(32-51A) Axial T1WI in a 31y patient with chronic liver failure demonstrates symmetric T1 shortening in the globi pallidi .

subsequent cerebrovascular events, seizures, or cognitive impairment.

Imaging

CT scans are invariably normal, and standard MR sequences (T2/FLAIR) typically show no abnormalities.

Nearly 80% of patients with TGA develop focal hippocampal abnormalities on DWI (32-49). Thin sections (3 mm) obtained at high b-values (at least 2,000) and higher field strength magnets increase sensitivity.

The typical findings of TGA are 1-2 mm of punctate or dot-like foci of restricted diffusion in the CA1 area of the hippocampus. These appear as hyperintensities along the lateral aspect of the hippocampus, just medial to the temporal horn. Lesions can be single (55%) or multiple (45%), unilateral (50-55%) or bilateral (45-50%) (32-50). The body of the hippocampus is most commonly involved, followed by the head.

DWI abnormalities in TGA increase significantly with time following symptom onset. Between 0-6 hours, 34% show foci of restricted diffusion. This increases to 62% in patients imaged between 6 and 12 hours and to 67% of patients between 12 and 24 hours. By day three, 75% of patients demonstrate abnormalities. Follow-up scans typically show complete resolution by day 10.

A few reported cases have demonstrated both hypoperfusion and hypometabolism in the hippocampus on PET or SPECT.

(32-51B) Coronal T1 C+ scan shows the symmetric basal ganglia hyperintensity as well as hyperintensity in both cerebral peduncles and substantia nigra . Findings are classic for chronic hepatic encephalopathy.

Differential Diagnosis

The two major differential diagnoses of TGA are stroke and seizure. A strategic embolic stroke isolated to the mesial temporal area, thalamus, or fornix can produce isolated amnestic syndromes and mimic TGA clinically. TGA lesions are often multiple. Their exclusive location in the hippocampus mitigates against typical embolic infarcts. However, acute isolated punctate hippocampal infarction can be indistinguishable from TGA based on imaging studies alone.

Seizures can cause transient diffusion restriction but typically involve moderate to large areas of the cortex. The dot-like lesions in TGA are distinctly different from the cortical gyriform ribbons of restricted diffusion seen in status epilepticus and the posterior-predominant lesions seen in hypoglycemic seizures.

Thiamine deficiency with acute Wernicke encephalopathy can present as a fulminant disorder with relative preservation of consciousness. Lesions are found in the medial thalami, mammillary bodies, periaqueductal region, and tectal plate. The hippocampi are spared.

Miscellaneous Disorders

Hepatic Encephalopathy

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver disease. HE is classified into three main groups: minimal HE (also known as latent or subclinical HE), chronic HE, and acute HE.

Although the precise mechanisms responsible for HE remain elusive, elevated blood and brain ammonia levels have been strongly implicated in the pathogenesis of hepatic encephalopathy.

Ammonia is metabolized primarily in the liver via the urea cycle. When the metabolic capacity of the liver is severely diminished, ammonia detoxification is compromised.

Nitrogenous wastes accumulate and easily cross the bloodbrain barrier. Ammonia and its principal metabolite, glutamine, interfere with brain mitochondrial metabolism and energy production. Increased osmolarity in the astrocytes causes swelling and loss of autoregulation and results in cerebral edema.

We first discuss chronic HE, then focus on the acute manifestations of liver failure and its most fulminant manifestation, hyperammonemic encephalopathy.

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Chronic Hepatic Encephalopathy

Chronic hepatic encephalopathy is a potentially reversible clinical syndrome that occurs in the setting of chronic severe liver dysfunction. Both children and adults are affected. Most patients have a longstanding history of cirrhosis, often accompanied by portal hypertension and portosystemic shunting.

NECT scans typically are normal or show mild volume loss. In the vast majority of cases, MR scans show bilateral symmetric hyperintensity in the globi pallidi and substantia nigra on T1WI, probably secondary to manganese deposition (32-51). T1 hyperintensity has also been reported in the pituitary gland and hypothalamus but is less common. The T1 hyperintensity in the striatopallidal system may decrease or even disappear completely after liver transplantation.

