GP include fatalities involving methamphetamine, cocaine, and opiates, as well as cyanide and methanol poisoning. Bilateral symmetric pallidal lesions have also been described following severe anemia associated with gastrointestinal hemorrhage.
Metabolically Toxic Alcohols
The metabolically toxic alcohols include methanol, ethylene glycol (EG), and diethylene glycol, which all have relatively minimal toxicity but are metabolized, initially by alcohol dehydrogenase (ADH), into highly toxic acidic metabolites. These compounds are readily available worldwide in various commercial products (such as windshield-washer fluid, antifreeze, and fuels) as well as in homemade or illicit alcoholic beverages, both of which are responsible for most of the poisonings, from either unintentional or intentional ingestion. Exposure to diethylene glycol is the least common and will not be further discussed but may occur in epidemics, mostly due to illicit or uninformed substitution for more expensive and less toxic compounds in liquid medications. It was the solvent in an elixir responsible for deaths of 105 children in the United States in 1937, and to passage of the 1938 Federal Food, Drug, and Cosmetic Act, which required that all components of a drug product be demonstrated as safe prior to marketing.
Ethanol toxicity is addressed in chapter “Acquired Metabolic Diseases: Imaging Patterns” of this section.
Delayed diagnosis is the main reason for poor outcomes as early treatment is normally very successful. Definitive tests are not readily available, and diagnosis is therefore often based on imperfect surrogate exams. The treatment of these poisonings consists of ADH inhibition by either ethanol or fomepizole, bicarbonate to reverse the metabolic acidosis, and hemodialysis to enhance the elimination of the alcohols and their metabolites. Ethanol has at least 10 times the affinity for ADH compared to methanol and 20-fold higher than ethylene glycol, while fomepizole is even more effective and with less frequent side effects.
Definition of Entity and Clinical Highlights
Methanol (methyl alcohol, wood alcohol, CH3OH) is a clear colorless liquid with smell and taste similar to ethanol. Acute poisoning may lead to visual disturbances including blindness and serious neurological symptoms, which can be permanent in survivors. Although overall relatively infrequent, poisonings also occur in outbreaks, resulting in severe morbidity and mortality. Severity of metabolic acidosis, low level of consciousness, and negative serum ethanol on admission are the parameters associated with mortality.
Methanol intoxication is a global problem with high mortality as well as long-term visual sequelae and severe brain damage in survivors. The poisoning usually occurs after oral ingestion of industrial liquids, such as windshield-wiper fluid or antifreeze, or consumption of contaminated alcoholic beverages. Cases with methanol intoxication via inhalation and even by the transdermal route have been reported, as it can also be absorbed by the respiratory system or skin. According to the World Health Organization, about one third of all consumed beverage alcohol is unrecorded (either illegally made, home-produced, or smuggled), and it is these beverages that are responsible for mass poisonings, such as the documented twenty-first century outbreaks in Norway, Romania, Estonia, Sudan, Iran, Libya, Kenya, and Czech Republic.
The similarity to ethanol in appearance and odor may lead to accidental methanol use, which is causing less behavioral intoxication compared to ethanol, and can be excreted unaltered through the lungs and kidneys. However, the major route of excretion is metabolism in the liver by ADH. The initial CNS depression is followed by a latent period (usually 12–24 h but even up to 72 h, if ethanol was co-ingested), while methanol gets metabolized into formaldehyde and further into formic acid, which has the highest toxicity. The accumulation of formic acid causes metabolic acidosis and inhibits mitochondrial respiration, impairing the cytochrome oxidase activity, which is also considered responsible for optic nerve demyelination. Leukotriene-mediated neuroinflammation and lipid peroxidation may also play significant roles in the acute poisoning. The severity of the damage varies among patients exposed to the same amounts of methanol, indicating individual variations in susceptibility, likely due to certain genetic predispositions.
The classic neuropathologic injuries in acute methanol poisoning are necrosis of putamen and subcortical white matter, frequently complicated by hemorrhage. There is also demyelination and atrophy of the optic nerve. Lesions in the caudate nucleus, brainstem, cerebellum, and cerebral cortex are observed less commonly. Various explanations have been proposed for the selective vulnerability of the putamen to formic acid: poor venous drainage, inadequate arterial flow, hypotension and ischemia, higher rates of oxygen consumption, greater sensitivity of the striatum neurons, and specific direct histotoxic effect of formic acid.
Clinical Scenario and Indications for Imaging
Acute symptoms include disorders of vision, headache, nausea and vomiting, fatigue, and abdominal pain. In more severe poisonings, seizures or coma may occur. The hallmark laboratory findings are severe metabolic acidosis with high anion gap and increased osmolal gap, and methanol poisoning should be considered in every patient with metabolic acidosis of unknown origin.
As altered mental status and decreased visual acuity are common presenting symptoms, head CT and/or MRI is performed in many patients. The combination of visual loss, acidosis, and bilateral putaminal necrosis is helpful in establishing the diagnosis when a history of methanol ingestion is not known. However, the initial CT and even MRI scans are frequently normal, and treatment should not be delayed for imaging when intoxication is suspected.
The treatment is based on prompt administration of either fomepizole or ethanol. Because of increased half-life of methanol following administration of these antidotes, hemodialysis is an integral part of therapy in severe poisoning as it eliminates both methanol and formic acid and corrects metabolic acidosis. The type of dialysis or antidote does not appear to affect mortality. Adjunctive therapies include sodium bicarbonate for correction of severe acidosis and, possibly, folic acid (theoretically accelerating metabolism of formic acid to carbon dioxide). Active case finding and prehospital ethanol administration in patients with suspected poisoning may improve outcomes in large-scale outbreaks. Intravenous erythropoietin combined with high-dose steroids is a promising new treatment for methanol optic neuropathy, which has been considered untreatable (Pakdel et al. 2018).
Calcium supplementation is indicated in EG intoxication if hypocalcemia, due to formation of calcium oxalate crystals, significantly contributes to symptoms such as muscle spasms or seizures. Pyridoxine and thiamine could, at least in theory, prevent the formation of oxalic acid by facilitating the conversion of glyoxylic acid to nontoxic metabolites.
