The neurotoxicity of ammonia has been studied extensively, but its relationship with endogenous intoxication is still not completely understood. Blood ammonia concentration higher than 300-500 µmol/L is associated with severe central nervous system (CNS) dysfunction, including cerebral edema and coma (1). The intestine and the muscles are the main sources of ammonia. When the hepatic urea cycle is nonfunctional, ammonia is not transformed into urea and, hence, ammonia free base (NH₃) crosses the blood-brain barrier (BBB). The BBB has a much lower permeability to the ammonium ion (NH₄⁺), which implies that the diffusion of ammonia across the barrier depends partly on arterial blood pH (2,3,4). Once in the brain, ammonia is buffered by combining with glutamate in the formation of glutamine in the astrocytes via the action of the enzyme glutamine synthetase (GS). Once glutamine is formed in the astrocyte, it is released via the glutamine transporter SNAT5 into the extracellular space where it is taken up by neurons via SNAT1 and SNAT2 receptors. Glutamine in neurons is transformed into glutamate, and then γ-aminobutyric acid (GABA). Glutamate in brain tissue is in millimolar concentration (˜1-2 mmol/L) and constitutes the metabolic pool of this amino acid. Glutamate packaged within synaptic vesicles is a very small fraction of this “metabolic” pool, and within these vesicles its concentration is ˜20 mmol/L. Synaptic vesicle glutamate is released in a calcium-dependent manner on electrical stimulation, and its action is excitatory in neurotransmission. This metabolism illustrates the concept of the “Glutamate-Glutamine Cycle” in the brain (Fig. 66.2) (5). The enzyme GS functions at near maximal capacity during normal physiologic conditions (6). The brain’s capacity to synthesize glutamine can be easily exceeded and hyperammonemia rapidly ensues. One of the hypotheses (extrapolated from animal studies) for the induction of brain edema during hyperammonemia is decreased expression of SNAT5 and the consequent trapping of glutamine inside the astrocyte, thereby resulting in cell swelling and brain edema. Glutamine is not only an osmotic agent but also a direct participant in the release of glutamate by surrounding

neurons. The downregulation of SNAT5 can result in a decrease in excitatory neurotransmission in the brain and lead to excessive neuroinhibition, which is characteristic of encephalopathy in hyperammonemia (5,6,7,8). Glutamine is also thought to disrupt mitochondrial permeability by interference with the mitochondria-permeability-transition process and liberation of free radicals through hydrolysis of ammonia, all subsequently leading to mitochondrial swelling and dysfunction (9). Another hypothesis for hyperammonemia-induced encephalopathy is injury through the effect of increased production of glutamine that leads to an excess of extracellular glutamate, which induces neuronal hyperexcitability through activation of a subgroup of the glutamate family of receptors, the N-methyl-D-aspartate (NMDA) ionotropic receptors. Activation of NMDA receptors leads to depolarization and downstream changes in nitric oxide (NO) metabolism, disturbances in sodium/potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) function, mitochondrial dysfunction, energy failure, and oxidative stress, together causing cell death (10). Finally, a high level of ammonia has the potential for participating in causing brain injury and cerebral edema by inducing hyperemia in cerebral blood flow (CBF) and by impairing cerebral autoregulation (11,12).

A number of human disorders are associated with hyperammonemia. IEM with hyperammonemia include primary urea cycle enzyme defects and secondary inhibition of urea cycle metabolism by organic acidurias (i.e., propionic, methylmalonic aciduria) (1).

The urea cycle is the final common pathway for the excretion of waste nitrogen in mammals. For more details on these diseases, please refer to Chapter 113.

Reye-like illness is characterized by the combination of liver disease and metabolic encephalopathy. In 1980, the Centers for Disease Control defined Reye syndrome as requiring the each of the following criteria for diagnosis: an acute noninflammatory encephalopathy with microvesicular fatty metamorphosis of the liver, confirmed by biopsy or autopsy; a threefold increase of transaminases and/or ammonia; absence of cerebrospinal fluid (CSF) pleocytosis; and no other reasonable explanation for neurologic presentation with hepatic abnormality (13). The last criterion requires careful consideration and clinical expertise to identify other potential conditions. Therefore, whether Reye syndrome should be accepted as a diagnostic label before all other possible causes have been excluded is debatable (14). In this setting, we prefer to use the term “Reye-like illness.”

The clinical features and electron microscopy of liver biopsy in patients with Reye syndrome are compatible with hepatotoxicity caused by acute, reversible mitochondrial failure. Mitochondria provide most of the energy for hepatic cell function via oxidative phosphorylation through the tricarboxylic acid cycle (15). Reye syndrome has a number of potential causes, and it is likely that these involve a mechanism in which mitochondrial failure results in impaired glucose homeostasis, ammonia metabolism, and hepatocyte function.