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Acute-On-Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is acute deterioration in liver function in an individual with preexisting chronic liver disease, commonly cirrhosis. Hepatic and extrahepatic organ failure—often renal dysfunction—is common in ACLF and is associated with substantial short-term mortality. Precipitating factors include bacterial and viral infections, alcoholic hepatitis, and surgery. In more than 40% of cases, no precipitating event is identified.

Changes in consciousness as a result of acute hepatic encephalopathy are common and range from mild confusion to coma. Imaging reflects a combination of chronic liver disease (see above) and superimposed changes of acute liver dysfunction, such as hyperammonemia with cortical edema (see below) or Wernicke encephalopathy (32-52).

Acute Hepatic Encephalopathy and

Hyperammonemia

Terminology. Acute hepatic encephalopathy (AHE) is caused by hyperammonemia, which can be both hepatic and nonhepatic. Hyperammonemia, systemic inflammation (including sepsis, bacterial translocation, and insulin resistance), and oxidative stress are key factors mediating clinical deterioration.

Etiology. Although acute hepatic decompensation is the most common cause of hyperammonemia in adults, drug toxicity is also an important consideration. Valproate, asparaginase, acetaminophen, and chemotherapy have all been implicated in the development of hyperammonemic encephalopathy. Other important nonhepatic causes of hyperammonemia include hematologic disease, parenteral nutrition, bone marrow transplantation, urinary tract infection, and fulminant viral hepatitis.

Inherited urea cycle abnormalities or organic acidemias such as citrullinemia and ornithine transcarbamylase deficiency are other potential causes of acute hyperammonemic encephalopathy (see Chapter 31).

Many patients with AHE have multiple systemic and metabolic abnormalities. Hypoxic injury, seizures, and hypoglycemia all exacerbate the acute toxic effects of ammonia on the brain.

Pathology. AHE is characterized grossly by laminar necrosis of the cerebral cortex. Severe cytotoxic edema in astrocytes with anoxic neuronal damage is the typical histologic appearance of AHE.

Clinical Issues. Early clinical manifestations of hyperammonemia can be seen with plasma ammonia levels of 55-60 μmol/L. Irritability, lethargy, vomiting, and somnolence are typical. Progressively decreasing consciousness, seizures, and coma are the principal manifestations of severe AHE and are usually seen when ammonia levels are at least four times the normal range.

AHE is a life-threatening disorder with high morbidity and mortality. There is a significant positive correlation between arterial ammonia and the presence of brain herniation.

Recognition and aggressive treatment of AHE are critical to patient outcome. Therapeutic strategies fall into one of three categories, ammonia-lowering strategies, treatment aimed at modulation of neurotransmitter action, and strategies aimed at modulating inflammation.

Imaging. In the early stages of AHE, NECT scans may show only minimal cerebral edema with mild sulcal effacement. As the brain swelling increases, the gray-white matter interfaces are "blurred," the hemispheres become diffusely hypodense, and complete central brain descending herniation ensues (3253A).

On T1WI, the gyri appear swollen and hypointense. The CSF spaces are compressed. Bilaterally symmetric T2/FLAIR hyperintensity in the insular cortex, cingulate gyri, and basal ganglia is typical, as is relative sparing of the perirolandic and occipital regions (32-53B). More diffuse cortical injury with involvement of the thalami and brainstem is also common. The hemispheric white matter is typically spared.

AHE restricts strongly on DWI (32-53C) (32-53D). MRS may show a glutamate-glutamine peak at short echo times.

Differential Diagnosis. The major differential diagnoses of AHE/hyperammonemia are hypoglycemia, hypoxic-ischemic encephalopathy, status epilepticus, and Wernicke encephalopathy. Hypoglycemia is a common comorbidity in patients with chronic HE. Acute hypoglycemia typically affects the parietooccipital gray matter, whereas early AHE may spare the posterior cortex. Serum glucose is low, and ammonia is normal.

