Systemic metabolic diseases

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Systemic metabolic diseases

INTRODUCTION

Normal neuronal metabolism depends on systemic homeostasis of a range of metabolites, including glucose, electrolytes, amino acids, and ammonia. The term ‘metabolic encephalopathy’ describes the generalized brain dysfunction that results from systemic metabolic derangements. These may be primary, resulting from inherited diseases of metabolism, or secondary, caused by systemic diseases such as liver cirrhosis, renal failure, hypothermia, hyperthermia, neoplasia (including tumor lysis syndrome), and adrenal failure. The most common metabolic abnormalities associated with encephalopathy are: hypercalcemia, hyponatremia, hyperuricemia, hypoglycemia, hyperuremia, hypercreatininemia, hyperammonemia, lactic acidosis and hyperthermia.

The encephalopathy ranges from mild confusion to coma. Seizures, psychiatric and motor abnormalities may occur. The course is variable: some patients progress rapidly to coma, others have a more indolent course. In general, acquired metabolic disorders produce a widespread, symmetric pattern of injury. Some predominantly involve the deep gray nuclei and cerebral cortex. Others mainly affect myelin.

Diagnostic assessment will generally include measurement of body temperature, serum electrolytes (including, calcium, phosphate and magnesium), glucose, creatinine, ammonia, albumin, liver enzymes (including aspartate aminotransferase and alanine aminotransferase), bilirubin, serum and urine osmolality, urinary sodium, and toxicological studies. Imaging of the brain, MRI in particular, but also magnetic resonance spectroscopy, diffusion MRI, and positron emission tomography, are often valuable. Electroencephalography is useful in differentiating organic from psychiatric conditions, identifying epileptogenic activity and monitoring the degree of cortical or subcortical dysfunction but has little specificity in differentiating etiologies.

HYPOGLYCEMIA

MACROSCOPIC APPEARANCES

The brain is usually congested and mildly swollen. There may be little else of note or, in some cases, ill-defined dusky discoloration of the cerebral cortex, caudate nucleus, and putamen.

ETIOLOGY OF HYPOGLYCEMIC BRAIN INJURY

The principal source of energy in the CNS is glucose. Its uptake by nerve cells is independent of insulin. Neuronal stores of glucose and glycogen are relatively small and the requirement practically continuous. During periods of fasting, adults and, to a lesser extent, children are able to obtain some energy from metabolism of ketones, but a blood glucose level of less than 1.5 mmol/L (25–30 mg/100 mL) leads to brain damage within 1–2 hours.

Although the energy deficit is similar to that in hypoxic-ischemic encephalopathy, hypoglycemic brain insult has distinctive metabolic, brain imaging, electroencephalographic, and histopathologic findings.

The commonest cause of hypoglycemia sufficiently severe to cause CNS damage is an excess of exogenous insulin or other hypoglycemic drugs. Other causes include:

• primary hyperinsulinism (usually due to an islet cell adenoma)

• severe liver disease (hypoglycemia may be the sole initial manifestation of a hepatic tumor)

• adrenal insufficiency

• nesidioblastosis (in neonates).

The effects of hypoglycemia are not solely due to the energy deficit. Experimental studies have demonstrated release of aspartate, and to a lesser extent glutamate, which probably contribute to neuronal damage through excitotoxic mechanisms.

HYPOGLYCEMIA

Hypoglycemia is a frequently encountered cause of altered mental status in clinical practice.

Patients typically present with headache, confusion, irritability, incoordination, and lethargy, leading to stupor and coma.

Seizures are common, especially in children under 1 year of age.

MRI typically reveals signal change in the temporal, occipital, and insular cortex, hippocampus, and basal ganglia, often with sparing of the thalami. The deep white matter may appear abnormal, with symmetric hyperintensity in the internal capsule, corona radiata, and splenium in T2-weighted images.

Prolonged or frequent episodes of hypoglycemia result in permanent CNS dysfunction.

The lesions are similar to those of acute hypoxia–ischemia (see Chapter 8), but not identical. In general, the pattern of injury is that of selective degeneration of neurons rather than frank infarction. Affected neurons are shrunken with hypereosinophilic cytoplasm. The nuclei are initially pyknotic, but later become more eosinophilic and appear to blend in with the cytoplasm (nuclear dropout) (Fig. 22.1). As in hypoxia, the subiculum and CA1 field of the hippocampus are particularly vulnerable, while CA3 and 4 are less, and CA2 is least vulnerable. In the cerebral neocortex, the large neurons in laminae 3, 5, and 6 are most likely to be involved. The caudate nucleus and putamen, particularly the small neurons, are highly vulnerable to hypoglycemia. In infants, the dentate nucleus may also be affected (Fig. 22.1). In contrast to hypoxic–ischemic brain injury, Purkinje cells are usually spared. The regions of the brain particularly vulnerable to hypoglycemia are shown in Figure 22.2.