While bilateral putaminal hemorrhage, especially with associated frontal and insular white matter lesions, is almost pathognomonic for acute methanol poisoning; symmetric involvement of putamen (and caudate nucleus) may be seen in patients with anoxic injury, uremic encephalopathy/metabolic acidosis of other etiology, Wilson disease, Leigh disease, and even Creutzfeldt-Jacobs disease. This is discussed in chapter 4 of this section and in the “Leukodystrophies and Inherited Metabolic Conditions” chapter. Hemorrhages in the region of the putamen may also be found following use of psychostimulants (cocaine and amphetamines).
The patients with hemorrhagic brain lesions tend to have more severe acidosis on admission and bilateral hemorrhagic necrosis of the putamen and caudate, subcortical necrosis, and symmetrical bilateral necrosis of the brainstem have been all associated with poor clinical outcomes. A gradual development of the imaging findings appears to start with a focal or pericapsular edema, which is followed by nonhemorrhagic necrosis of putamina over the first few days (despite the absence of formic acid and methanol in the serum), and, finally, hemorrhage in the regions of former necrosis after 10–14 days of hospitalization; blood products are sometimes detected on the follow-up outpatient MRI only (Zakharov et al. 2016).
Despite the progress in diagnosis and treatment of methanol poisoning, morbidity and mortality are still high, mainly due to an often difficult and therefore delayed diagnosis. If therapeutic measures are inadequate or delayed, mortality may exceed 40% and survivors frequently suffer serious sequelae, primarily visual impairment and movement disorders such as dystonia or parkinsonism. Methanol poisoning has also been associated with executive dysfunction and explicit memory impairment in survivors, supposedly due to basal ganglia dysfunction and disruption of frontostriatal circuitry, which is proportional to the number of brain lesions on MRI. A striking regression of the putaminal lesions on follow-up MRI studies has been found to correlate with absence of extrapyramidal sequelae and complete neurological recovery.
Definition of Entity and Clinical Highlights
Ethylene glycol [C2H4(OH)2, EG] is a common organic solvent, found in numerous household products and a main constituent of antifreeze. Due to its sweet taste and an odor resembling ethanol, it is sometimes inadvertently consumed. EG poisoning is associated with acute kidney injury, which can lead to irreversible kidney failure and with severe neurological damage.
Most poisonings are accidental, sometimes following transfer from the original container, but suicidal and even homicidal ingestions also occur. It is second only to methanol as a cause of inadvertent lethal poisoning in the USA. Nearly a fourth of the affected individuals are under 19 years of age, and over 10% of poisonings occur in children under the age of 6. Unlike methanol, EG has not been responsible for outbreaks of mass poisoning. However, media coverage of stories involving poisonings has been associated with a surge of copycat suicidal and homicidal attempts.
EG is metabolized by ADH to glycoaldehyde, and subsequently through a series of enzymes converted to glycolic acid, glyoxylic acid, and ultimately oxalic acid. It is these metabolites that are responsible for the toxic effects with multiorgan damage. Glycolic acid is the main culprit for severe metabolic acidosis, while oxalic acid also binds to calcium, leading to the formation of insoluble calcium oxalate crystals and hypocalcemia. Calcium oxalate crystals deposit in several organs, causing acute renal failure (primarily due to acute tubular necrosis) and myocardial, neurological, and pulmonary dysfunction. The toxic EG metabolites have numerous deleterious effects at the cellular level including impairment of oxidative phosphorylation, cellular respiration, glucose metabolism, and DNA replication. Similar to methanol toxicity, there are significant differences in individual susceptibility.
Autopsy studies have demonstrated crystalline deposits of calcium oxalate within the walls of small cerebral blood vessels with accompanying perivascular edema and inflammation. The intervening brain parenchyma shows variable degrees of vacuolization with evidence of neuronal loss, axonal swellings, and a patchy infiltrate of activated microglial cells. These changes tend to be more prominent in the midline thalamic nuclei and brainstem pontine nuclei. The leptomeninges may show a sparse inflammatory exudate. Renal tubular necrosis with calcium oxalate crystal deposition is a characteristic finding.
Clinical Scenario and Indications for Imaging
Acute EG intoxication usually proceeds through three successive stages: initial inebriation, followed by cardiopulmonary dysfunction, and finally severe acute kidney failure (approximately 30 min–12 h, 12–24 h, and 24–72 h after ingestion, respectively). However, the onset and progression of the clinical course is often not consistent or predictable. In stage 2, the accumulation of the toxic organic acids formed by EG metabolism leads to metabolic acidosis, hypocalcemia, muscle spasms, QT interval prolongation, and congestive heart failure. If untreated, death most commonly occurs during this period. Stage 3 kidney failure is secondary to formation of calcium oxalate crystals, resulting in decreased or absent production of urine, red blood cells, and excess proteins in the urine and elevated blood levels of potassium. Severe lethargy, coma, depression, vomiting, and seizures may be seen. The kidney failure is typically reversible, although weeks or months of supportive care including hemodialysis may be required.
The clinical diagnosis may be difficult in the absence of an appropriate history of ingestion. High index of suspicion for EG poisoning is essential in the presence of profound metabolic acidosis with an increased anion gap and high osmolal gap, which may be associated with hypercalcemia. Prompt treatment with an antidote, bicarbonate, and hemodialysis are the cornerstones of patient management, which may prevent the injury to the brain and kidneys. Antidote administration within 6 h is associated with better outcomes, unlike earlier time to dialysis, and fomepizole appears to reduce the need for hemodialysis.
Reduced diffusion within the white matter tracks of corona radiata and internal capsules may be present. Cases with isolated hemorrhagic globus pallidus lesions, simulating carbon monoxide toxicity, as well as bilateral hemorrhagic necrosis of putamen with involvement of white matter and globus pallidus, suggesting methanol intoxication, have been described in a few cases.
The characteristic lesions on neuroimaging studies tend to regress and even fully disappear after 5–35 days, even in patients with fatal outcomes. Delayed cranial nerve palsies, especially seventh nerve palsy, may present in EG poisoning survivors. Global cognitive impairment a few weeks post initial admission shows partial improvement at 6 months follow-up, however with remaining deficits in processing speed, naming, and constructional ability. EG intoxication therefore appears capable of causing lasting neuropsychological sequelae despite relatively normal neuroradiologic findings.