Hypoxic-ischemic encephalopathy may be difficult to distinguish from AHE on imaging alone. Nevertheless, symmetric involvement of the insular cortex and cingulate gyri should suggest AHE. Status epilepticus is usually unilateral, and, although the thalamus is often involved, the basal ganglia

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are generally spared. Wernicke encephalopathy affects the medial thalami, mammillary bodies, tectal plate, and periaqueductal gray matter. The cerebral cortex and basal ganglia are less commonly involved.

ACUTE vs. CHRONIC HEPATIC ENCEPHALOPATHY

Chronic Hepatic Encephalopathy

•More common

•Etiology

○Chronic severe liver disease (cirrhosis)

•Imaging

○T1 hyperintense globi pallidi, substantia nigra

○Probably due to manganese deposition

Acute Hepatic Encephalopathy

•Rare

•Etiology

○Usually associated with hyperammonemia

○Acute liver decompensation (viral hepatitis, etc.)

○Drug toxicity (acetaminophen, valproate, etc.)

○Parenteral nutrition, infection

•Imaging findings = those of hyperammonemia

○Bilateral swollen T2/FLAIR hyperintense gyri

○Most severe: insular cortex, cingulate gyri

○± Basal ganglia, thalami

○DWI 4+

○MRS may show glutamate-glutamine peak

Bilirubin Encephalopathy

Terminology

Bilirubin encephalopathy (BRE), also known as kernicterus, is caused by hyperbilirubinemia. A milder form of chronic BRE is termed bilirubin-induced neurologic dysfunction (BIND).

Etiology

In kernicterus, the liver is basically unable to conjugate insoluble bilirubin into water-soluble bilirubin diglucuronide.

It is unclear how bilirubin gets into the brain. Neonatal hyperbilirubinemia results in unconjugated bilirubin passing across an immature or compromised blood-brain barrier.

Hyperbilirubinemia is associated with a number of predisposing conditions, including prematurity, hemolytic disorders (especially blood group incompatibility), breast feeding, significant loss of birth weight, polycythemia, and dehydration. Inherited or acquired defects of bilirubin conjugation, glucose metabolism, GI transit disorders, and drugs that compete with bilirubin for albumin binding are other factors that increase the risk of BRE.

Pathology

The cardinal gross pathologic feature is yellow discoloration of the globi pallidi, mammillary bodies, substantia nigra, subthalamic nuclei, hippocampi, dentate nuclei, and spinal cord (32-54). The major histologic feature of acute BRE is

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(32-54) Coronal autopsy specimen of bilirubin encephalopathy shows obvious yellow staining of the globi pallidi . (Courtesy R. Hewlett, MD.)

neuronal necrosis with little or no inflammatory reaction. Demonstration of bilirubin pigment within the neurons is uncommon.

Clinical Issues

Although neonatal jaundice is common, kernicterus is rare in developed countries. The estimated incidence in the United States is approximately five cases per year.

Not all infants with kernicterus exhibit symptoms. Neonates with overt hyperbilirubinemia present in the first few days of life. Jaundice, stupor, hypotonia, and poor sucking are followed by opisthotonus and hyperreflexia.

Findings in children with classic chronic kernicterus vary in severity. Most show some type of movement disorder, most commonly athetosis. Other abnormalities include auditory disturbances, oculomotor impairments (particularly upward gaze), and teeth with dysplastic enamel. Frank mental retardation is relatively uncommon.

Patients with BIND may show subtle neurodevelopmental disabilities without the classic clinical findings of kernicterus.

(32-55A) Axial T1WI in a 5d girl with bilirubin encephalopathy shows hyperintensity in the subthalamic nuclei and substantia nigra .

(32-55B) Sagittal T1WI in the same patient shows the hyperintensity in the subthalamic nuclei , midbrain , and dentate nuclei .

Imaging

MR is the procedure of choice, as CT is almost always normal. T1 scans during the acute stages of BRE show bilaterally symmetric hyperintensities in the globi pallidi (GP), subthalamic nuclei, substantia nigra, hippocampi, and dentate nuclei (32-55). The thalami and cortex are typically spared. T2 scans are typically normal in the acute stage.