22.1 Acute hypoglycemic injury. (a) Severe hypoglycemic hippocampal injury due to insulin overdose. Most of the nuclei in the dentate fascia are shrunken and pyknotic. Many of the large neurons in the end folium (CA4) show nuclear dropout. (b) Hypereosinophilic neurons in the dentate nucleus of an infant with acute fatal hypoglycemia due to nesidioblastosis. In adults with hypoglycemia, the dentate nucleus is, like the Purkinje cell layer, usually spared.

22.2 Schematic illustration of the cerebrum and cerebellum showing the neurons that are particularly vulnerable to hypoglycemia in the adult brain.

Infants dying from hypoglycemia may show widespread neuronal degeneration throughout the brain.

FINDINGS IN LONG-TERM SURVIVORS OF SEVERE HYPOGLYCEMIA

MACROSCOPIC APPEARANCES

The cerebral cortex may appear thinned and the hippocampi shrunken and discolored (Fig. 22.3). The white matter is reduced in bulk and the ventricles are dilated. There may be marked atrophy of the caudate nucleus and putamen (Fig. 22.3).

22.3 Chronic changes after hypoglycemic injury. (a) Macroscopic findings in long-term survivor of severe hypoglycemia. Granular and atrophic neocortex in a survivor of an insulin overdose. The hippocampus and tail of the caudate nucleus are also severely shrunken. (b) Macroscopic features several weeks after an insulin overdose. The cerebral cortex is congested and focally thinned, particularly in the orbital frontal region and in the depths of sulci over the cerebral convexities. The corpus striatum is congested and there is irregular shrinkage of the caudate nucleus so that the medial surface is uneven.

MICROSCOPIC APPEARANCES

The cerebral cortex shows laminar neuronal loss and gliosis associated with capillary proliferation (Fig. 22.4). There is often dense subpial gliosis. The hippocampal pyramidal cell layer and subiculum are replaced by a loose meshwork of glial tissue (Fig. 22.5). The white matter is usually rarefied and gliotic. The caudate nucleus and putamen are diffusely gliotic (Fig. 22.4). The globus pallidus is relatively spared. Moderate neuronal loss and gliosis may be evident in the thalamus. As in acute hypoglycemia, the cerebellar cortex, including the Purkinje cells, is relatively spared (Fig. 22.4).

22.4 Chronic effects of severe hypoglycemia. (a) The cerebral cortex shows laminar neuronal loss, gliosis, and capillary proliferation. Several remaining neurons are mineralized (arrows). (b) The putamen is diffusely gliotic. (c) There is relative sparing of the cerebellar cortex, including the Purkinje cells.

22.5 Microscopic features 6 weeks after an insulin overdose. (a) The hippocampal pyramidal cell layer and subiculum are replaced by a loose meshwork of glial tissue and capillaries. (b) Higher magnification view of the pyramidal cell layer (arrowheads) and the dentate fascia (arrows), both of which are severely gliotic.

DISTURBANCES OF BODY TEMPERATURE

HYPOTHERMIA

This may cause apathy, confusion, obtundation, and coma. Choreoathetosis has been reported in a small proportion of patients after deliberate induction of deep hypothermia with cardiopulmonary bypass for cardiac surgery. No consistent neuropathologic abnormalities have been described. Hypothermia is increasingly being used to reduce the mortality and morbidity associated with hypoxic-ischemic encephalopathy in neonates.

HYPERTHERMIA

ETIOLOGY OF HYPERTHERMIA

This is most commonly due to strenuous physical exertion under hot and humid conditions, but may also be a consequence of an infection or drug reaction. Predisposing conditions include diabetes mellitus, alcoholism, intoxication with certain drugs (particularly 3,4–methylenedioxymethamphetamine (Ecstasy), and other amphetamines) and disorders in which there is impaired sweating (e.g. anhidrotic ectodermal dysplasia).

Mild to moderate hyperthermia develops in a significant proportion of stroke patients (in some series as many as 50%) and is associated with increased morbidity and mortality. Hyperthermia may convert salvageable penumbra to ischemic infarct. Fever is also common after brain and spinal cord injury and tends to worsen histopathological and behavioral outcome. In experimental studies, mild hyperthermia exacerbates free radical generation, inflammation, excitotoxicity, apoptosis and genetic damage after injury.

Malignant hyperthermia is an autosomal dominant disorder of the skeletal muscle characterized by a hypermetabolic response to all commonly used inhalation anaesthetics and depolarizing muscle relaxants. The clinical syndrome includes high fever, muscle rigidity, hypercapnia, tachycardia and myoglobinuria as result of rhabdomyolysis due to increased carbon dioxide production, oxygen consumption, and muscle membrane breakdown. Susceptibility to malignant hyperthermia results from mutations in calcium-channel proteins that mediate excitation–contraction coupling. Mutations in the gene on chromosome 19q13 that encodes the ryanodine receptor calcium-release channel are most often responsible, but mutations of the genes encoding some types of voltage-dependent calcium and sodium channels can also cause this disorder. Some ryanodine receptor gene mutations cause central core disease of muscle as well as malignant hyperthermia. The brain usually appears normal, even in fatal cases, but may show changes related to acute hyperthermia.