Organic solvents are found in almost any household cleaning agent or propellant, glue, and lighter fluid. They are highly lipophilic and may consist of various compounds that belong to several chemical families, including aromatic hydrocarbons, aliphatic hydrocarbons, alkyl halides, nitrites, ethers, ketones, and alcohols. Industrial organic solvents are also known as paint thinners or just “thinners” and toluene, an aromatic hydrocarbon, is typically the main ingredient. Toluene is also considered the most neurotoxic of the organic solvents.
Definition of Entity and Clinical Highlights
Toluene (methylbenzene) is a colorless liquid and a common component of many household products and industrial solvents. Exposure to toluene may be occupational, but it is the recreational abuse that has become widespread health and social problem throughout the world. Regular long-term abuse of toluene causes severe and irreversible cognitive impairment.
The first reports of solvent abuse, which is particularly prevalent but often overlooked form of substance abuse among adolescents, were published in the 1950s. School-based surveys revealed the rates of experimental solvent use up to 26%, likely due to its ease of access and low cost. The common methods of delivery are “sniffing” (direct inhalation of solvent from a container), “huffing” (inhalation of solvent by holding a soaked rag over the nose and mouth), and “bagging” (inhalation of solvent from a plastic bag). Toluene is typically inhaled for a transient sensation of euphoria and can become addictive. Acute effects include sudden sniffing death syndrome, asphyxia, and serious injuries. Chronic inhalant abuse can damage multiple organ systems and exposure during pregnancy can cause fetal abnormalities. Long-term occupational exposures, such as in dry cleaning, aviation, and chemical industries, may lead to chronic intoxication.
Despite its high prevalence and serious health and social consequences, relatively little is known about the mechanism of solvent-induced toxicity. Following inhalation, toluene, which is considered the cause of CNS toxicity, is easily absorbed by the lungs. Because of its high lipid solubility, it readily diffuses and accumulates in tissues with high lipid content, including the brain. Mechanisms of action appear to be similar to those of CNS depressants such as alcohol or barbiturates, however on a shorter time frame. The onset of symptoms occurs within seconds and typically disappears in 30 min or less. Toluene acts as N-methyl-D-aspartate (NMDA) receptor antagonist and free radical-induced lipid peroxidation by toluene or its metabolites has been suggested; however, the exact mechanism of injury remains unknown.
The autopsy findings reveal that long-term toluene exposure affects both grey and white matter with diffuse global atrophy. A severe loss of neurons in three layers of parietal cortex and of cerebellar Purkinje cells has been found, along with widespread demyelination, preferentially involving the cerebellar and periventricular white matter. There is also axonal degeneration of the long tracts extending into the spinal cord and optic nerve atrophy may be present.
Clinical Scenario and Indications for Imaging
Acute intoxication following inhalation is characterized by reversible behavioral changes, euphoria, hallucinations, and ataxia (“spray heads”), which may be followed by headache, nausea, and vomiting. Diagnosis is difficult and relies almost entirely on a thorough history and a high index of suspicion as no specific laboratory tests exist. Treatment is generally supportive because there are no reversal agents.
Chronic toluene toxicity can cause insomnia, dementia, progressive cerebellar dysfunction, secondary Parkinson disease, and visual and hearing loss. The cognitive deficits include attention deficit, memory dysfunctions, and visuospatial impairment. Timely diagnosis is important because patients may experience improvement in symptoms and deficits with cessation of exposure, whereas continued inhalant intoxication leads to severe permanent impairment.
On MR spectroscopy, the NAA levels are decreased, and myo-inositol increased in the cerebellar white matter and centrum semiovale, while no abnormalities have been detected in the thalami. Both the MRI and MRS findings correlate with the duration of abuse. In a group of patients who inhaled toluene for at least 1 year, the incidence of MRI abnormalities was as follows: white matter lesions in almost one half (two thirds after 3 years), atrophy in over a quarter (over a half after 5 years), and thalamic T2 hypointensity in a fifth (over a half after 6 years) (Aydin et al. 2002).
The severity of the white matter disease, smaller grey matter volumes, and development of thalamic hypointensity are correlated with the duration of abuse. The abnormal MRI findings are usually seen after at least 3–4 years of chronic abuse and are unfortunately irreversible at the time of detection. The cognitive deficits are associated with lower gray matter volumes in the frontal and parietal cortices of chronic toluene abusers.
Solvent abusers have abnormal MRI findings more frequently and perform more poorly than users of cocaine and alcohol on measures of working memory and executive cognitive functions. Also, a strong dose-response relationship was found in the presence of MRI abnormalities indicating that MRI may be more useful than neuropsychological tests for sorting out the presence of neurological abnormalities, including low-level solvent exposure in the occupational setting.
Opioid narcotics are a first-line treatment for pain and sales of prescription opioids (such as hydrocodone, oxycodone, codeine, fentanyl, meperidine, and methadone) have been increasing over the past few decades along with a rise in their nonmedical use, which has reached epidemic proportions in the United States. Unlike these synthetic opioids, heroin and morphine are alkaloid compounds derived from naturally occurring opium. Heroin has been the most commonly abused opioid and has the most significant adverse effects on the brain.
Definition of Entity and Clinical Highlights
Heroin (diacetylmorphine) is particularly susceptible to abuse and addiction, as approximately 23% of individuals who use heroin once go on to become dependent on it. Out of all recreational illegal drugs, heroin is considered to result in the highest overall harm to individuals and society. It has primary or direct, and secondary effects on the brain. Primary effects may be acute and chronic and include neurovascular disorders, leukoencephalopathy, and atrophy, while secondary complications are related to associated diseases, primarily infections.
Available data indicate that the nonmedical use of prescription opioids is a strong risk factor for heroin use. Among heroin users entering substance-abuse treatment programs, a significant shift in the pattern of the first opioid used was noted – in the 1960s, more than 80% reported that their first opioid was heroin; conversely, in the 2000s, 75% of users initiated opioid use with prescription narcotics.