Chronic BRE may show T2/FLAIR hyperintensity in the typical areas. Bilateral hippocampal sclerosis with volume loss and T2 hyperintensity is common.

DWI is normal in both acute and chronic BRE. MRS shows decreased NAA:Cho and NAA:Cr ratios. Preterm infants with BRE may demonstrate increased glutamate-glutamine.

Differential Diagnosis

The major imaging differential diagnoses of BRE are the other disorders that cause GP abnormalities. The GP is an area of especially high metabolic activity with significant glucose and oxygen demands, which is thus vulnerable to a number of metabolic and systemic diseases.

In term neonates with suspected BRE, the major differential diagnosis is acute hypoxic-ischemic injury (HII). In term HII, the putamen is the most commonly affected site. T2/FLAIR hyperintensity and restricted diffusion are typical in HII but absent in BRE.

Bilaterally symmetric T1 hyperintense GP are seen in chronic liver failure, hyperalimentation, and nonketotic hyperglycemia. Neurofibromatosis type 1 can also cause mild T1 shortening in the GP. Late sequelae of carbon monoxide poisoning can cause T1 shortening and T2 hyperintensity in the medial GP.

Uremic Encephalopathy

Uremic encephalopathy (UE) is a well-known complication in patients with renal failure and is characterized by a brain syndrome with various neurologic symptoms. UE can occur with any uremia, including glomerulonephritis, hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura.

Presentation and imaging findings depend on the site and extent of CNS involvement. Three general patterns have been described.

The most common type of UE is characterized by cortical involvement. Patients present with confusion, visual impairment, and headaches. Imaging findings are usually those of typical PRES (see above), and the edema is vasogenic. In especially severe cases, the cortex is diffusely affected (3256). Imaging abnormalities usually reverse when uremic toxins are removed by dialysis and metabolic acidosis is corrected.

In the basal ganglia type of UE, the patients are usually chronic diabetics who present with acute onset of encephalopathy. Movement disorders are common, and bilateral symmetrical T2/FLAIR hyperintensity in the basal ganglia and internal and external or extreme capsules are typical MR findings. Lesions may exhibit restricted diffusion. Hemorrhage is rare, and findings usually regress after dialysis.

Less commonly, nondiabetic, nonhypertensive dialysis-naive patients with uremia present with an atypical, predominately white matter pattern of involvement. Bilateral, symmetric

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T2/FLAIR hyperintensities and restricted diffusion in the centrum semiovale are present (32-57).

Hyperthermic Encephalopathy

Acute heat-related illness is a spectrum of disorders that ranges from minor heat cramps and heat exhaustion to lifethreatening heat stroke. Heat stroke is defined clinically as a core body temperature exceeding 40°C. It can cause delirium, seizures, and coma. Morbidity and mortality in patients suffering from heat stroke range between 10 and 50%.

Heat stroke can be exertional (exercise-induced) and nonexertional (classic) heat stroke. Classic heat stroke risk factors include high ambient temperature and humidity, dehydration, alcohol abuse, and some medications (antihypertensive or psychiatric). Both ends of the age spectrum—infants and the very old—are especially susceptible.

(32-56A) T2WI in an encephalopathic 8y girl with HUS and acute renal failure shows diffuse swelling with hyperintensity of the basal ganglia , thalami, and cortex . (3256B) DWI shows marked, symmetric restricted diffusion throughout the entire cortex , basal ganglia , and thalami. Uremic encephalopathy with combined cortical and basal ganglia involvement is shown.

(32-57A) T2WI in 13y girl with uremia and metabolic acidosis shows symmetric, confluent hyperintensity in the corona radiata . (3257B) DWI and ADC (not shown) demonstrate restricted diffusion in the WM of both hemispheres. This is acute uremic encephalopathy.

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Because the Purkinje cells in the cerebellum are especially susceptible to thermic injury, typical NECT findings include diffuse cerebellar edema (32-58A). The cerebral cortex and subcortical white matter can also appear diffusely hypodense

(32-58B).

