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).