Toxic and Metabolic Disorders

Abstract

Metabolic diseases are mostly congenital inborn errors leading to functional defects in metabolic pathways, whereas toxic and metabolic diseases in adults are usually acquired. MRI is the cornerstone in the assessment of these patients. The final diagnosis is often established in combination with laboratory findings and/or genetic analysis. Imaging patterns are almost invariably bilateral and often symmetric or nearly symmetric. The basal ganglia and thalami are often involved in acquired metabolic and toxic diseases. This chapter focuses on the most common inborn errors of metabolism that can present or persist into adulthood, as well as on the most common acquired metabolic and toxic disorders, relevant to daily clinical practice.

FormalPara Learning Objectives

• To be familiar with the most common metabolic disorders presenting or persisting into adulthood.

• To evaluate the most common toxic encephalopathies, relevant to daily clinical practice.

• To recognize the typical imaging patterns of these disorders on MRI and be able to postulate a differential diagnosis.

FormalPara Key Points

• MRI is the cornerstone in the assessment of CNS manifestations of toxic and metabolic diseases, in combination with laboratory and/or genetic testing.

• Imaging patterns are almost invariably bilateral and often symmetric or nearly symmetric. In acquired metabolic and toxic diseases, the basal ganglia and thalami are often involved.

• Adult-onset cerebral ALD accounts for about 5% of cases and presents typically with extensive symmetric white matter lesions displaying contrast enhancement in the regions of active demyelination.

• Metachromatic leukodystrophy is the most common hereditary leukodystrophy. Krabbe disease is a differential diagnosis.

• MELAS should be considered when stroke is encountered in adolescents, especially when there are multiple infarcts in different stages.

• Alexander disease presents with abnormalities in the lower brainstem.

• Wernicke encephalopathy typically presents with abnormalities around the midline organs in the diencephalon or mesencephalon.

• Subacute combined degeneration is the only toxic-metabolic disease presenting with abnormalities in the medulla.

• Hypoglycemic encephalopathy presents with cytotoxic edema in the gray matter structures with typical sparing of the thalami.

1 Introduction

Metabolic diseases in children are mostly congenital inborn errors leading to functional defects in metabolic pathways, whereas toxic and metabolic diseases in adults are usually acquired.

Congenital metabolic disorders in children are a vast and highly specialized field, and the detailed knowledge of these belongs to the remit of tertiary referral centers.

This chapter focuses on the most common inborn errors of metabolism that can present or persist into adulthood, as well as on the most common acquired metabolic and toxic disorders, relevant to daily clinical practice [1].

The clinical presentation of these patients is often non-specific. Neuroimaging is the cornerstone in the workup of patients suspected of being affected by a toxic or metabolic disorder. The final diagnosis is most often reached in combination with laboratory analysis and genetic testing in case of congenital disorders.

Magnetic resonance imaging (MRI) is the preferential imaging modality to assess toxic and metabolic disorders in the brain due to its superior contrast resolution. Nonetheless, computer tomography (CT) has an added value in the detection of intracranial calcifications. Susceptibility-weighted imaging (SWI) is a valid alternative for detecting intracranial calcifications, especially when using phase information. Nonetheless, the accuracy is lower compared to CT.

The topographic distribution of brain pathology in toxic and metabolic disorders is a reflection of the metabolic pathways involved and the metabolic activity, often depending on age. Imaging patterns are almost invariable bilateral, often symmetrical or near-symmetrical. The basal ganglia and thalami are especially susceptible to injury due to their extensive energetic requirements related to the involvement in a myriad of processes related to the pyramidal and extrapyramidal systems.

2 Most Common Congenital Metabolic Disorders Presenting or Persisting into Adulthood

2.1 X-Linked Adrenoleukodystrophy (ALD)

X-linked adrenoleukodystrophy is a disorder of peroxisomal fatty acid beta-oxidation leading to the accumulation of long-chain fatty acids, which can manifest itself in childhood (typically around 7 years of age) or in adult life. Adult-onset cerebral ALD accounts for about 5% of cases and usually presents with psychiatric symptoms, followed by dementia, ataxia, and seizures. As an X-linked disorder, ALD is more frequent in males. However, around 15–20% of heterozygote female carriers become symptomatic.