MR may demonstrate T2/FLAIR hyperintensity in the cerebellum, basal ganglia/thalami, hippocampus, and cerebral cortex (32-58). Restricted diffusion in the affected areas is common.

Osmotic Encephalopathy

Acute electrolyte and osmolality disorders can cause alarming alterations in mental status. Extreme hyperosmolality is rare; hypoosmolar states are much more common. The most common hypoosmolar state is hyponatremia, and the most common osmotic encephalopathy is osmotic demyelination syndrome (ODS).

Terminology

ODS was formerly called central pontine myelinolysis (when it affected only the pons) or, if it involved both the pons and extrapontine myelinolysis, osmotic myelinolysis. ODS is now the preferred term.

Etiology

ODS occurs with osmotic stress, classically occurring when wide fluxes in serum sodium levels are induced by too-rapid correction of hyponatremia. ODS also occurs in many other disorders, such as AIDS, organ transplantation (particularly liver), hemodialysis, correction of hypoglycemia or hypernatremia, and hematologic malignancies (i.e., leukemia and lymphoma).

Serum hypotonicity triggers cells to lose inorganic and organic osmolytes to prevent catastrophic swelling. If the rise of serum tonicity surpasses the point of intracellular organic

osmole generation, the cells shrink, injuring oligodendroglial cells and separating myelin from axons. Oligodendrocytes, which form the myelin sheaths, are particularly vulnerable to osmotic changes. Myelin sheaths can rupture and split when osmotic stress on oligodendrocytes is severe.

Pathology

Location. ODS is traditionally considered primarily a pontine lesion (32-59) (32-62). However, multifocal involvement is common and typical. Only 50% of ODS cases have isolated pontine lesions. In 30% of cases, myelinolytic foci occur both outside and inside the pons. The basal ganglia and hemispheric WM are common sites. WM demyelination is exclusively extrapontine in 20-25% of cases.

Other parts of the CNS that can be involved in ODS include the cerebellum (especially the middle cerebellar peduncles), basal ganglia, thalami, lateral geniculate body, and hemispheric WM. Some ODS cases involve the cortex.

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Gross Pathology. Grossly, the central pons is abnormally soft and exhibits a rhomboid or trident-shaped area of grayish tan discoloration. The peripheral pons is spared. Laminar cortical necrosis can occur in ODS, either primarily or in association with hypoxia or anoxia. In such cases, the affected cortex appears soft and pale.

Microscopic Features. Microscopically, ODS is characterized by myelin loss with relative sparing of axons and neurons. Active demyelination without evidence of significant inflammation is typical. The presence of reactive astrocytes and abundant foamy, lipid-laden macrophages is characteristic.

Clinical Issues

Epidemiology and Demographics. ODS is a rare disorder, and its exact prevalence is unknown. It can occur at any age but is most common in middle-aged patients (peak = 30-60 years).

(32-59) Graphic shows acute osmotic central pontine demyelination . Note sparing of peripheral WM, traversing corticospinal tracts . (32-60) Low-power photomicrograph shows acute CPM with Luxol fast blue (myelin) stain. Note that demyelination (pink) largely spares the periphery of the pons and crossing transverse pontine WM tracts (blue). (From Agamanolis DP, Neuropathology, 2e, 2012.)

(32-61) Gross pathology of remote CPM shows triangular shape of brown discolored demyelinationin the central pons. (From Agamanolis DP, op cit.) (32-62) T2WI shows classic acute osmotic demyelination in CPM . The peripheral pons is spared as are the corticospinal tracts and transverse pontine fibers.

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There is a moderate male predominance. Pediatric patients with ODS typically have diabetes or anorexia.

The most common causes of ODS are rapid correction of hyponatremia, alcoholism, liver transplantation, and malnutrition.

Comorbid conditions that predispose patients to developing ODS include renal, adrenal, pituitary, and paraneoplastic disease. Prolonged vomiting (e.g., hyperemesis gravidarum), severe burns, transplants, and prolonged diuretic use may all contribute to the development of ODS.