The pathophysiology of hepatic encephalopathy is far from being understood. Its main mechanistic cause may be through ammonia-induced neurotoxicity, that is, astrocytic swelling and cytotoxic brain injury (see above for discussion) (16,17). However, hyperammonemia is certainly not the only mechanism at fault since some patients with severe encephalopathy continue to have normal ammonia levels. The other potential mechanisms are multiple and complex, involving (a) the combined toxic effects of accumulated ammonia and glutamine, mercaptans, fatty acids, and phenol; (b) increased “GABAergic tone”; (c) changes in BBB; and (d) disturbances in neurotransmission (18,19).

The “increased GABAergic tone” hypothesis, which is supported by the presence of increased benzodiazepine receptor
ligand levels in patients with hepatic encephalopathy, was first considered a possibility when similarities between evoked potential in rats with liver failure and animals treated with GABA receptor agonists were noted (13). Animal studies in models of hepatic encephalopathy have also demonstrated a beneficial effect on arousal of administering flumazenil, a GABA receptor antagonist. A few studies in humans have shown the same benefit (20), but the origin of increased GABA receptor agonists in hepatic encephalopathy is unclear; it is possible that the agonist or a precursor is contained within the food cycle, is synthesized by gastrointestinal flora, or that there is occult ingestion of pharmaceutical benzodiazepine (21,22). It is also possible that endogenous levels of the neurosteroid hormone dehydroepiandrosterone sulfate, found to be low in humans with cirrhosis, may contribute to increased GABAergic tone. Improvement in encephalopathy after administering flumazenil supports this hypothesis. However, the improvement is transient and incomplete, which demonstrates the importance of other toxic mechanisms in the pathogenesis of hepatic encephalopathy, such as glutamine-induced astrocytic swelling (see above).

Among the amino and organic acid disorders, those that most frequently cause patients to be admitted to the PICU for acute metabolic encephalopathy are maple syrup urine disease (MSUD), propionic aciduria (PA), and methylmalonic aciduria. Hyperammonemia and/or the accumulation of intermediate metabolites (due to downstream enzyme defects) are involved in the pathophysiology of acute encephalopathy and are reversible with specific treatment.

In MSUD, deficiency of branched-chain ketoacid dehydrogenase disrupts the normal breakdown of branched-chain amino acids (i.e., leucine, isoleucine, and valine) and leads to accumulation of branched-chain amino acids and branchedchain ketoacids. In acute encephalopathic crises, there is a high risk of cerebral edema and brain stem herniation (23,24). The mechanism of brain edema is not completely understood but is related to the neurochemical changes caused by the accumulation of leucine and α-keto isocaproic acid (αKIC, derivative product of leucine accumulation), with depletion of neurotransmitters (glutamate, GABA, and dopamine). Plasma leucine concentration and duration of exposure to a high leucine level appear to correlate with encephalopathy (25). At the cellular level, αKIC induces apoptosis in rat glial and neuronal cells (26), which may be related to αKIC-induced complex 1 inhibition in the respiratory chain followed by cytochrome c release from the mitochondria in the cytosol (26,27). This energy failure is likely to be responsible for cerebral edema because Na⁺/K⁺-ATPase fails to maintain membrane gradients leading to cell swelling (24). Also, immediate depletion of neurotransmitters such as dopamine and serotonin, by limiting the availability of their precursors (i.e., tyrosine and tryptophan), may be responsible for early neurobehavioral changes (28).

In patients with propionic and methylmalonic aciduria, selective and symmetrical necrosis of the globi pallidi is observed during acute decompensation (29). Many toxic products accumulate in these two conditions, and their respective underlying neurotoxic mechanisms are unknown, but may involve energy failure via respiratory chain enzyme deficiencies and secondary mitochondrial damage. Hyperammonemia is frequently observed with neurotoxicity (30).

Wilson disease is associated with an initial neurologic presentation between the ages of 10 and 20 years in one-third of cases. In this disorder, oxidative damage may be caused by accumulation of copper in the basal ganglia (31).

Under normal conditions, the brain relies on a constant supply of glucose from the blood for oxidative metabolism and function. It stores only a little glycogen in astrocytes and does not perform gluconeogenesis. Glucose has to be transported across the BBB via glucose transporter proteins expressed in the brain, mainly as the GLUT-1 glucose transporter. Mutations in this gene are associated with hypoglycorrhachia without hypoglycemia. Disorder of carbohydrate metabolism, glycogen storage disease, hyperinsulinism, and fatty acid oxidation disorders (FAODs) and certain disorders of amino acid metabolisms may present with severe hypoglycemia. During prolonged fasting, the brain can switch to lactate oxidation and increase ketone body uptake to partially restore energy balance. At a critical glucose concentration, however, the brain receives inadequate glucose to support its needs (32). Specific neurons of the superficial cerebral cortex, basal ganglia, and hippocampus are most vulnerable, but lesions in white matter have also been reported.

