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Chapter 15 Neurologic Manifestations of Systemic Disease Child Neurology Chapter 15 Neurologic Manifestations of Systemic Disease R † ‡ § || John H. Menkes, Burton W. Fink, Carole G. H. Hurvitz, Carol B. Hyman, Stanley C. Jordan, and Frederick Watanabe Departments of Neurology and Pediatrics, University of California, Los Angeles, UCLA School of Medicine, and Department of Pediatric Neurology, Cedars-Sinai Medical Center, Los Angeles, R † California 90048; Department of Pediatrics, University of California, Los Angeles, UCLA School of Medicine, Los Angeles, California 90048; Department of Pediatrics, University of California, Los ‡ Angeles, Center for the Health Sciences, and Department of Pediatric Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Pediatrics, University of § Southern California School of Medicine, and Children's Hospital of Los Angeles, Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Pediatrics, University of California, Los Angeles, UCLA School of Medicine, and Department of Pediatric Nephrology and Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles, California 90048; and ||Department of Pediatrics, University of California, Los Angeles, UCLA School of Medicine, and Center for Liver Diseases and Transplantation, Cedars-Sinai Medical Center, Los Angeles, California 90048 Metabolic Encephalopathies Hypoxia and Hypoglycemia Brain Death Disorders of Acid–Base Balance Disorders of Electrolyte Metabolism Diagnosis of the Metabolic Encephalopathies Neurologic Complications of Pulmonary Disease Neurologic Complications of Gastrointestinal and Hepatic Disease Hepatic Encephalopathy Neurologic Complications of Liver Transplantation Vitamin E Deficiency States Whipple Disease Neurologic Complications of Renal Disease Uremia Complications of Treatment of Chronic Uremia Hemolytic Uremic Syndrome Neurologic Complications of Cardiac Disease Congenital Heart Disease Obstructive Lesions Coarctation of the Aorta Cyanotic Congenital Heart Disease Acquired Heart Disease Neurologic Sequelae after Intervention Techniques Cardiac Catheterization Neurologic Complications of Hematologic Diseases Anemia Neonatal Polycythemia Coagulation Disorders Thrombocytopenic Purpuras Neonatal Alloimmune Thrombocytopenia Thrombotic Thrombocytopenic Purpura Hemorrhagic Disease of the Newborn Neurologic Complications of Neoplastic Disease Leukemia Neurologic Complications from Antineoplastic Agents Lymphoma and Hodgkin Disease Neurologic Complications of Endocrine Disorders Thyroid Gland Parathyroid Gland Adrenal Gland Pituitary Gland Diabetes Chapter References METABOLIC ENCEPHALOPATHIES Extracerebral diseases can interfere with normal brain function by impairing the necessary supply of oxygen and glucose or by disturbing the ionic environment of neurons, glia, and cell processes. Hypoxia and Hypoglycemia Pathophysiology Hypoxia-ischemia, hypoglycemia, and status epilepticus induce energy failure with consequent brain damage ( 1,2 and 3). The significant differences in the time course and distribution of brain damage that result from these three insults are depicted in Table 15.1. Primary events involve the release of glutamate and other excitatory amino acids and an increase in free cytosolic calcium concentration. Secondary ( downstream) events include activation of calcium-dependent protein kinases and phosphorylases and hydrolysis of phospholipids with accumulation of diacylglycerides. The role of nitric oxide synthase, and free radical–mediated cell damage, and the altered expression of growth factors, heat shock, and stress proteins in cell death resulting from energy failure, have been reviewed by Siesjö ( 4), Choi (5), and Massa (6) (Fig. 15.1). TABLE 15.1. Neurobiological differences among ischemia, hypoglycemia, and epilepsy FIG. 15.1. Schematic diagram illustrating events resulting from energy failure. (DAG, diacylglycerides; FFA, free fatty acids; LPL, lysophospholipids; PAF, platelet activating factor; NO, nitric oxide; XDH, XO, xanthine oxidase, reduced and oxidized forms.) (From Siesjö BK. A new perspective on ischemic brain damage? Prog Brain Res 1993;96:1. With permission of the author.) Cerebral function requires an adequate supply of oxygen and glucose. In adults, glucose is the only substrate oxidized by the brain, although under nonphysiologic conditions such as starvation, structural proteins and lipids can be used as well. The brain of an infant or younger child can oxidize substrates other than glucose, notably ketone bodies, and possibly glycerol and fatty acids ( 7,8). Glucose is supplied to the brain by the bloodstream and enters neurons and glia by facilitative transport. Six isoforms of facilitated glucose transporters (GLUT) have been cloned and are expressed in brain. Quantitatively GLUT1 and GLUT3 are the most important glucose transporters in brain. GLUT1 is expressed in the blood–brain barrier, whereas GLUT3 is the principal neuronal glucose transporter ( 9). Compared with its rate of use, the glucose reserve of the brain, which is in the form of glycogen, is minute, and increased energy demands, as occur during a seizure, necessitate an increased rate of glucose transport across