Opioids act by attaching to three main classes of opiate receptors – mu, delta, and kappa. Heroin is highly lipophilic, readily crosses the blood-brain barrier, and can act on all three receptor types. Mu receptor activation triggers a complex cascade of intracellular signaling events, which ultimately lead to an increase in dopamine release in the nucleus accumbens. The resulting burst of dopamine in this critical area of the reward circuitry becomes strongly coupled with the subjective “high” that is caused by drugs of abuse.
Heroin neurotoxicity has multiple manifestations depending on the route of administration. Intravenously injected heroin can result in cerebral infarcts, with or without associated valvular heart disease. This may in some cases be a direct effect either through stimulation of mu receptors in vascular smooth muscles with resulting vasospasm or due to immune-mediated vasculitis. However, heroin frequently contains toxic contaminants, and injection of these impurities is likely the main cause of embolic infarctions. Postanoxic encephalopathy is one of the more frequent complications of intravenous heroin abuse.
“Chasing the dragon” refers to inhalation of smoke from heroin heated on a piece of foil, and it is associated with spongiform leukoencephalopathy (heroin-induced subacute leukoencephalopathy – HSLE, heroin-associated spongiform leukoencephalopathy – HASL). It is this particular toxic effect of heroin that will be further discussed in more detail. A specific etiology has not been identified and the prevailing theory suggests intermittent exposure to a toxic additive activated by heat or a combustion by-product, which may lead to dysfunction of the oligodendrocyte mitochondria. It could also be a direct effect of the highly lipophilic heroin and genetic predisposition may play a role. HSLE is a rare occurrence in heroin users; however, the number of undetected cases in drug-related deaths may be high.
HSLE falls along the spectrum of spongiform encephalopathy, with cerebral and cerebellar white matter degeneration, particularly involving the corticospinal and solitary tracts. Histology shows multivacuolar degeneration of oligodendrocytes with formation of intracytoplasmic vacuoles within the myelin sheath.
Clinical Scenario and Indications for Imaging
Ischemia is the most common acute neurovascular complication and typically involves globus pallidus – GP infarcts are present in approximately 5–10% of chronic heroin users. Additionally, diffuse symmetric white matter T2 hyperintensities compatible with microangiopathy can be seen.
HSLE occurs almost exclusively following inhalation of heroin vapors (“chasing the dragon”) and initial clinical appearance may be mistaken for withdrawal symptoms. Mortality is high (estimated at 23%) due to the nonspecific presentation and often unknown or unreliable clinical history. Brain MRI and/or CT are essential for prompt recognition and diagnosis, which is critical for timely treatment (Geibprasert et al. 2010, Tamrazi and Almast 2012).
The three clinical stages of HSLE have been described: stage 1 includes mostly cerebellar symptoms; slightly over a half of the patients develop stage 2, with worsening cerebellar and new extrapyramidal symptoms; a quarter of the intermediate stage patients advance to stage 3 with progressive stretching spasms, akinetic mutism, central pyrexia, and eventually death.
The disorder is self-limiting in most cases without progression to stage 3. Complications such as hydrocephalus and diffuse cerebellar swelling may require neurosurgical intervention. It seems that prolonged intensive care is of paramount importance and that white matter abnormalities may be slowly regressive. Following prolonged supportive care and ubiquinone (coenzyme Q) antioxidant therapy, the outcome was favorable in a patient who had stretching spasms for several days.
The most important secondary complication of heroin abuse is infections, particularly following endocarditis due to nonsterile intravenous administration. About a half of drug users with endocarditis will eventually develop neurologic complications, primarily brain abscesses (most commonly due to Staphylococcus aureus) and mycotic aneurysms involving cortical arteries or perforators, seen as small fusiform dilations with proximal and distal irregular narrowing on vascular imaging studies. These entities and imaging findings are discussed in the chapter “Neuroimaging in Bacterial and Mycobacterial Infections of the Brain and “Cerebrovascular Disease” section.
MR spectroscopy helps differentiate HSLE from other leukoencephalopathies demonstrating increased lactate and decreased N-acetyl aspartate (NAA) in the white matter, without grey matter abnormalities. In contrast to demyelination, there is no elevation of choline or lipid peaks. Heroin may also be responsible for acute myelopathy with T2 hyperintensity and cord expansion extending over multiple levels. In a few recently reported cases, a more diffuse and nonspecific cerebral white matter involvement with sparing of the subcortical U fibers has been noted.
MRI findings of spongiform leukoencephalopathy secondary to heroin vapor inhalation can progress despite apparent abstinence of the drug and during clinical improvement, suggesting the imaging changes may represent an evolving injury.
Use of illicit central stimulants (psychostimulants, stimulants) is a growing health problem. Common stimulants include cocaine, amphetamine, methamphetamine, ecstasy, and, increasingly, synthetic cathinones (or “bath salts”). Multiple drugs of abuse are associated with neurovascular complications; however, central stimulants are the hallmark drugs well known for producing both ischemic stroke and intracranial hemorrhage.
Definition of Entity and Clinical Highlights
Cocaine is a highly lipid soluble alkaloid, which is quickly absorbed across mucous membranes. Multiple neurological complications of cocaine include both ischemic and hemorrhagic cerebrovascular events, leukoencephalopathy, brain atrophy with chronic abuse, and increased incidence of congenital malformations in the setting of maternal use.
Cocaine is one of the most frequently used illegal recreational drugs, derived from the leaves of the coca plant as a hydrochloride salt. It is a fine white powder in this form, which can be snorted, rubbed along the oral gum line or injected. It can also be chemically modified with sodium bicarbonate and water into a free alkaloid and smoked as “crack.” Its effects can last from 5–10 min to an hour, depending on the amount taken and the route of administration. Cocaine binds tightly to the dopamine transporter to block its function. Dopamine subsequently accumulates within the synaptic cleft resulting in prolonged and enhanced dopaminergic signalling. It is also a vasoconstrictor via its inhibition of norepinephrine reuptake in the autonomic nervous system. Additionally, cocaine reversibly blocks sodium channels, interfering with the propagation of action potentials. Its major metabolites (primarily benzoylecgonine) are eliminated from the body over a period of several days. These active metabolites may continue to build up and contribute to the manifestation of adverse neurobiological complications several days after cocaine use.