Neuroleptic malignant syndrome is a rare idiosyncratic reaction to neuroleptic or other antidopaminergic drugs (e.g. metoclopramide). It can also be precipitated by abrupt withdrawal of dopaminergic medication. The classical manifestations are pyrexia, encephalopathy, autonomic instability (including tachycardia, labile blood pressure, excessive sweating, sialorrhea, incontinence), tremor, muscle rigidity, and leukocytosis but these may not all be present.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain often appears normal or only mildly edematous. Some patients develop a bleeding diathesis, which may be associated with parenchymal or meningeal hemorrhages. Parenchymal petechial hemorrhages may be found adjacent to the third and fourth ventricles. Cerebellar Purkinje cell loss has been reported. Other described abnormalities are similar to those of hypoxic–ischemic damage (see Chapter 8) and probably result from a combination of cardiovascular collapse and an increased metabolic rate (Fig. 22.6). In patients with malignant hyperthermia, skeletal muscle may show central cores.

22.6 Hyperthermia. Cerebellar cortex from a patient who collapsed and later died after spending several hours in a steam tent. The systemic necropsy findings were in keeping with heat stroke. Examination of the brain revealed changes indistinguishable from those of acute hypoxic–ischemic neuronal injury, as illustrated by these Purkinje cells with shrunken, pyknotic nuclei, and hypereosinophilic cytoplasm.

DISORDERS OF SERUM ELECTROLYTES

Body water content is tightly regulated by actions of antidiuretic hormone (ADH), the renin-angiotensin-aldosterone system, norepinephrine, and by the thirst mechanism. Abnormalities of water balance manifest with disturbances of osmolality and sodium concentration (dysnatremias). Dysnatremias are relatively common clinical entities that cause significant morbidity and occasional mortality.

MACROSCOPIC APPEARANCES

Typically, the basis pontis includes a fusiform region of gray discoloration, which is abnormally soft and appears granular on sectioning (Fig. 22.7). The extent of the lesion is variable. Its cross-sectional area is usually greatest in the upper part of the pons, where only a narrow rim of subpial tissue may be spared (Fig. 22.8). It may involve the middle cerebral peduncles, but rarely extends rostrocaudally beyond the confines of the pons and lower midbrain. The lesion may be asymmetric, being largely or completely confined to one side of the pons.

22.7 ODS. Transverse sections through the brain stem in CPM showing gray discoloration and slight granularity of much of the basis pontis.

22.8 Sections of the pons in CPM. (a) There is extensive loss of myelin. Note the sparing of myelin in a narrow rim of subpial tissue and in small ‘islands’ within the base of the pons. (b) In an adjacent section, axons are seen to be well preserved.

The reported frequency of extrapontine lesions varies, but careful examination will reveal lesions in other parts of the CNS such as the cerebellum (Fig. 22.9), lateral geniculate body, capsula externa or extrema, subcortical cerebral white matter (Fig. 22.10), basal ganglia, thalamus, or internal capsule in 25–50% of cases. In up to 25% of patients the lesions may be exclusively extrapontine.

22.9 ODS: extrapontine demyelination. This section shows extrapontine demyelination in the white matter in the cerebellum. (Luxol fast blue/cresyl violet)

22.10 Subcortical demyelination in ODS. (a) Gray discoloration of the demyelinated subcortical white matter (arrows) in a case of extrapontine myelinolysis associated with ODS. (b) Solochrome cyanin staining confirms the presence of subcortical demyelination involving white matter in the crests of gyri (arrows).

MICROSCOPIC APPEARANCES

The microscopic appearances of CPM are of active demyelination (Fig. 22.11). The lesions contain reactive astrocytes and large numbers of foamy lipid-laden macrophages (Fig. 22.12), but only very scanty lymphocytes. Silver impregnation may reveal some axonal fragmentation, but most neuronal somata and axons are intact. Within the lesions, cranial nerves or central ‘islands’ of transverse pontine fibers or corticospinal tracts may be preserved (see Fig. 22.8).

22.11 Preservation of neuronal somata and axons in ODS. (a) Section of pons stained to show myelin. (b) Section of pons adjacent to (a) stained for axons. There is good preservation of neuronal somata and axons within the zone of demyelination.

22.12 Foamy macrophages in ODS. Higher magnification of the zone of demyelination in ODS reveals large numbers of foamy macrophages.

DIFFERENTIAL DIAGNOSIS OF ODS

The distribution of lesions, their identical age (if multiple), the paucity of lymphocytic inflammation, and clinical circumstances should allow this disorder to be distinguished from multiple sclerosis.

Poor myelin staining of the deeper part of the pons due to inadequate fixation may on cursory examination lead to a misdiagnosis of ODS.