The typical MRI appearance is T2- and FLAIR-hyperintense white matter abnormalities starting in the parieto-occipital regions with early involvement of the splenium of the corpus callosum and corticospinal tracts. These signal abnormalities correspond to areas of demyelination. Active demyelination at the edge of the lesions is associated with contrast enhancement and restricted diffusion on diffusion-weighted imaging (DWI) (Fig. 9.1) [2].

Fig. 9.1

A 16-year-old boy presented with progressive gait difficulties and behavioral disturbances. MRI shows extensive white matter lesions centered around the splenium of the corpus callosum, extending in the biparietal white matter. Similar but less pronounced abnormalities can be seen in the frontal lobes centered around the genu of the corpus callosum. Furthermore, there is hyperintensity on T2-weighted sequences along the corticospinal tracts. There is associated contrast enhancement in the areas of active demyelination. The diagnosis of X-linked adrenoleukodystrophy was confirmed on genetic testing. (a) Transverse T2-weighted image. (b) Transverse T2-weighted image. (c) Transverse T2-weighted image. (d) T1-weighted black blood image after gadolinium administration. (e) T1-weighted black blood image after gadolinium administration

Adrenomyeloneuropathy (AMN) is an adult phenotype with onset in the second decade to middle age, presenting with slowly progressive spastic paraparesis, bladder and bowel dysfunction, sexual dysfunction, and peripheral neuropathy, related to predominant involvement of the spinal cord. Typical imaging appearances include increased T2/FLAIR signal in the posterior limbs of the internal capsules, brainstem, and cerebellar white matter which may be followed by spinal cord atrophy.

2.2 Globoid Cell Leukodystrophy (Krabbe Disease)

Globoid cell leukodystrophy (GLD) has been linked to a mutation in the GALC gene on chromosome 14, leading to a deficiency of galactosylceramide β-galactosidase that causes accumulation of sphingolipids in the lysosomes. Late adolescent and adult forms (10%) present with slowly progressive gait abnormalities or spastic paresis. Other features include cognitive decline, seizures, and cortical blindness.

MRI shows predominantly posterior T2/FLAIR-hyperintense white matter changes with sparing of the U-fibers and involvement of the splenium of the corpus callosum, extending along the corticospinal tracts into the posterior limbs of the internal capsules and the pyramidal tracts. In some cases, there is a bilateral hyperdense signal on CT, corresponding to T1-hyperintense and T2-hypointense signal in the thalami. The affected areas do not show contrast enhancement.

Other lysosomal storage diseases, such as gangliosidoses and neuronal ceroid lipofuscinosis may also show the typical thalamic signal alterations. Metachromatic leukodystrophy is a differential diagnosis.

2.3 Metachromatic Leukodystrophy (MLD)

Several variants of metachromatic leukodystrophy have been described, all of which have deficient activity of arylsulfatase A, which results in defective degradation of sulfatides in the lysosomes and impaired myelination or dysmyelination. It is the most common hereditary leukodystrophy.

Approximately 20% of MLD patients have disease onset in adulthood, often with psychiatric symptoms, followed by spastic paraparesis, cerebellar ataxia, and cognitive decline.

MRI demonstrates symmetrical areas of confluent T2-hyperintense signal in the periventricular white matter with sparing of the subcortical U-fibers. Early involvement of the peritrigonal or periatrial white matter, corpus callosum, and cerebellar white matter is common, showing typically a “tigroid” pattern of radiating stripes. The white matter around the frontal horns is often affected to a lesser degree. As opposed to ALD, there is no contrast enhancement of the lesion edge. The lesions show restricted diffusion. Occasionally, multiple cranial nerve enhancement can be observed.

The main differential diagnosis is Krabbe disease, as the tigroid pattern has also been described in this disorder.

2.4 Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a typical example of a mitochondrial disorder, with the involvement of multiple organs and often predominant manifestations in the central nervous system. About 40% of patients present in late childhood or early adulthood.

Clinical features are muscle weakness, extreme tiredness, and gastrointestinal symptoms such as vomiting and abdominal pain. Other features include seizures, hearing loss, and neuropsychiatric dysfunction.

MRI demonstrates a combination of infarcts in different stages, not confined to the major vascular territories. There is a predilection for the parieto-occipital regions and the cortical and deep gray matter. Vascular imaging is normal. The signal intensity of the lesions on T2/FLAIR-weighted sequences, diffusion-weighted imaging, and T1-weighted sequences with and without contrast depends on the time of onset.