Cocaine-induced brain damage can be divided into primary effects with toxic encephalopathy, secondary effects of compromised cerebral blood flow with ischemic and hemorrhagic stroke, and tertiary effects due to hypoxia as a result of cardiopulmonary collapse. For not clearly understood reasons, the alkaloid form is associated with equal frequency of ischemic and hemorrhagic strokes, whereas the hydrochloride form has much higher rates of hemorrhage. The causes of ischemic stroke include vasoconstriction, vasculitis due to unknown additives or impurities, and direct effects of cocaine on hemostasis (increased platelet aggregation and procoagulant effect by depletion of antithrombin III and protein C). Ischemic strokes may be present anywhere in the brain, but most often involve subcortical white matter in the MCA territory, basal ganglia, or midbrain (especially if used together with amphetamines). Almost a half of the patients have an underlying vascular pathology: AVM or aneurysm, which most likely rupture due to elevated blood pressure and increased heart rate from sympathomimetic effects of the drug. In patients without an underlying vascular pathology, the intraparenchymal hemorrhages are most often located in the deep grey matter.
Cocaine and other central stimulants also affect the integrity of the blood-brain barrier, which contributes to their toxicity. Cocaine facilitates migration of immune cells into the CNS and increases the secretion of pro-inflammatory cytokines. Cocaine-related leukoencephalopathy is most likely metabolic in nature and/or related to the substances used to adulterate the cocaine, out of which levamisole (originally an antihelminthic agent, which also has immune modulating properties and has been used for treatment of inflammatory disorders) is considered the main culprit. Levamisole increases endogenous opiate levels in the brain and alters monoaminergic function, which may at least in part explain its popularity as a cocaine additive.
Cocaine mixed with alcohol is one of the most frequent recreational drug combinations, which results in prolonged euphoric effects, with potentially lethal neurovascular or cardiovascular complications. The synergism is likely multifactorial due to enhanced cocaine absorption and inhibition of elimination, as well as formation of active metabolites, primarily cocaethylene. As with heroin, cocaine abusers are at increased risk for contracting infectious diseases such as HIV and HCV, not only from shared contaminated needles/drug paraphernalia but also from engaging in risky sexual behaviors during intoxication.
The autopsy histological findings of cocaine-related leukoencephalopathy may vary with survival period. Prominent axonal injury and axonal spheroids are observed with shorter survival and spongiform changes become apparent with a longer disease course. Necrosis has been found in all cases and its appearance changed with longer survival (acute and chronic complete infarct pattern), while no significant primary demyelination has been detected. These findings suggest that the primary defect is hypoxic-ischemic injury, predominantly in the white matter. Spongiform leukoencephalopathy likely represents the longer-survival incomplete infarct pattern, which may be more common with polydrug abuse.
Brain biopsy of presumed levamisole-induced lesions demonstrates active demyelination including myelin loss and accumulation of perivascular lymphocytes.
Clinical Scenario and Indications for Imaging
The association of cocaine use with sudden death due to myocardial ischemia and infarction is well recognized, and this risk appears to be amplified by concomitant cigarette smoking and alcohol consumption. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of its toxicity. Cocaine is the most frequent drug of abuse associated with cerebrovascular events. Hemorrhages generally occur within 1 h after use and frequently present over an extended time course with headache, encephalopathy, and bilateral neurological abnormalities. Cocaine-related deaths may also be a result of seizures followed by respiratory arrest. Seizures may be induced as a result of any combination of cocaine-induced hyperexcitability: cardiac arrhythmia, intracranial hemorrhage (from hypertension), and/or cerebral ischemia. Sudden death may occur following a single initial use or after repeated abuse.
Presumed levamisole-induced leukoencephalopathy has been successfully treated in the early phase with steroids, possibly combined with plasmapheresis or immunoglobulins in most patients.
Cocaine leukoencephalopathy, in contrast to heroin, does not show cerebellar involvement and preference for the posterior cerebral white matter; instead, there is a diffuse deep supratentorial white matter T2 hyperintensity predominantly affecting the frontal lobes being, with sparing of the subcortical U fibers, without contrast enhancement. MR spectroscopy shows increased lactate and decreased NAA levels. Another form of cocaine-related encephalopathy presents with (multi)focal and recurrent white matter lesions, which may also involve the brainstem and cerebellum variably exhibiting contrast enhancement, surrounding vasogenic edema and diffusion abnormalities. This type of leukoencephalopathy resembling demyelinating diseases may be associated with levamisole. Given the prevalence of cocaine abuse, it has been suggested that patients presenting with white matter disease indicative of ADEM or MS should be reviewed with respect to cocaine use.
Prominent nonspecific (“small vessel disease” type) T2 hyperintensities in the periventricular white matter tend to persist even after abstinence. Cerebral atrophy, presumably also due to chronic ischemia, is seen in late stages of chronic cocaine abuse: frontal lobes are typically most severely affected, followed by the temporal lobes.
Individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology, which is a strong risk factor for developing Parkinson’s disease later in life.
Amphetamines are available as capsules, tablets, or fluids. They can be swallowed, crushed and snorted, injected intravenously, or smoked. Like cocaine, amphetamine and its derivatives lead to an indirect stimulation of the nervous system through the release of neurotransmitters from their storage sites in nerve terminals via an inhibition of the vesicular monoamine transporter. This results in increased concentrations of norepinephrine, dopamine, and serotonin in the cytoplasm, which in turn leads to an increase in neurotransmitter activity. Acting through a variety of mechanisms, in addition to the release of dopamine from the mesocorticolimbic system and the nigrostriatal dopamine neurons, these drugs inhibit metabolic enzymes (such as CYP2A6 and MAO) and act as direct agonists on serotonin (5-HT) receptors. However, amphetamine lacks the ion channel-blocking properties of cocaine. Subsequent to these acute effects, the drugs produce persistent damage to dopamine and serotonin release in nerve terminals, gliosis, and apoptosis.
