Toxic and Metabolic Brain Disease

CHAPTER 47 Toxic and Metabolic Brain Disease

Toxic and metabolic brain disease encompasses a vast and heterogeneous group of disorders that can cause a great deal of confusion to both clinicians and radiologists. Diagnosis of these disorders can be challenging, because their clinical and imaging characteristics are often nonspecific. A number of systems have been proposed to classify these disorders and have been based on, among other things, clinical features, histologic features, and biochemical features. Each classification system has its own relative advantages and disadvantages, and no one system is perfect from an imaging standpoint.

Even the distinction between “toxic disorders” and “metabolic disorders” is often unclear. Most metabolic disorders cause brain injury through the actions of accumulated toxic substances within brain tissue and can therefore reasonably be considered to be forms of toxic disease. For instance, in phenylketonuria, deficiency of the enzyme phenylalanine hydroxylase, which is responsible for the metabolism of phenylalanine to tyrosine, results in accumulation of alternate phenylalanine breakdown products that are toxic to developing brain structures.

Conversely, external toxins cause brain injury by disturbing normal cellular metabolism. Therefore, one could just as reasonably consider toxic disorders to be acquired forms of metabolic disease. Regardless of what one ultimately calls these disorders, they all produce the same end result, namely, injury to brain tissue.

Perhaps the most straightforward method of categorizing this broad family of diseases is to divide them into those that are congenital and those that are acquired. Congenital metabolic diseases, also commonly referred to as inborn errors of metabolism, usually manifest in infancy or early childhood and include several families of disease, such as the mitochondrial disorders, lysosomal storage disorders, peroxysomal disorders, and Golgi complex disorders. These diseases are not discussed here.

Acquired metabolic disorders can occur in adults and children and can be related to nutritional deficiencies, abnormalities of glucose and electrolyte levels, impaired organ function (liver and renal failure), or the effects of exogenous toxins.

Exogenous toxins may exert their effects on tissue either directly or indirectly. With direct toxicity, a toxin is able to cause tissue injury on its own without requiring metabolism into another compound. Indirect toxicity results when substances that are not directly toxic to tissues are subsequently broken down into toxic metabolites.

Specific toxins tend to affect specific regions of the brain selectively. This so-called selective vulnerability seen in toxic and acquired metabolic disease reflects several important physiologic factors, including, but not limited to, (1) regional cerebral blood flow and oxygen demand, (2) neurotransmitter distribution, (3) specific chemical affinities and vulnerabilities, and (4) developmental maturation at the time of intoxication. Each of these factors plays a role in determining what structures in the brain are affected and, ultimately, the clinical syndrome that arises as a result of exposure to a particular toxin.

In this chapter we review several of the more common toxic and metabolic brain disorders seen in the adult population.


Osmotic myelinolysis is a neurologic disorder seen primarily in the setting of chronically malnourished alcoholics. It occurs when rapid changes in serum osmolality take place, and the most common scenario in which it is seen is aggressive iatrogenic correction of hyponatremia. The result is extensive demyelination classically within the pons but also affecting other sites in the brain. Alternate names include central pontine myelinolysis and osmotic demyelination syndrome.



Hemichorea-hemiballismus (HCHB) is a syndrome associated with nonketotic hyperglycemia in patients with poorly controlled diabetes mellitus and is characterized by sudden onset of hemiballismus or hemichorea. This syndrome is also called hemiballismus-hemichorea, chorea-ballismus with nonketotic hyperglycemia, and nonketotic hyperglycemia.


Neurodegeneration with Brain Iron Accumulation

Neurodegeneration with brain iron accumulation (NBIA) is an autosomal recessive disorder characterized by dystonia, parkinsonism, and brain iron accumulation. Classic and atypical forms of disease have been described. In the classic form, disease onset is early and symptoms are rapidly progressive. In the atypical form of the disease, onset is later in life and symptoms progress more slowly. Other names include Hallervorden-Spatz syndrome, Hallervorden-Spatz disease, and pantothenate kinase–associated neurodegeneration (PKAN).


In the majority of patients with NBIA, the disease has been linked to a mutation in the PANK2 gene located on chromosome 20p13. PANK2 encodes a pantothenate kinase involved in the biosynthesis of coenzyme A from vitamin B5. PANK2 mutations are shown in all cases of classic NBIA and approximately one third of cases of the atypical form.9 Although the genetic mutation causing most cases of the disorder has been identified, the exact mechanism of tissue injury is not known. It has been hypothesized that deficiency of PANK2 leads to accumulation of cysteine-containing neurotoxic compounds in highly sensitive regions of the brain, resulting in tissue damage and edema. Accumulation of excess iron in normally iron-rich brain structures is suspected to be secondary to tissue damage in the disease.10


Wilson’s Disease

Wilson’s disease is a rare, autosomal recessive defect of copper metabolism that causes accumulation of abnormal amounts of copper in various tissues, with a predilection for involvement of the brain, kidney, and liver. Manifestations of Wilson’s disease include liver disease and neurologic symptoms. Alternate names include hepatolenticular degeneration, progressive lenticular degeneration, and Westphal-Strümpell pseudosclerosis.