2.5 Fabry Disease (Galactocerebrosidase Deficiency)

Fabry disease is a lysosomal storage disease related to a deficiency of a-galactosidase. It is an X-linked inherited disorder with varied clinical presentations and an estimated prevalence of 1 in 50,000. The deposition of globotriaosylceramide-3 in the endothelium and smooth muscles leads to the involvement of multiple organ systems, including the blood vessels, heart, and kidneys.

Macro- and microvascular complications are the leading CNS manifestations, with the first cerebrovascular event usually occurring around 40 years of age.

CT and MRI features are those of macrovascular disease (acute or chronic infarcts and parenchymal hemorrhage) and signs of microvascular disease (hyperintense foci in the periventricular and subcortical white matter and cerebral microhemorrhages).

Characteristic MRI features of Fabry disease are the uni- or bilateral T1 hyperintense signal in the pulvinar of the thalamus (the “pulvinar sign”) and ectasia of the basilar artery on MR angiography, which has been found to be one of the best indicators of the presence of the disease in adults. Nonetheless, the incidence of the “pulvinar sign” is low, around 3%.

The main differential diagnosis is with the other lysosomal storage diseases.

2.6 Alexander Disease

Defects in the glial fibrillary acidic protein gene have been identified as the underlying cause of Alexander disease. Approximately 25% of patients present in adulthood, most commonly with bulbar dysfunction, pyramidal involvement, cerebellar ataxia, and sleep abnormalities.

In adult-onset disease, MRI findings consist of atrophy and abnormal T2-hyperintense signal within the medulla oblongata and upper cervical cord, which has been termed a “tadpole” appearance. The upper brainstem is almost never involved. Sometimes, there are periventricular white matter changes.

2.7 Primary Familial Brain Calcification (PFBC)

Primary familial brain calcification, formerly known as idiopathic basal ganglia calcification, bilateral strioapallidodentate or Fahr disease is a group of genetic disorders with currently 4 known mutations that are inherited in an autosomal dominant pattern. Symptomatic patients present in the late 40 s with a mostly Parkinsonian movement disorder, followed by cognitive decline, cerebellar features, and speech disorders.

Symmetrical calcification involving the lentiform nuclei, caudate nuclei, thalami (especially the posterolateral part), and dentate nuclei is mostly readily detected by CT. The cerebral and cerebellar cortex and the brainstem can be affected to a lesser degree. On MRI, the structures involved may show high signal on T1-weighted spin echo sequences and signal loss on susceptibility-weighted imaging. In some cases, there are additional confluent white matter lesions.

The differential diagnosis encompasses causes of secondary calcifications, primarily hypoparathyroidism.

3 Acquired Metabolic/Toxic Disorders

3.1 Wernicke Encephalopathy (WE)

Wernicke encephalopathy (WE) is caused by a deficiency of vitamin B1 (thiamine), which may be due to alcohol abuse, malabsorption, poor nutrition, increased metabolism, or iatrogenic elimination (hemodialysis). Thiamine depletion leads to failure of conversion of pyruvate to acetyl-CoA and α-ketoglutarate to succinate and the lack of Krebs cycle resulting in cerebral lactic acidosis with intra- and extracellular edema, swelling of astrocytes, oligodendrocytes, myelin fibers, and neuronal dendrites.

The classic clinical triad of ocular dysfunctions (nystagmus, conjugate gaze palsy, ophthalmoplegia), ataxia, and confusion is observed only in 30% of cases. Treatment consists of thiamine infusion, which can prevent progression to Korsakoff’s dementia or death.

MRI shows T2/FLAIR hyperintensities in the periaqueductal and medial thalamic regions, mammillary bodies, hypothalamus, tectum, and cerebellum. The supratentorial lesions are most often symmetric. Contrast enhancement occurs most often in the mammillary bodies (80% of cases), often prior to T2 hyperintensities, or in the periaqueductal regions (50% of cases). The diffusivity of the lesions may vary.

Imaging abnormalities may regress with treatment. However, the prognosis is usually poor once there is cortical involvement or T1-hyperintense signal in the thalami and mammillary bodies indicating hemorrhage.

Chronic cases show atrophy of the mammillary bodies.