The mechanism to explain the profound hypoglycemic effects on neurons appears to be mediated by both an early tetrotodo toxin-sensitive component and a more prolonged period of toxic NMDA receptor activation (33). Of importance, correction of plasma glucose concentration alone does not interrupt this cell death process. Oxidative DNA damage seems to be critical in the sequence of events leading to hypoglycemia-induced neuronal injury (34,35,36,37), but the source and mechanism of oxidant are not completely understood. Mitochondria have been implicated as a source of neuronal superoxide production in glutamate excitotoxicity and contribute to hypoglycemia-induced neuronal death. Furthermore, it has been proved that reactive oxygen species are generated in neurons at the time of glucose reperfusion. Oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) is the primary source of superoxide generation in the hypoglycemic reperfusion process. Reactive oxygen species can damage DNA, which in turn induces poly-(ADP ribose) polymerase 1 (PARP-1), which consumes much ATP and imposes further bioenergetic stress on the neuronal energy supply during hypoglycemia-induced neuronal death (38,39).

Mitochondria are essential in cellular energy metabolism and cellular homeostasis. They also play a key role in the mitochondrial pathway to apoptosis. Cellular respiration’s first stage takes place in the inner mitochondrial membrane and consists of glycolysis of carbohydrates into pyruvate. The pyruvate is transported to the inner mitochondrial matrix, where it is converted to acetyl coenzyme A (acetyl CoA). The Krebs cycle achieves complete oxidation of acetyl CoA to produce two molecules of carbon dioxide and conserve free energy in the form of NADH (reduced form of nicotinamide adenine dinucleotide) and FADH₂ (reduced form of flavin adenine dinucleotide). Therefore, its major function is catabolic. Amino acids, fatty acids, and carbohydrates can enter mitochondria as intermediates of the Krebs cycle. Then, the reaction of oxidative phosphorylation takes place in the mitochondrial matrix, for which NADH and FADH₂ are the “substrates.” The electron transport chain (a series of respiratory complexes) results in phosphorylation of the majority of cellular ADP to ATP.

Mitochondrial disorders result in impaired respiratory chain activity or impaired oxidative phosphorylation. Tissues with high-energy demand are most commonly involved in mitochondrial diseases: neurons, myocardial and skeletal muscles, liver, and kidneys. The brain is particularly vulnerable, given the neuronal requirement for ATP to maintain ionic gradients for electrical activity. The basal ganglia and their high metabolic needs are particularly at risk for insult. Primary defects in mitochondrial energy metabolism include pyruvate dehydrogenase (PDH) complex deficiency, tricarboxylic acid cycle deficiencies, and respiratory chain defects. These diseases can be caused by mutations in the mitochondrial DNA (maternal or sporadic transmission), mutations in nuclear DNA (Mendelian transmission), or defects of communication between the nuclear and mitochondrial genome. The term mitochondrial encephalomyopathies was first used in 1977 to describe the CNS implications in patients with mitochondrial alterations in their muscle biopsies (40). The clinical presentation of a mitochondrial disease in children is often nonspecific with myopathy associated with CNS involvement, such as cognitive impairment, ataxia, seizures, and impaired consciousness (somnolence to coma). These clinical problems may manifest early in life, in childhood, or later in life. Altered conscious state is particularly frequent in Leigh syndrome. Necrosis of the basal ganglia and brain stem nuclei, and stroke-like cortical lesions are often features of mitochondriopathies; nonspecific findings on brain imaging are also common (see Chapter 59) (41). Most of these diseases are currently untreatable.

FAODs comprise another group of diseases with impaired mitochondrial energy metabolism. The encephalopathy observed in these diseases is not fully understood and may result from multifactorial insults, including limited fuel for the brain due to hypoglycemia along with abnormally low ketones, hyperammonemia, and a decrease in CBF due to circulatory failure (42).

Thiamine (vitamin B1) has an important role in several metabolic processes. It is an essential coenzyme in the pentose phosphate pathway and the tricarboxylic acid (Krebs) cycle. The pentose phosphate pathway contains the enzyme transketolase that requires thiamine diphosphate to function. In the tricarboxylic acid cycle, thiamine acts as a coenzyme, with magnesium as a cofactor, in the decarboxylation of pyruvate (the pyruvate dehydrogenate complex) and in the α-ketoglutarate dehydrogenase (α-KGHD) complex. It also participates in the conversion of five-carbon to six-carbon sugars by means of the enzyme transketolase (43). Thiamine deficiency, therefore, decreases the amount of energy available to the brain and increases the concentrations of several metabolites. Patients nourished with total parenteral nutrition are at risk for thiamine deficiency if they also have renal losses of thiamine (e.g., patients on chronic dialysis) or increased thiamine requirements because of systemic illness. Other causes of thiamine deficiency include organ transplant, gastrointestinal surgery, malignancy, and acquired immunodeficiency syndrome. In adults, thiamine deficiency is most often seen in chronic alcoholism. Administration of glucose to severely thiamine-deficient patients can deplete stores even further and acutely exacerbate an encephalopathy and heart failure. It is always more prudent to administer thiamine in the at-risk population before glucose administration and refeeding after starvation (11). The features are highly variable and may manifest by sudden collapse and death, or seizures, or by the classic, but extremely rare, triad of gait ataxia, confusion, and ocular abnormalities (44). If missed, it can lead rapidly to death.

The osmolality of a solution is determined by the particles in that solution. Sodium, glucose, and urea are the primary osmoles of the extracellular space. Potassium is the primary osmole of the

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