Similar to cocaine, coronary artery spasm may be induced in individuals with or without atherosclerotic disease and may lead to myocardial infarction. Neurobiological complications may include insomnia, hyperexcitability, aggressive behavior, and convulsions. Amphetamine-induced seizures also have the potential to induce cardiovascular failure and death. After cocaine, amphetamines are the second leading cause of strokes in persons under 45 years of age. In a chronic user, the strokes usually occur in the first few hours after ingestion, initially typically manifesting with a headache, which then progresses into a focal deficit and impaired level of consciousness.
Especially when used chronically and intravenously, amphetamine and methamphetamine are the drugs most commonly associated with vasculitis on histology. This, along with a sudden elevation in blood pressure, may result in subarachnoid or intracerebral hemorrhage and ischemic infarction, primarily affecting small vessels. The presumed mechanisms include vasoconstriction as well as acute hypersensitivity reaction, perhaps due to contaminants in the solution, if injected intravenously. Similar to cocaine and likely due to these complications, chronic amphetamine abuse may result in brain atrophy with neuronal damage and glial proliferation.
Methamphetamine and Ecstasy
Ecstasy (3,4-methylenedioxymetamphetamine, MDMA), along with methamphetamine from which it is derived, is the most commonly abused of the amphetamines. Methamphetamine (METH) may be taken orally as a pill, but the crystalline form, often referred to as “ice” or “crystal meth,” is typically smoked, and may also be injected, with a subsequent euphoria that can last for hours. Ecstasy is usually ingested orally, commonly perceived as safer than other stimulants and a popular party drug due to its stimulating and mild hallucinatory effects. “Molly” (slang for “molecular”) refers to the pure crystalline powder form of the drug that is perceived by users as being even safer, as it is free of adulterants such as methamphetamine. Ecstasy may also be snorted in powder form and is commonly taken in combination with other substances of abuse, including smoked as an additive to marijuana.
In distinction to METH, ecstasy causes a rapid surge of serotonin release. Serotonin is the most potent vasoconstrictor in the brain, which may lead to a prolonged vasospasm with necrosis of the brain by stimulating 5-HT2A receptors in small vessels. The occipital cortex and globus pallidus are the most vulnerable brain regions due to the highest concentration of these receptors, which explains the relatively higher frequency of infarctions in these regions on imaging studies. There is also increasing evidence for a specific toxic effect on serotonergic axons in the thalamus. Ecstasy can lead to neurovascular inflammation, hemorrhage including SAH and potentially even de novo aneurysm formation with subsequent rupture, of intracranial and spinal arteries. Serious intracranial hemorrhagic complications have been seen in young healthy patients without preexisting cerebrovascular lesions following ingestion of the allegedly safe “Molly.”
While amphetamine derivates do not have specific neuroimaging correlates, they have also been associated with strokes as well as grey matter atrophy and an increase in T2 hyperintense white matter lesions on MRI. Polysubstance abuse by amphetamine users (frequently combined with ethanol, cocaine, and heroin) further complicates efforts to isolate the neuroimaging characteristics.
Cannabis (marijuana) is the most commonly used illicit drug and is generally regarded as having low acute toxicity. Tetrahydrocannabinol (THC) is the primary psychoactive component of natural cannabis, causing activation of the cannabinoid receptors that are heterogeneously distributed in the brain.
Acute cannabis toxicity typically manifests with neurobehavioral symptoms and vomiting. Cannabis use is also associated with an increased risk of psychosis in vulnerable individuals. While ischemic strokes have been reported in the literature, due to the widespread use of the drug and confounding problems of polydrug abuse, it is difficult and often impossible to establish whether these strokes are truly associated with cannabis or other drugs or are purely coincidental. The stroke pattern is nonspecific with imaging findings indistinguishable from those in strokes of other causes. There are a handful reported cases of brain infarcts occurring after use of marijuana without any confounding factors. A combination of direct THC neurotoxicity causing mitochondrial dysfunction and increased hydrogen peroxide production along with cerebral hypoxia/ischemia due to drug-induced vasoconstriction has been proposed as the underlying pathophysiological mechanism for natural cannabis.
Synthetic Cannabinoids (SCBs) are the widest class of novel psychoactive substances and their consumption for recreational purposes is a fairly recent and rapidly growing trend. SCBs first emerged in Europe, where they were marketed as “Spice” and then quickly spread throughout the USA as “K2.” Although often assumed to be “safe” and “legal” alternatives to cannabis, SCBs induce adverse effects that are rarely associated with THC. The increased toxicity may in part result from the combined actions of a complex mixture of different SCBs and their active metabolites. SCBs are also blended with additional compounds and several other toxic contaminants have been identified in various preparations. Many of the adverse effects are similar to natural cannabis but with greater toxicity. In addition to psychosis and seizures, cases of myocardial infarction, embolic stroke, and cardiac arrest have been reported due to use of SCBs. On the other hand, unlike cannabis, the typical urine drug screens will not detect these drugs effectively.
Exposure to heavy metals is a common phenomenon due to their prevalence in food and environment; their toxicity remains a major concern for public health. Concurrent exposure to heavy metals may have long-lasting effects on the brain. While the exact toxicological mechanisms are still unclear, the combination of metals may produce additive/synergetic effects as they share many common pathways for causing cognitive dysfunction.
Definition of Entity and Clinical Highlights
Lead is ubiquitous in our environment and is widely used in industry as a metal or as a compound. It has no physiologic role and is toxic to multiple organ systems including the CNS and lead exposure is arguably the oldest known occupational health hazard. Worldwide, lead intoxication (plumbism) most often occurs in 1–3-year-old children due to chewing of lead paint. The prevalence and severity of childhood lead poisoning have been greatly reduced with the removal of lead from paint and automotive fuel. Acute encephalopathy is a serious complication, which can be fatal or leave permanent neurological sequelae. Lead toxicity is much less common in adults and encephalopathy is rare. Chelation agents are used in therapy, but avoidance of further exposure to lead is the main modality of treatment.