CALCIUM DISTURBANCES AND FAHR’S DISEASE

Mild cerebral calcification, particularly of the basal ganglia, is a frequent incidental finding, especially in the elderly. More extensive calcification can occur in numerous medical conditions, including a variety of infections (e.g. intrauterine cytomegalovirus infection or toxoplasmosis), metabolic and endocrine (especially parathyroid) disorders, and genetic syndromes (e.g. Cockayne syndrome, see Chapter 5). Fahr’s disease refers to familial idiopathic calcification of the basal ganglia, also known as striopallidodentate calcinosis. The more general term Fahr syndrome is sometimes used to encompass both Fahr’s disease and basal ganglia calcification secondary to other disorders.

FAHR’S DISEASE, AND ETIOLOGY OF BASAL GANGLIA CALCIFICATION

Fahr’s disease may be inherited as an autosomal dominant or recessive disorder.

Linkage to chromosome 14q was demonstrated in one family with dominantly inherited Fahr’s disease.

Non-idiopathic basal ganglia calcification may result from hypoparathyroidism or pseudohypoparathyroidism.

A sporadic dementing disease, termed diffuse neurofibrillary, tangles with calcification (DNTC), largely confined to Japanese patients, is characterized by mineralization of the brain in a pattern identical to that of Fahr’s disease, but also neuronal loss, gliosis, and neurofibrillary tangles in the hippocampus, cerebral neocortex, basal ganglia, thalamus, subthalamus, substantia nigra, locus ceruleus, and occasionally in other brain stem structures and the dentate nucleus. Lewy bodies and neurites are present in the amygdala, hippocampus, and usually also the substantia nigra and dorsal motor nucleus of the vagus, and astrocytes immunopositive for α-synuclein occur in the hippocampus and temporal neocortex. A high proportion of patients also have TDP-43-positive neuronal and glial cytoplasmic inclusions, predominantly in the temporal lobe (see also Chapter 28).

Intrauterine infections, mitochondrial encephalopathies, tuberous sclerosis, systemic lupus erythematosum involving the CNS, and myotonic muscular dystrophy are other causes of basal ganglia calcification.

FAHR’S DISEASE

Age at onset of clinical symptoms in Fahr’s disease is 30–60 years.

Despite the variable distribution and severity of calcification, the clinical manifestations are relatively stereotyped and include headache, vertigo, extrapyramidal movement disorders, stroke-like events, seizures, ataxia, spastic paraplegia, cognitive and psychiatric disorders.

Infantile and juvenile basal ganglia calcification may also be associated with microcephaly, optic atrophy, pigmentary macular degeneration, and glaucoma.

The intracranial calcification is readily demonstrable radiologically; calcification in primary hypoparathyroidism is usually more diffuse than that in Fahr’s disease.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Vascular calcification and scanty parenchymal mineral deposits are a common incidental finding in the pallidum and, to a lesser extent, in the hippocampus and dentate nucleus, particularly in old age. The mineralization in Fahr’s disease is, however, much more extensive and can involve the cerebral sulci, basal ganglia (particularly the globus pallidus), dentate nucleus, subthalamus, red nucleus, and other regions (Fig. 22.13). In addition to calcium, the concretions contain iron, magnesium, aluminum, and glycoproteins. The calcification of the media and adventitia of blood vessels may be associated with intimal fibrosis and narrowing, in some cases completely occluding the lumen (Fig. 22.14). The extent of associated neuronal degeneration and gliosis is variable and may be partly related to the degree of ischemia.

22.13 Vascular and parenchymal mineralization in Fahr’s disease. (a) In the cerebellar cortex and white matter. (b) In the caudate nucleus.

22.14 Vasculopathy in Fahr’s disease. (a,b) Vascular mineralization and the associated intimal fibrosis may stenose or occlude the lumen of affected blood vessels in Fahr’s disease.

HYPERCALCEMIC ENCEPHALOPATHY

Primary hyperparathyroidism is the inappropriate secretion of parathyroid hormone and is the most common cause of hypercalcemia. In addition, cancer-induced hypercalcemia occurs in 5–30% of patients with cancer during the course of their disease, depending on the type of tumor. Low parathyroid hormone serum levels together with high calcium levels in a cancer patient may suggest a cancer-induced hypercalcemia.

It may lead to cognitive impairment, seizures, visual abnormalities and headaches, associated with predominantly posterior white matter abnormalities, characterizing the so-called ‘posterior reversible encephalopathy syndrome’ (PRES). Neuroimaging demonstrates symmetrical posterior cortical and subcortical lesions. The pathogenesis is incompletely understood, although it seems to be related to the breakthrough of autoregulation and endothelial dysfunction. It has been described in an increasing number of medical conditions, including hypertensive encephalopathy, eclampsia, and immunosuppressive treatment, renal insufficiency, and rheumatologic diseases. Several case reports highlight the importance of considering hypercalcemia as the cause of onset of behavioral alterations and worsening of mental condition in elderly patients with cognitive decline.