3.2 Subacute Combined Degeneration (SCD)

Subacute combined degeneration is a disorder of the spinal cord secondary to vitamin B12 deficiency, characterized by potentially reversible demyelination of the posterior and lateral columns. Clinical presentations are spastic paraparesis and spinal ataxia.

MRI demonstrates longitudinal, extensive T2 hyperintense signal in the posterior and lateral columns of the cervical spinal cord and to a lesser extent of the dorsal spinal cord. On transverse T2-weighted images, the pathological T2-hyperintense signal in the posterior spinal cord is called the “inverted V-sign.” Findings may regress after adequate B12 administration. Chronic non- or undertreated cases show spinal cord atrophy. Brain abnormalities in patients with SCD are rare. There are a few case reports of leukoencephalopathy with T2-hyperintense signal in the centrum semiovale and enhancement of the optic nerves.

3.3 Osmotic Demyelination Syndrome (ODS)

Osmotic demyelination syndrome includes central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) and occurs in patients with hyponatremia that has been corrected too quickly.

The traditionally proposed pathophysiological mechanism is a disruption of the blood–brain barrier resulting in vasogenic edema, white matter compression, and myelinolysis. Additional implicated mechanisms are cerebral dehydration, intramyelinic edema, and oligodendrocyte degeneration. The most common damage is in the central pontine fibers. Extrapontine demyelination which may affect the basal ganglia, thalami, lateral geniculate nucleus, cerebellum, or cerebral cortex occurs in combination with CPM or in isolation in approximately 10% of cases.

Clinical symptoms of CPM include paralysis, dysphagia, dysarthria, and pseudobulbar palsy.

The typical feature of central pontine myelinolysis is T2/FLAIR-hyperintense signal in the central pons showing a symmetric “trident” or “bat-wing”-pattern, due to sparing of the peripheral fibers and the axons of the corticospinal tracts.

In the acute phase, there is restricted diffusion. This may occur within 24 h of symptom onset and precede the signal abnormalities on T2 or FLAIR-weighted sequences. The ADC values usually return to baseline within 3–4 weeks. CPM can appear moderately hypointense on T1-weighted sequences and rarely shows contrast enhancement [3].

If the patient survives the acute phase, the pontine lesions can cavitate and appear markedly hypointense on T1-weighted images.

3.4 Hepatic Encephalopathy

The term hepatic encephalopathy includes a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction. Most cases are associated with cirrhosis and portal hypertension or portal-systemic shunts, but the condition can also occur in acute liver failure [4].

Classical MR abnormalities in chronic hepatic encephalopathy include high signal intensity in the globus pallidus on T1-weighted images, and less frequently, in the substantia nigra and the tegmentum of the midbrain, without corresponding abnormalities on CT or T2-weighted imaging (Fig. 9.2). The accumulation of manganese is considered the cause of the signal alterations. Diffuse T2-hyperintense signal of the white may accompany the signal changes in the basal ganglia.

Fig. 9.2

A 69-year-old patient with chronic alcohol abuse and liver cirrhosis presented with a reduced level of consciousness and delirium MRI imaging findings present typical intrinsic T1 hyperintense changes in the basal ganglia, compatible with hepatic encephalopathy. No major atrophic changes are noticed on the FLAIR-weighted images. (a) Transverse T1-weighted image. (b) Sagittal T1-weighted image. (c) Transverse FLAIR-weighted image. (d) Transverse FLAIR-weighted image

The signal alterations improve or disappear completely after restoration of the liver function.

On the contrary, in acute hepatic encephalopathy, there is a bilateral symmetric T2-hyperintense signal and swelling of the cortical gray matter, associated with restricted diffusion. Most commonly, the insula, thalami, the posterior limb of the internal capsule, and the cingulate gyrus are affected. In more severe cases, there may be additional involvement of the subcortical white matter, the remaining cortex, and the midbrain. These imaging abnormalities are thought to reflect cytotoxic edema secondary to acute hyperammonemia and are reversible with adequate therapy.

3.5 Hypoglycemic Encephalopathy

An acute decrease in serum glucose levels arises from an excess of exogenous or endogenous insulin or hypoglycemia-inducing drugs. This causes a decline in the function of the cell membrane ATPase pump and consequently a release of excitatory neurotransmitters such as aspartate. Patients present with coma.