Exposure to lead can take place either through inhalation of dust, fumes, vapors, or ingestion of contaminated foods or drinks. Because of its cumulative property, it can exert toxic effects at any level of exposure. Exposures have decreased dramatically with the elimination of lead-based paints, but poisonings continue to be seen, primarily in areas with older housing. Young children are prone to hand-to-mouth behaviors, which increases the intake of lead. Adult exposures tend to be occupational, such as by inhalation of lead-containing dusts related to remodeling of old homes, in battery manufacturing factories, and lead-glazed ceramics production, as well as with traditional ayurvedic medicine usage. Exposure through drinking water is occasionally seen with use of lead-containing pipes. Used lead-acid batteries are a major source of lead and organic lead compounds were historically a part of automotive fuel, causing significant lead deposits in the soil.
Lead colic was known to ancient physicians since the time of Hippocrates, but encephalopathy was first described in 1925, and it is much more common in children. Symptoms typically occur with serum levels over 40 μg/dl (normal <5 μg/dl in children, <25 μg/dl in adults), but adverse health effects have been documented even at lower levels. The usual manifestations of lead poisoning in adults are abdominal colic, anemia, and peripheral motor neuropathy. The largest series of 23 adults with lead encephalopathy occurred following consumption of illicit liquor contaminated by lead. Other manifestations include a dark blue lead line on the gums, hypochromic microcytic anemia, chronic tubulointerstitial renal disease, and lead bands at epiphyses of the long bones.
Ingested lead is absorbed by a higher rate in children or after fasting, while calcium, vitamin D, and iron deficiencies accelerate the absorption. Most of absorbed lead is deposited in bones, especially in adults. Many of the neurotoxic effects of lead are due to its ability to substitute for calcium in cellular processes. The adult brain is more resistant to the toxic effects, in part because of its capacity to sequester lead away from its mitochondrial site of action within cerebral and cerebellar neurons.
The brain is typically swollen and congested in acute encephalopathy, occasionally with petechial hemorrhages. Extensive tissue destruction with cavitation and thickening of the veins with cellular disorganization of their walls is present in severe chronic lead poisoning. There is also demyelination of the cerebral and cerebellar white matter. A specific pattern of calcifications in the vessel walls and perivascular spaces is found on histology, with small calcospherites which coalesce to form circumferential deposits in larger vessels. This distribution supports dystrophic calcification mechanism following vascular injury. The calcifications are most prominent in the cerebellum (granular layer, corpus medullare and dentate nuclei), while cerebral cortex, white matter, and deep gray matter structures may also be affected.
Clinical Scenario and Indications for Imaging
Acute lead encephalopathy presents as headache, vomiting, and ataxia. Severe poisoning can cause seizures, coma, and even death. Chronic encephalopathy due to lead toxicity presents with loss of concentration and memory, depression, lethargy, irritability, headache, tremor, ataxia, seizures, and behavioral abnormalities. In severe cases, development of cerebellar or cerebral edema may lead to lethal outcome. Chronic lead exposure in children leads to deficits in verbal intelligence, reading, mathematics, visual and spatial skills, fine and gross motor skills, language skills, and memory.
These alterations in mental status may represent an indication for an MRI and/or CT scan of the brain, especially if lead poisoning is not suspected. Neuroimaging, on the other hand, plays a minor role in the diagnosis of suspected plumbism. Plain skeletal and abdominal radiographs have been extensively used and may respectively reveal metaphyseal bands and lead foreign bodies in the gastrointestinal tract.
Acute lead encephalopathy presents as cerebral and especially cerebellar edema, predominantly in the cerebellar vermis, and may act as a midline posterior fossa mass, occluding the fourth ventricle with resultant obstructive hydrocephalus.
Primary and secondary prevention is of utmost importance and the first and most critical step in the treatment of lead poisoning is the removal of patients from the site of exposure and elimination of possible sources of lead. Chelating agents (D-penicillamine, DMSA – succimer, CaNa2EDTA, dimercaprol – BAL) are recommended only with high levels of lead (over 45 μg/dl); the specific agent and route of administration is chosen according to the blood level and symptoms. The imaging abnormalities may resolve following chelation therapy, along with clinical improvement with or without complete resolution of symptoms. The deficits may be irreversible, including cognitive decline in children, again indicating that emphasis should be on prevention rather than cure.
Definition of Entity and Clinical Highlights
Mercury exists in elemental (metallic), inorganic, and organic (methylated) forms. Organic mercury and mercury vapor are readily absorbed and cause essentially selective toxicity to the nervous system. The general population is primarily exposed to organic mercury from fish consumption, while artisanal small-scale gold mining is the world’s largest anthropogenic source of mercury vapor emission. As with toxicity from other heavy metals, the first step in treatment is to remove or substantially reduce the source of exposure, which may be all that is required in most cases.
The route of exposure and efficiency of absorption depends on the form of mercury. Mercury vapor is well absorbed through the respiratory route, but absorption of liquid elemental mercury is negligible. Therefore, the potential release of mercury from amalgam fillings in MRI scanners is likely without clinical relevance. Oral absorption of inorganic mercury compounds (used in skin-lightening and antiseptic creams and ointments) is poor to moderate depending on the precise form, while oral absorption of organic mercury is nearly complete. Organic mercury is most commonly found in methylmercury form (CH3Hg+). Once absorbed, mercury is distributed primarily to the CNS and kidneys. Methylmercury poorly crosses the blood-brain barrier, but it gets demethylated to elemental mercury, which passes the barrier easily. Mercury vapor is lipid soluble and highly diffusible, easily crossing the blood-brain barrier and placental barrier. Hg2+ ion, produced by oxidation of the vapor within cells, is believed to be the chief toxic species.
Occupational exposure is generally to mercury vapor and can nowadays occur in mining, thermometer factories, and dentistry. It was common in hat industry in the eighteenth and nineteenth centuries. In artisanal small-scale gold mining, mercury is used for gold-extraction, putting miners and nearby residents at risk of chronic metallic mercury vapor intoxication, which is affecting millions of people in parts of Africa, Southeast Asia, and South America. Gold miners add liquid mercury to the milled gold-containing ore, which results in a mercury-gold compound, called amalgam. Miners smelt this amalgam to obtain gold, vaporizing it and thereby inhaling the toxic fumes.