In hyponatremic patients, the initial step is to differentiate hypotonic from nonhypotonic hyponatremia. The former is further differentiated on the basis of urine osmolality, urine sodium level, and volume status. Recently identified parameters including fractional uric acid excretion and plasma copeptin concentration improve diagnostic accuracy.

Presentation. The most common presenting symptoms of ODS are altered mental status and seizures. A biphasic clinical course is common. As normonatremia is restored, mental status improves but can then rapidly deteriorate. Other findings include pseudobulbar palsy, dysarthria, and dysphagia. Movement disorders are common when myelinolysis involves the basal ganglia.

Natural History. The outcome of ODS varies significantly, ranging from complete recovery to coma and death. Some patients survive with minimal or no residual deficits. In severe cases, the patient may become quadriparetic and "locked in."

Treatment Options. Initial serum sodium in ODS is usually under 115-120 mmol/L and serum osmolality less than 275 mOsm/kg. Although there is no consensus regarding the optimal correction rates for hyponatremia, correction of more than 12 mmol/L/day seems to increase the risk of ODS.

ODS may also occur (1) in normonatremic patients and (2) independent of changes in serum sodium!

Imaging

General Features. Imaging findings in ODS typically lag 1 or 2 weeks behind clinical symptoms.

CT Findings. NECT scans can be normal or show hypodensity in the affected areas, particularly the central pons (32-63A).

MR Findings. Standard MR sequences may be normal in the first several days. Eventually, ODS becomes hypointense on T1WI and hyperintense on T2/FLAIR. The lesions are typically well demarcated and symmetric. Pontine ODS is often round or sometimes "trident"-shaped (32-61) (32-63C). The peripheral pons, corticospinal tracts, and transverse pontine fibers are spared (32-62). Involvement of the basal ganglia and hemispheric WM is seen in at least half of all cases ("extrapontine myelinolysis").

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T2* (GRE, SWI) shows no evidence of hemorrhage.

In approximately 20% of acute ODS cases, enhancement in the midline and rim of the affected region may form a distinct "trident-shaped" lesion. Late acute or subacute ODS lesions may demonstrate moderate confluent enhancement on T1 C+ (32-64). Enhancement typically resolves within a few weeks after onset.

DWI is the most sensitive sequence for acute ODS and can demonstrate restricted diffusion when other sequences are normal (32-64D) (32-65). DTI shows disruption of central pontine WM with sparing of peripheral, transverse tracts (3266).

Differential Diagnosis

The major differential diagnosis of "central" ODS is pontine ischemia-infarction. Basilar perforating artery infarcts involve the surface of the pons and are usually asymmetric.

(32-67A) T1WI of the posterior fossa in a patient with newly diagnosed multiple sclerosis shows no abnormalities. (32-67B) More cephalad scan through the basal ganglia shows no abnormalities. Signal intensity in the globi pallidi is normal.

(32-67C) Axial T1WI in the same case 12 years later after multiple scans with GBCA were administered to assess disease course and treatment response shows distinct hyperintensity in both dentate nuclei . (3267D) More cephalad T1WI shows interval development of T1 shortening in both globi pallidi . Note less striking but definite hyperintensity in the pulvinars of both thalami. This is presumed gadolinium deposition.

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Demyelinating disease can involve the pons but is rarely symmetric. Sagittal FLAIR scans usually demonstrate lesions elsewhere, especially along the callososeptal interface.

Neoplasm rarely mimics ODS. Pontine gliomas can expand the pons and appear hyperintense on T2/FLAIR scans. They are neoplasms of children and young adults. Metastatic disease in the posterior fossa is typically in the cerebellum, not the pons.

The major differential diagnosis of extrapontine ODS with basal ganglia and/or cortical involvement is metabolic disease.

Hypertensive encephalopathy (PRES) can involve the pons but does not spare the peripheral WM tracts. The basal ganglia are affected in Wilson disease and mitochondrial disorders, but the pons is less commonly involved.