HYPERCALCEMIC ENCEPHALOPATHY

The most common causes are primary hyperparathyroidism and malignancies (particularly in association with widespread involvement of bone).

The clinical presentation is typically with confusion, seizures, visual abnormalities and headaches.

In patients with hypercalcemia, this presentation may signal the development of posterior reversible encephalopathy syndrome (PRES), in which MRI signal abnormalities associated with edema are demonstrable in the cerebral white matter, most often in the parietal and occipital lobes. Other causes of PRES include accelerated hypertension, eclampsia, immunosuppressive treatment, renal failure, and autoimmune vasculitides and connective tissue diseases.

The neuropathological findings in fatal cases include microvascular necrosis, perivascular exudates, microhemorrhages and edema (see Chapter 10 for further description of the microscopic changes in accelerated hypertension).

LIVER DISEASE

ACQUIRED HEPATIC ENCEPHALOPATHY

ETIOLOGY AND PATHOGENESIS OF ACQUIRED HEPATIC ENCEPHALOPATHY

This is a complication of severe liver disease or chronic portacaval shunting.

The pathogenesis is not fully understood. The typical astroglial abnormalities are largely due to the hyperammonemia, which is probably also directly or indirectly responsible for many of the neurologic disturbances.

Other factors that have been implicated include:

• Elevated levels of benzodiazepine-like substances that bind to part of the γ-aminobutyric acid receptor.

• Alterations in glutamatergic and serotoninergic transmission.

Molecular studies reveal reduced expression of GFAP and the glutamate transporter EEAT-2. Impaired EEAT-2-mediated uptake of glutamate may cause it to activate the NMDA receptor-mediated cGMP-NO signal transduction pathway, resulting in oxidative injury.

ACQUIRED HEPATIC ENCEPHALOPATHY

Inattentiveness and impairment of short-term memory are typical early manifestations.

Later features include confusion, which is often associated with asterixis (a flapping tremor of the outstretched hands), drowsiness, stupor, and coma.

Patients often have a musty breath odor (fetor hepaticus), and a tendency to hyperventilation, resulting in respiratory alkalosis.

MRI may reveal increased T1-weighted signal in the globus pallidus, subthalamus and midbrain, and cortical edema and hyperintensity with perirolandic and occipital sparing in T2-weighted images. Magnetic resonance spectroscopy shows reduction of choline and myoinositol, and elevated glutamine and glutamate.

Acute hepatic encephalopathy can be rapidly fatal. Chronic or repeated episodes of hepatic encephalopathy may lead to neuropsychiatric disturbances, dysarthria, ataxia, and choreoathetosis.

Patients may also develop spasticity and gait disturbances (hepatic myelopathy).

Chronic hepatic encephalopathy/myelopathy may be ameliorated by liver transplantation.

MICROSCOPIC APPEARANCES

The only consistent finding in acute hepatic encephalopathy is the presence of Alzheimer type II astrocytes. These have an enlarged vesicular nucleus with marginated chromatin, and scanty cytoplasm with little or no demonstrable glial fibrillary acid protein. They occur in the:

Deep layers of the cerebral cortex.

Caudate nucleus and putamen (Fig. 22.15).

22.15 Alzheimer type II astrocytes. (a) Alzheimer type II astrocytes (arrows) in the putamen tend to have an enlarged, oval, vesicular nucleus and very scanty cytoplasm. (b) Alzheimer type II astrocytes in the pallidum tend to have an irregularly lobulated nucleus (arrow).

Pallidum (where they are often particularly prominent) (Fig. 22.15).

Thalamus, subthalamus, and hypothalamus.

Dentate nucleus of the cerebellum.

Brain stem.

Alzheimer type II astrocytes in the cerebral cortex, striatum, thalamus, and hypothalamus tend to have a round nucleus, while the nucleus of those in the pallidum, subthalamus, dentate nucleus, and brain stem is often irregularly lobulated. Alzheimer type II astrocytes may also be seen in non-hepatic metabolic encephalopathies (e.g. associated with uremia).

Chronic or recurrent hepatic encephalopathy may also cause:

Patchy pseudolaminar necrosis and microcavitation in the depths of sulci at the junction of cerebral cortex and white matter (Fig. 22.16). The necrosis may extend into the cerebral white matter and can also involve the cerebellar white matter in severe cases.

22.16 Chronic hepatic encephalopathy. (a) Microcavitation at the junction of cerebral cortex and white matter. (b) Neuronal loss and microcavitation in the dorsal pole of the putamen.

Neuronal loss, gliosis and, in severe cases, microcavitation, which are most prominent in the dorsal pole of the putamen (Fig. 22.16).

In chronic hepatic myelopathy, there is degeneration of corticospinal tract fibers.