Organic mercury was used in the past as fungicide and as preservative (Thimerosal) in some vaccines until recently. Most modern exposures to organic mercury are through ingestion of contaminated fish, first reported in the 1950s in Japan as an epidemic traced back to contamination by a nearby factory, also referred to as Minamata disease. Methylmercury bioaccumulates up the food chain and large predatory species such as tuna and swordfish may contain high concentrations of mercury in their tissue. It is believed that methylmercury is primarily responsible for the brain damage in Minamata disease and may be related to inhibitory effects on GABA receptors and apoptosis. The selective vulnerability of certain brain areas has been attributed to differences in repair capacities of neurons. In the fetus, organic mercury disrupts the cytoarchitecture of the developing brain and has been associated with neuropsychological changes after birth.
Clinical Scenario and Indications for Imaging
Elemental mercury poisoning is characterized by the triad of intentional tremor, gingivitis, and erethism (bizarre behavior with excessive irritability). Typical symptoms of chronic metallic mercury intoxication in gold miners are tremor, ataxia, coordination problems, excessive salivation, and metallic taste. Classic symptoms of organic mercury poisoning are circumferential constriction of the visual fields, ataxia, and sensory disturbance, primarily perioral and extremity paresthesia.
Impairment of hearing and speech, and abnormal eye movements may also develop. There is typically a latent period between mercury exposure and symptom onset, lasting weeks to months.
Significant pathological changes are essentially limited to the nervous system. Acute poisoning with organic mercury leads to swelling of the brain and meninges with perivascular edema and cerebral demyelination. Neurons may show swelling or shrinkage with cytoplasmic eosinophilia, and occasional ischemic changes. The calcarine region, precentral and postcentral gyri, as well as Heschel’s (transverse temporal) gyri are predominantly affected. Late findings include prominent atrophy including degeneration of the pyramidal tracts, optic radiations, and central cerebral white matter. Disintegration and loss of neurons are basic findings on microscopic examination, and in more severe cases, the neurons in the calcarine area may entirely disappear (status spongiosus). Involvement of the cerebellar hemispheres is in the deeper portions, including loss of granule cells with preserved Purkinje cells. The sensory peripheral nerves are damaged selectively with regeneration in prolonged cases.
A few reports of inorganic and elemental mercury poisoning were associated with small T2 hyperintense cerebral white matter and deep grey matter lesions, which improved with treatment.
Clinical Cases and Sample Reports
History, clinical course, imaging and laboratory findings:
A 37-year-old male presented with sopor following unexplained agitation, restlessness, and disorientation on waking up after a night out with friends.
Metabolic acidosis with an increased anion gap, hypocalcemia, and slightly increased urea and creatinine levels were found on emergency admission.
Brain CT (a) was unremarkable.
Within a few hours, the patient was in coma and creatinine levels were increasing. Following hemodialysis, the patient regained consciousness and informed the clinical team that antifreeze had been poured into his drink.
Follow-up brain MRI 8 days after the admission revealed extensive central symmetrical T2 hyperintensities and slight swelling of the deep grey matter structures (transverse T2w and FLAIR, b and c, respectively). T2 hyperintensities with mild swelling were also present in the pons, predominantly dorsal (d). The involved supratentorial (arrows) and infratentorial (arrowhead) areas were T1 hypointense (e) and demonstrated increased diffusion (f). There was no evidence of hemorrhage.
The patient fully recovered.
Clinical history: A 24-year-old male presented with acute ataxia and dysarthria, reported increasing disbalance and clumsiness with multiple falls over 1 week.
Imaging findings: Brain MRI following admission shows bilateral symmetric T2 hyperintensity of the posterior limb of the internal capsule and posterior cerebral white matter (a). The signal alteration extends infratentorially with symmetric focal brainstem and diffuse cerebellar white matter T2 hyperintensity, giving the “bearded skull” appearance (b). The involved areas demonstrate increased diffusion on ADC maps (c). There were no additional lesions.
Clinical history: A 37-year-old female presented with thunderclap headache, followed by dehydration, hyperthermia, and rapidly developing aphasia, 12 h after ingesting ecstasy at a rave party.
Imaging findings: Brain MRI following admission reveals small scattered DWI bright lesions in the left MCA territory (a, b) with corresponding low signal on ADC maps (not shown), consistent with acute infarcts. Cerebral MRA shows multifocal arterial stenoses, most severe of the left greater that right proximal MCAs and ACAs (c and d). A follow-up MRA (e) demonstrates complete resolution of the findings.
A list of intracranial abnormalities on imaging studies caused by selected exogenous toxins. T2 hyperintense lesions on MRI are hypodense when present on CT images
Common or possible
Globus pallidus and cerebral WM BL symmetric T2 hyperintense lesions, reduced diffusion
Cerebral WM reduced diffusion (delayed leukoencephalopathy); cerebellar, hippocampal, other deep GM; hemorrhage
(Dorsolateral) putamen and cerebral WM BL symmetric T2 hyperintensity; hemorrhage in many cases
Other basal ganglia, including isolated globus pallidus reduced diffusion
Central mediobasilar BL symmetric T2 hyperintensity: deep GM, hippocampi, dorsal brainstem
Reduced diffusion WM involvement
BL symmetric WM T2 hyperintensity, loss of WM-GM differentiation; T2 hypointense BL thalami
T2 hypointense BL basal ganglia and cerebral cortex
Infratentorial and posterior cerebral WM BL symmetric T2 hyperintensity
Infarcts (globus pallidus); diffuse WM T2 hyperintensity, sparing of U fibers
Infarcts (globus pallidus, WM, other), intra and extra-axial hemorrhages, arterial irregularity and stenoses
Diffuse WM T2 hyperintensity, sparing of U fibers; focal demyelinating lesions (cocaine)
BL symmetric T2 hyperintensity posterior thalamus, lentiform nucleus, external capsule, insula; cerebellar and cerebral subcortical calcification
BL symmetric cortico-subcortical T2 hyperintensity, involving primarily occipital lobes and vermis
BL symmetric occipital cortico-subcortical T2 hyperintensity; occipital, vermian, and perirolandic BL symmetric atrophy
Scattered small T2 hyperintense WM lesions; isolated cerebellar atrophy
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