CT can demonstrate enhancing hypodensities in the basal ganglia, cerebral cortex, hippocampus, and substantia nigra.

MRI is more sensitive and shows a T2-hyperintense signal as well as restricted diffusion in the posterior limb of the internal capsule, hippocampi, the basal ganglia, cortical areas, and splenium of the corpus callosum. These changes are likely to reflect cytotoxic edema, and extensive changes on DWI in the basal ganglia and deep white matter are associated with poor clinical outcomes.

The thalami are typically spared, and this allows a differential diagnosis with hypoxic ischemic encephalopathy where the thalami are most often involved.

3.6 Hyperglycemic Encephalopathy

Hyperglycemia occurs in uncontrolled diabetes mellitus and can lead to osmotic derangements in the basal ganglia and subthalamic region. The clinical presentation is fairly typical with hemichorea and hemiballismus, and the pathological process is hence described as non-ketotic hyperglycemia with hemichorea-hemiballismus.

Imaging findings on CT consist of a hyperdense signal in the putamen and caudate nucleus, typically contralateral to the side of the patient’s symptoms. On MRI, there is a T1-hyperintense signal. The findings are almost invariably unilateral or with a striking asymmetry in rare bilateral cases.

After correction of blood glucose, the imaging abnormalities usually regress.

3.7 Hypoxic Ischemic Encephalopathy (HIE)

The pattern of brain injury in HIE depends on the level of brain maturation at the time of onset of the acute event and the severity and duration of the insult. HIE in adults results in symmetric involvement of the basal ganglia, thalami, and cortex and may be mild, moderate, or severe. The optimal time frame to image is 3–5 days after onset.

The affected areas show restricted diffusion on DWI. In the hyperacute events, reduced values on the ADC maps may be more pronounced than the hyperintensity on the b1000 maps. Afterwards, there is a corresponding hyperintense signal on T2- and FLAIR-weighted sequences and hypodense signal on CT, often accompanied by swelling of the injured gray matter structures. After 5 days, pseudonormalization of diffusivity occurs on the ADC maps.

The clinical context of HIE is mostly clear. However, in the unconscious patient of unknown etiology, a combined pathophysiology with a toxic cause or a differential diagnosis may be considered.

3.8 Drug-Induced Encephalopathy

Drug-induced changes to the brain result from acute intoxication or following long-term use of a number of drugs. Drug-induced encephalopathy is a disease entity that results from acute or chronic impaired cerebral metabolism, not causing focal but more diffuse structural brain lesions.

The imaging findings are very heterogeneous as are the drugs that can cause those changes. There is often a mix of acute and chronic changes present, including acute ischemic changes and others. Some drug-induced changes can result in not only diffuse but also focal structural lesions.

The list of drugs that can cause drug-induced encephalopathic changes is long and includes analgesics, antibiotics, neuromodulating medications, and chemotherapeutics.

More typical imaging changes reflect vasogenic and cytotoxic brain edema, posterior reversible leukoencephalopathy syndrome (PRES), leukoencephalopathy, and others.

4 Concluding Remarks

Toxic and metabolic diseases encompass a wide range of pathologies, often characterized by a specific pattern of findings. MRI is an important facet of the assessment, in combination with laboratory and/or genetic testing. Findings are almost invariably bilateral and often symmetric or nearly symmetric. In acquired metabolic and toxic diseases, the basal ganglia and thalami are often involved.

Most entities discussed in this chapter present a fairly specific imaging pattern. However, in congenital metabolic disorders presenting or persisting into adulthood, there may be overlap between entities and a differential diagnosis may be necessary in attendance of the results of genetic testing. In acquired metabolic-toxic disorders, clinical information and laboratory testing are warranted to aid in the final diagnosis.

Take-Home Messages

• Symmetric or nearly symmetric white matter lesions and/or pathologic changes in the basal ganglia and thalami are suspected of toxic-metabolic encephalopathy.

• The most common congenital leukodystrophies presenting or persisting into adulthood present with extensive lesions in the parieto-occipital white matter and involvement of the corticospinal tracts.

• Acquired metabolic-toxic disorders present with specific involvement of the basal ganglia and thalami, except for subacute combined degeneration, which is a disorder presenting with demyelination in the medulla.

• The pattern of brain injury in hypoxic ischemic encephalopathy depends on the severity and the duration of the event. Findings may be subtle.