the blood–brain barrier. Approximately 85% of glucose used by the adult brain is oxidized to CO either through the Krebs tricarboxylic acid cycle, or after conversion to a-amino acids, mainly 2 glutamic and aspartic acids. For these reactions, a constant oxygen supply (3.3 mL/100 g tissue per minute) is required. Glycolysis to lactate accounts for only approximately 10% of glucose used by the adult brain. The brain of newborn infants has a lower cerebral oxygen consumption and converts a considerably greater proportion of glucose to lactate and pyruvate (7). Values for cerebral metabolic rates for oxygen range from 0.4 to 1.3 mL/100 g per minute in term infants without neurologic injury, and 0.06 to 0.54 mL/100 g per minute in apparently normal preterm infants of 26 to 32 weeks' gestation ( 10). These values reflect the increased glycolytic ability of the immature brain and its reduced energy demands, in part a consequence of its reduced synaptic density. Reduced energy demands also explain to some degree the relative resistance of the newborn brain to hypoglycemic and hypoxic damage. See Chapter 5 for a more extensive discussion of perinatal asphyxia. There is no constant relationship between blood glucose levels and the severity of neurologic symptoms, because the neurologic symptoms also reflect glucose levels within the brain, tissue energy requirements, and the ability of brain to draw on anaerobic glycolysis and other substrates for its metabolic needs ( 8). The quantity of oxygen used by the brain is a function of the cerebral blood flow and the concentration difference for oxygen between arterial and cerebral venous blood. The principles involved in the measurement and calculation of brain oxygen consumption are discussed by Kety ( 11). Neurologic symptoms can result from a reduction in arteriovenous oxygen difference. Such a reduction is seen in cyanotic congenital heart disease. According to Tyler and Clark, cerebral disturbances are encountered when the arterial oxygen saturation is 60% or less, although considerable individual differences occur in the degree to which the brain is susceptible to oxygen deprivation ( 12). Cerebral anoxia also can result from reduced cerebral blood flow. The rate of cerebral blood flow depends on two factors: the pressure head (the difference between the arterial and venous pressure) and the resistance to blood flow through the cerebral vasculature. In aortic stenosis and in breath-holding spells, reduction of cerebral blood flow can induce neurologic symptoms, particularly syncope and seizures. Several factors determine the extent and permanence of central nervous system (CNS) damage resulting from cerebral anoxia. These include the age of the subject, body temperature, extent and duration of anoxia, and intracellular pH. Siesjö and Plum ( 13) and more recently by Auer and Siesjö (14) have reviewed the pathophysiology of anoxic brain damage beyond the neonatal period. Brain regions containing a high density of excitatory amino acid (e.g., glutamate) receptors are the most vulnerable to hypoxic-ischemic insult, a finding that can at least partially account for patterns of hypoxic brain injury. This topic is more extensively covered in Chapter 5. The fact that damage from these insults can be attenuated by pharmacologic blockage of excitatory neurotransmission with receptor antagonists has triggered the search for similar agents suitable for clinical use (5). At present none are in general use in clinical situations. Pathologic Anatomy Bakay and Lee (15) and Auer and Siesjö (14) have described the basic pathologic alterations in the hypoxic brain. Structural damage can be limited to neurons or, if the hypoxia is more severe, it also involves glia and nerve fibers. The microscopic changes in neurons subjected to energy failure have been delineated by Auer and Beneviste (16). As a rule, associated glial cell damage is proportional to neuronal damage. In gray matter, astrocytes swell as a result of cellular overhydration, whereas in white matter, the intercellular space enlarges because of extracellular edema and alterations in the walls of the cerebral capillaries. Areas most sensitive to hypoxia, as occurs after sudden cardiac arrest, are the middle cortical layers of the occipital and parietal lobes, the hippocampus, amygdala, caudate nucleus, putamen, anterior and dorsomedial nuclei of the thalamus, and cerebellar Purkinje cells ( 17). Brainstem nuclei are more likely to be involved in infants than in older children. When hypoxia is accompanied by hypotension, the ischemic lesions are concentrated along the arterial boundary zones of the cerebral cortex and cerebellum. With a prolonged insult, ischemic lesions tend to become generalized. In hypoglycemia, there is selective neuronal necrosis of the superficial cortical layers, the hippocampus, and dentate gyrus. The cerebral cortical lesions are most conspicuous in the insular and the parieto-occipital cortices ( 18). The thalamus and nonneuronal elements are spared unless hypoglycemia is severe and prolonged (19,20 and 21). Damage to Purkinje cells is less than occurs after hypoxia (16,22). Infarction or hemorrhage are usually absent, even after a severe hypoglycemic