Opalski cells are altered astrocytes with a small central nucleus and abundant, finely granular, deeply eosinophilic cytoplasm. More usually associated with Wilson’s disease (see below), they may also be seen in non-Wilsonian chronic hepatic encephalopathy (Fig. 22.17).

22.17 Opalski cells in the subthalamus in hepatic encephalopathy due to portacaval shunting. These cells have a small hyperchromatic nucleus and abundant granular deeply eosinophilic cytoplasm (arrows). Note also the presence of numerous Alzheimer type II astrocytes with irregularly lobulated nuclei.

HEPATOLENTICULAR DEGENERATION (WILSON’S DISEASE)

ETIOLOGY OF HEPATOLENTICULAR DEGENERATION (WILSON’S DISEASE)

This autosomal recessive disorder is caused by mutations in a copper-transporting ATPase gene (ATP7B) encoded on chromosome 13q14.3.

ATP7B is expressed most strongly in liver and brain, and is necessary for the export of copper from the cell.

Defective mobilization and excretion of copper leads to its accumulation in the liver, brain, and other organs.

ATP7B shares over 80% amino acid identity with ATP7A, the copper-transporting ATPase that is defective in Menkes’ disease (see Chapter 6), and is probably involved in the import of copper into the cell.

HEPATOLENTICULAR DEGENERATION

The worldwide incidence is approximately 12–30/million.

Age at onset ranges from 5 to 35 years. Patients with ATP7B mutations that severely disrupt ATPase function present with liver failure and cirrhosis in early childhood. Neurologic disease develops only after adolescence, in patients with less severe mutations, and typically includes dysarthria, dysphagia, dystonia and painful muscle spasms, coarse tremor, neuropsychiatric disturbances, and dementia. However, a wide range of oculomotor, cerebellar, speech, movement, pyramidal, autonomic, and seizure disorders has been described.

Other findings are the presence of Kayser–Fleischer rings and azure lunulae, due to corneal and finger nail deposition of copper. Kayser–Fleischer rings are present in ~50% of patients with neurologic Wilson’s disease in contrast to <10% with hepatic Wilson’s disease.

Biochemical manifestations include low serum ceruloplasmin concentration, increased content of copper in the liver, and decreased secretion of copper in the urine. The diagnosis is confirmed by molecular genetic testing.

The chelating agents D-penicillamine and triethylenetetramine dihydrochloride are used to reduce tissue deposition of copper. Zinc acetate is also administered, to induce hepatic metallothionein, which sequesters copper in a non-toxic form.

In patients who fail to improve on chelating agents, liver transplantation may provide effective reversal of the hepatic failure and the non-neuropsychiatric neurological manifestations.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The putamen and caudate nucleus appear brown and shrunken, particularly the middle third of the putamen (Fig. 22.18). The putamen may be centrally cavitated. Histology of these nuclei reveals neuronal loss, scattered lipid- and pigment-laden macrophages, and many fibrillary astrocytes (Fig. 22.19). Alzheimer type II astrocytes (see acquired hepatic encephalopathy above) are abundant. The globus pallidus, subthalamic nucleus, thalamus, and brain stem are often involved, but less severely.

22.18 Wilson’s disease. Distribution of abnormalities within the cerebrum.

22.19 Histology of the putamen in Wilson’s disease. (a,b) show neuronal loss, pigment-laden macrophages, and gliosis of the putamen in a case of Wilson’s disease.

A distinctive but not entirely specific feature (see acquired hepatic encephalopathy, above) is the presence of Opalski cells, particularly in the globus pallidus (Fig. 22.20). Expression of glial antigens has been noted in some studies. Cells showing varied degenerative nuclear and cytoplasmic changes are often found in the basal ganglia, thalamus, and zona reticulata of the substantia nigra. Other abnormalities that may be present include foci of spongy degeneration in the cerebral cortex and white matter.

22.20 Opalski cells. These cells have small, darkly stained nuclei and granular eosinophilic cytoplasm (arrows).

ACERULOPLASMINEMIA

This is included here because it shares some of the metabolic abnormalities of Wilson’s disease. Unlike Wilson’s disease, however, cirrhosis does not occur and the neuropathologic findings are not related to liver dysfunction but to loss of the ferroxidase activity of the copper-binding protein ceruloplasmin.

Aceruloplasminemia, also known as ‘hereditary ceruloplasmin deficiency’, is an autosomal dominant disorder caused by mutation of the ceruloplasmin gene on chromosome 3q23–24. It usually presents in middle age with varying combinations of ataxia, choreoathetosis, blepharospasm, torticollis, cog-wheel rigidity, dementia, retinal degeneration, and diabetes mellitus. Kayser–Fleischer rings develop. Serum iron concentration is low and ferritin concentration is high.

Copper and iron accumulate in the liver, pancreas, retina, and brain, particularly in the basal ganglia, red nucleus, and dentate nucleus, which show neuronal loss and gliosis.