OSMOTIC DEMYELINATION SYNDROMES

Terminology, Etiology

•ODS (formerly pontine, extrapontine myelinolysis)

•Serum hypotonicity → cells lose osmoles, shrink

•Oligodendrocytes especially vulnerable to osmotic stress

•Note: can occur without serum sodium disturbances!

Location

•50% pons (spares periphery, transverse pontine tracts)

•30% pons + extrapontine (BG, thalami, WM)

•20-25% exclusively extrapontine

•± Cortical laminar necrosis

Imaging

•Hypointense on T1, hyperintense on T2

○"Trident" sign on T2WI, T1 C+ in acute ODS

•May restrict on DWI

fibrosis (NSF) was linked to GBCA administration in patients with advanced renal disease, and the FDA has subsequently mandated a "black box" warning on all patients with eGFRs less than 30 mL/min/1.72-m².

GBCA-related toxicities arise from the deposition of gadolinium ions in various tissues, which also varies among the different GBCAs. All GBCAs consist of a gadolinium ion (GD³ ) complexed with a chelating ligand. In general, macrocyclic and ionic agents have higher stability than linear and nonionic agents, respectively. Immediate adverse reactions to GBCAs are uncommon, and serious ones are exceedingly rare.

A number of studies have reported a significant correlation between the degree of hyperintensity in the dentate nucleus and globus pallidus on T1WIs and the number of previous GBCA administrations. Increased signal intensity of these structures on unenhanced T1WIs can be a possible consequence of multiple applications of GBCAs even in the absence of renal impairment (32-67).

Although some authors have used the term gadolinium deposition disease and linked it to various clinical symptoms, to date there are no well-controlled, independently validated studies that support such an association.

Iron Overload Disorders

Iron overload disorders encompass a broad spectrum of both inherited and acquired etiologies. Elevated brain iron in myelinated structures has been demonstrated in hemochromatosis and inherited neurodegeneration with brain iron accumulation. Inherited disorders of iron metabolism are discussed in Chapter 31. Acquired iron overload disorders are briefly addressed here.

Heavy Metal Deposition Disorders

Various metals are essential nutrients in humans; concentration abnormalities may cause metal deposition in the brain. Many metals affect the signal intensity of brain structures on MR. A few of these are discussed in this closing section. Gadolinium deposition from repeated MR contrast administration causes high signal intensity in the dentate nucleus, globus pallidus, and pulvinar.

Brain iron deposition occurs as a part of normal aging. However, excessive iron is neurotoxic. Ferritin, a protein that contains iron nanoparticles, induces reactive oxygen species formation and inhibits glutamate uptake from synaptic junctions, potentially leading to neurodegeneration.

Acquired brain iron overload is called siderosis. When iron deposition occurs along cranial nerves or the pial surface of the brain, it is termed superficial siderosis.

Hemochromatosis is the pathologic accumulation of intracellular iron in parenchymal tissues.

In the brain, superficial siderosis is more common than iron accumulation within the cortex itself (i.e., hemochromatosis). Superficial siderosis is usually caused by trauma, tumor, prior surgery, or repeated subarachnoid hemorrhage from an arteriovenous malformation or aneurysm. Amyloid angiopathy is a common cause of siderosis in elderly patients.

The pituitary gland, especially the anterior lobe, is very sensitive to early toxic effects from iron overload. Progressive iron deposition causes pituitary hypointensity on T2WI.

Manganese Deposition

Manganese overload causes high signal intensity in the globi pallidi on T1WI and is commonly identified in patients with chronic liver disease (32-51) (32-52).

Gadolinium Deposition

Gadolinium-based contrast agents (GBCAs) have been widely used in MR for almost 30 years. Initially, the use of GBCAs was felt to carry minimal risk. In 2006, nephrogenic systemic

Iron deposition in the choroid plexus occurs in the setting of hematologic dyscrasias such as sickle cell disease. NECT scans are typically normal, but T2* (GRE, SWI) MR shows symmetric "blooming" hypointensity in the choroid plexus. Superficial siderosis along the brain surfaces and cranial nerves is usually linked with repeated subarachnoid hemorrhages. T2* scans show "blooming" along the pial surfaces.