Characteristic MRI findings in Wilson’s disease are T1 hypointense and T2 hyperintense lesions, most commonly in the basal ganglia, with involvement most frequently in the putamina, followed by the caudate and globus pallidus. Lateral putaminal involvement is a characteristic feature. Thalamic involvement is also common and typically affects the lateral nuclei with relative sparing of the dorsomedial nuclei. Cerebellar involvement may also be seen, particularly in the superior and middle cerebellar peduncles. Involvement of the brain stem, in particular the midbrain, is also common and may be limited to the dorsal or periaqueductal regions (Fig. 47-6). Contrast enhancement with gadolinium is not typical.18

One sign considered characteristic of Wilson’s disease is the “panda sign” in which T2W images demonstrate hyperintensity in the midbrain superimposed on low signal in the substantia nigra and red nucleus, giving the appearance of a panda face (see Fig. 47-6B). Pontine involvement with features similar to central pontine myelinolysis can also be seen.14 Atrophy is common; and in addition to deep gray matter involvement, abnormalities in the cerebral white matter may be seen in approximately 25% of patients with Wilson’s disease. White matter lesions are usually T2 hyperintense, are asymmetric, and have a frontal lobe predilection.14 Signal changes have been shown to reverse with treatment, and improvement on follow-up MRI has been shown to correlate with clinical response to treatment.16

One report of MR spectroscopy in a patient with Wilson’s disease describes the presence of lactate, a decreased NAA/Cr ratio, and a markedly increased ADC in a putaminal lesion.14

Patients presenting primarily with hepatic disease may demonstrate T1W hyperintensities in the striatal regions, as can be seen in other forms of chronic liver failure.14


Ethanol is the most widely used substance of abuse worldwide. In the United States, the prevalence of alcohol abuse is approximately 6% among males and 2% among females.3 Long-term alcohol abuse is known to induce selective neuronal damage, but the exact mechanism of injury (direct toxicity vs. toxicity of breakdown products) is unknown. Among the most commonly recognized effects of chronic alcohol abuse seen on neuroimaging are cerebral atrophy and cerebellar atrophy. Cerebellar atrophy has a greater correlation with alcohol use and is typically more marked in the rostral vermis and adjacent superior cerebellar surfaces (Fig. 47-7). In addition, demyelinating lesions in the cerebral white matter, similar to those seen in multiple sclerosis, have been described. The pathogenesis of demyelination in these cases is unknown.2

A common finding in patients with alcoholic cirrhosis and other forms of liver failure is symmetric high-signal intensity in the basal ganglia (Fig. 47-8). This finding can be seen in the absence of signs of hepatic encephalopathy and is believed to be caused by the deposition of paramagnetic substances, including copper and manganese, which have bypassed the detoxification system of the liver. Manganese poisoning, which typically presents as levodopa-resistant parkinsonism, and prolonged total parenteral nutrition (which is known to increase serum levels of manganese) also demonstrate similar basal ganglia hyperintensities on T1W MRI.19

In addition to having direct toxic effects on the brain, ethanol is associated with a number of clinical syndromes affecting the brain, including osmotic myelinolysis (discussed earlier), Wernicke encephalopathy, and Marchiafava-Bignami disease.

Wernicke Encephalopathy

Wernicke encephalopathy is a neurologic disorder that results from chronic thiamine deficiency. The disease is characterized by ocular abnormalities, ataxia, and confusion.3 Korsakoff psychosis, also caused by chronic thiamine deficiency, is frequently seen in conjunction with Wernicke encephalopathy and is characterized by more severe cognitive dysfunction and memory loss. The combination of these two entities is known as Wernicke-Korsakoff syndrome.


Marchiafava-Bignami Disease

Marchiafava-Bignami disease is a rare complication of chronic alcoholism characterized by necrosis of the corpus callosum. First described in 1903, the disease was initially linked to the consumption of massive amounts of an inexpensive red wine produced in the central regions of Italy. The disease is now linked to consumption of any type of alcoholic beverage. This disorder is also referred to as primary degeneration of the corpus callosum.

Jan 22, 2016 | Posted by in NEUROLOGICAL IMAGING | Comments Off on Toxic and Metabolic Brain Disease
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