OTHER, RARE CAUSES OF BRAIN IRON ACCUMULATION

These include the primary neuroaxonal dystrophies (see Chapter 33) and neuroferritinopathy caused by mutation of the ferritin light chain gene, in which accumulation of iron and ferritin, formation of neuroaxonal spheroids and neuronal degeneration are most pronounced in the posterior putamen and cerebellar cortex.

REYE SYNDROME

Reye syndrome is an acute non-inflammatory encephalopathy associated with fatty degeneration of the viscera, particularly the liver. It is predominantly a disease of children and is commonest in the USA and UK. Its incidence has declined in recent years.

MACROSCOPIC APPEARANCES

Macroscopic examination often shows only cerebral congestion and brain swelling. In some cases reduced cerebral perfusion may produce obvious watershed infarcts. More severe raised intracranial pressure can cause global brain ischemia, resulting in widespread cortical laminar necrosis and hemorrhagic infarcts in the cortex, basal ganglia, diencephalon, and brain stem.

ETIOLOGY OF REYE SYNDROME

Multiple precipitating factors have been implicated including viral infections (most often influenza, parainfluenza, or varicella), drugs, especially acetylsalicylic acid (aspirin), and aflatoxin (derived from peanuts and grain contaminated by the fungus Aspergillus flavus).

The syndrome is thought to be due to injury to mitochondria, particularly in the liver, resulting in acute hyperammonemia, as well as accumulation of other toxic metabolites. The severity of disease correlates well with the degree of hyperammonemia.

The liver dysfunction and hyperammonemia probably contribute to the development of cerebral edema, but mitochondrial damage in endothelial cells and astrocytes may also play a role.

REYE SYNDROME

This is usually preceded by a ’flu-like or exanthematous viral illness.

The encephalopathy and hepatocellular dysfunction manifest acutely with vomiting, anorexia, and lethargy, progressing to stupor, convulsions, and coma.

There may be obvious hepatomegaly.

Biochemical investigation reveals hyperammonemia, elevated serum transaminase concentrations, and varying degrees of hypoglycemia.

Neurologic sequelae in survivors include spasticity, choreoathetosis, and mental retardation.

DIFFERENTIAL DIAGNOSIS OF REYE SYNDROME

Several inherited disorders of metabolism can simulate Reye syndrome:

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, an autosomal recessive disorder, is probably most often misdiagnosed as Reye syndrome.

Other disorders that may cause Reye syndrome-like attacks include deficiency of long-chain acyl-CoA dehydrogenase, primary carnitine deficiency, carnitine palmitoyl transferase I deficiency, ornithine transcarbamylase deficiency, carbamoylphosphate synthetase deficiency, 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency, mitochondrial trifunctional protein α-subunit deficiency, and glutaric aciduria.

MICROSCOPIC APPEARANCES

Histology reveals brain edema and ischemic changes of varying severity, but no inflammation. Electron microscopy has been reported to show features of cytotoxic edema with swollen astrocyte foot processes. In some reports mitochondrial abnormalities have been described, but these may be at least partly attributable to the effects of ischemia.

The liver shows diffuse microvesicular steatosis and, in fatal cases, usually includes large foci of coagulative necrosis. Like the brain, it is not inflamed.

PORPHYRIA

The porphyrias are inherited defects of metabolism characterized by overproduction and excretion of porphyrins or their precursors (Table 22.1):

Table 22.1

Enzyme defects and genetic loci in hepatic porphyrias (all are autosomal dominant disorders)

Subtype	Enzyme defect	Locus
Acute intermittent	Phorphobilinogen deaminase	11q24
Coproporphyria	Coproporphyrinogen III oxidase	3q12
Variegate porphyria	Protoporphyrinogen oxidase	1q22
Δ-aminolevulinic acid Dehydratase deficiency		9q34

In the erythropoietic porphyrias, porphyrins accumulate in normoblasts and red blood cells.

In the hepatic porphyrias, porphyrins or their precursors are overproduced by the liver.

Only the hepatic porphyrias produce neurologic disease.

The symptoms and signs of hepatic porphyrias are summarized in Table 22.2. They rarely begin before puberty. Factors that may precipitate acute disease include:

Table 22.2

Clinical features of hepatic porphyrias

Certain drugs (e.g. barbiturates, sulfonamides, griseofulvin, meprobamate, phenytoin, succinimides, steroids).

Infections.

Starvation.

Menstruation (some women experience attacks just before menstruation).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The autonomic, somatomotor, and sensory disturbances are due to an axonal neuropathy. Motor neurons in the spinal cord and brain stem nuclei may appear chromatolytic (Fig. 22.21). Distal degeneration of posterior column fibers has been reported in some cases.

22.21 Chromatolysis of lower motor neurons in porphyria. Chromatolytic cervical anterior horn cells in the spinal cord from a patient with acute intermittent porphyria.

No structural lesions have been identified to account for the CNS disturbances. The hypertension of acute attacks may be complicated by the development of hemorrhages or infarcts.

PANCREATIC DISEASE

PANCREATIC ENCEPHALOPATHY

This is thought to be due to the release of vasoactive peptides, hormones, enzymes, and cytokines, in acute pancreatitis, leading to oxidative damage, microcirculatory and electrolyte disturbances. It is characterized by delirium, hallucinations, seizures, and multifocal neurologic deficits 2–5 days after the onset of acute pancreatitis.

Celiac disease is characterized by jejunal villous atrophy and circulating IgA anti-endomysial and anti-gliadin antibodies. The anti-endomysial antibody is directed against tissue transglutaminase.

The disease is thought to be due to the sensitization of T cells by presentation, in conjunction with HLA-DQ2 or DQ8 cell-surface antigens, of gluten-derived gliadin peptides that have been deamidated by tissue transglutaminase.

Subsequent exposure of sensitized T cells to gliadin peptides results in an augmented immune response, with the release of cytokines, recruitment of other inflammatory cells, and damage of enterocytes.

The mucosal changes respond to dietary avoidance of gluten.

A small proportion (<10%) of patients with celiac disease develop neurologic complications. These respond to dietary manipulation only if this is started soon after their onset.

CELIAC DISEASE

This usually presents with malabsorption and diarrhea, but gastrointestinal symptoms may be mild or absent.

Reported CNS manifestations include progressive cerebellar ataxia, myoclonic epilepsy, complex partial seizures which are occasionally associated with transient blindness, internuclear ophthalmoplegia, multifocal leukoencephalopathy, dementia, and (mostly in a subgroup of Italian patients with celiac disease and epilepsy) parieto-occipital calcification. Most of these associated conditions show a poor response to gluten restriction.

Rarely, celiac disease results in myelopathy or peripheral neuropathy due to malabsorption and vitamin deficiency, particularly of vitamin E (see Chapter 21). Peripheral neuropathies, of axonal and demyelinating types, have also been reported and may respond to the elimination of dietary gluten.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The most consistent neuropathologic abnormality is cerebellar atrophy, with loss of Purkinje cells, Bergmann cell gliosis, and variable loss of granule cells (Fig. 22.22). There may be diffuse neuronal loss and gliosis in the dentate and inferior olivary nuclei (Fig. 22.22). Perivascular lymphocytic infiltrates have been described in the cerebellum in some cases, and probably represent an early phase of the cerebellar lesions in celiac disease. Focal neuronal loss and gliosis are occasionally seen in the basal ganglia, diencephalon, and brain stem nuclei. Little has been published on the neuropathologic findings associated with the cortical and subcortical parieto-occipital calcification that may occur in this disorder.

22.22 CNS changes in celiac disease. (a) Cerebellar atrophy, with loss of Purkinje cells, Bergmann cell hyperplasia, and rarefaction of the white matter. (b) The inferior olive is depleted of neurons and severely gliotic.

CROHN’S DISEASE AND ULCERATIVE COLITIS

Focal neurologic disturbances occasionally complicate these inflammatory bowel diseases. In some cases MRI has revealed white matter lesions thought to be due to vasculitis.

Neuropathologic data are lacking. Rarely, patients have developed cerebral infarcts or venous sinus thrombosis. As in other causes of malabsorption, neurologic disease may complicate nutritional deficiencies. There is some evidence that patients are at increased risk of multiple sclerosis, particularly if they are treated with tumor necrosis factor inhibitors such as infliximab.

RENAL DISEASE

UREMIC ENCEPHALOPATHY

Patients with uremia may develop an encephalopathy, the manifestations range from mild changes in cognition to delirium and even coma. Apathy, fatigue, incoordination, and twitching are usually prominent features. Some patients develop more severe motor disturbances (asterixis, myoclonus, chorea) and visual disturbances. Peripheral neuropathy is common. The pathogenesis is poorly understood, but presumably involves the accumulation of neurotoxic products of metabolism that are normally excreted in the urine.

Non-specific neuropathologic abnormalities have been described, including cerebral atrophy, gliosis, and foci of perivascular necrosis with accumulation of macrophages. Alzheimer type II astrocytes are often prominent. ODS has been reported (see above). Patients may also develop changes of hypertensive encephalopathy (see Chapter 10). MRI abnormalities can be seen in the basal ganglia, particularly in patients who also have diabetes mellitus; these changes are largely reversible on treatment and their neuropathological substrate is not known.

DIALYSIS ENCEPHALOPATHY

Two distinct CNS disorders have been associated with dialysis for end-stage renal disease:

Dialysis dysequilibrium syndrome.

Dialysis dementia.

Dialysis dementia is thought to be due to aluminum toxicity (see Chapter 25). Dialysis dysequilibrium syndrome is more commonly caused by hemodialysis than peritoneal dialysis. It consists of acute headache, nausea, muscle cramps, asterixis, myoclonus, and seizures, and is believed to be due to cerebral water intoxication caused by hypo-osmolality.