insult (1). As occurs in hypoxia, the accumulation of excitatory neurotransmitters plays an important pathogenetic role in neuronal damage and death ( 1). The predominant release of aspartate into extracellular fluid in response to hypoglycemia contrasts with the release of glutamate in hypoxia and may account for the differences in the distribution of neuronal damage. The presence of acidosis, as occurs in hypercapnia, aggravates hypoglycemic neuronal damage, as does concurrent hypoxia (22,23). Clinical Manifestations Hypoxia A number of clinical features are shared by all metabolic encephalopathies ( 24). The earliest symptom is a gradual impairment of consciousness. In infants, this can take the form of irritability, loss of appetite, and diminished alertness. Periods of hyperpnea can progress to Cheyne-Stokes respiration, a pattern of periodic breathing in which hyperpnea regularly alternates with apnea. The eyes move randomly, but ultimately, as the coma deepens, they come to rest in the forward position. When anoxia occurs acutely, consciousness is lost within seconds. In cyanotic congenital heart disease, anoxia can take the form of brief syncopal attacks, often after crying, exertion, or eating, and most frequently occurring during the second year of life. Usually, at the onset of the attack, the child cries, then becomes deeply cyanotic and gasps for breath. Generalized seizures can terminate the more severe cyanotic episodes. Should oxygen supply be restored immediately, recovery is quick, but when anoxia lasts longer than 1 to 2 minutes, neurologic signs persist transiently or permanently. These include impaired consciousness and decerebrate or decorticate rigidity. The prognosis for survival is relatively good for patients who after their anoxic episode exhibit intact brainstem function as manifested by normal vestibular responses, normal respiration, intact doll's eye movements, and pupillary light reactions (24). The longer the duration of coma, the less likely the outlook for full recovery. In the series of Bell and Hodgson, which included all age groups, 17.5% of patients comatose for longer than 24 hours could be discharged from the hospital, but 70% of these subjects experienced significant and permanent neurologic impairment (25). There is fairly good evidence that some children who survive a major hypoxic episode without apparent neurologic residua are left with permanent visuoperceptual deficits (26). The electroencephalogram (EEG) is of assistance in predicting the outcome of coma after cardiorespiratory arrest. A phasic tracing early in the recovery period indicates a good prognosis, whereas a flat EEG is never associated with full recovery except in cases of drug ingestion ( 27). Bilateral loss of cortical responses after median nerve stimulation on the somatosensory-evoked potential (SSEP) test is one of the best prognosticators for a poor outcome. Initial preservation of the cortical potentials does however not necessarily imply a good recovery (28,29). This is particularly true for small infants and serial SSEPs are indicated to ascertain whether they continue to remain intact (30). In term neonates the positive predictive value of an abnormal SSEP is also excellent, but in premature infants a normal response after stimulation of the median nerve had a poor predictive value with respect to normal outcome ( 30,31). Near Drowning In near drowning, the length of coma has even more significant prognostic implications than after cardiorespiratory arrest, and, as a rule, there is an all or nothing outcome, with few children experiencing mild degrees of neurologic damage. None of the patients still comatose in 15 to 30 minutes after their rescue survived without major neurologic residua, and 60% of subjects in this group died. In a Hawaiian series, all children who ultimately survived intact made spontaneous respiratory efforts within 5 minutes of rescue, and the majority of those did so within 2 minutes (32). The experiences from several other centers are similar in that all children who still required cardiopulmonary resuscitation on arrival at the hospital experienced permanent severe anoxic encephalopathy. Interestingly, the presence of convulsions does not indicate a bad prognosis although their persistence beyond 12 hours does. Fields concurs with that observation and lists the following factors that predict poor outcome: (a) submersion for more than 5 minutes; (b) serum pH below 7.0 at time of admission to the emergency room; (c) the need for cardiopulmonary resuscitation in the emergency room; (d) a delay before the first postresuscitation gasp; and (e) poor initial neurologic evaluation on resuscitation ( 33). Immersion in cold or icy water appears to give a better chance for survival (34). SSEPs and an EEG obtained during the second 24 hours after the accident have been used as additional prognostic indicators ( 35). Numerous treatment regimens, many of unproved benefit, have been used for cerebral salvage. These include induced hypothermia, barbiturate coma, and intracranial pressure monitoring to control cytotoxic cerebral edema. None of these have been effective in improving the ultimate outcome ( 34,36). The neurologist attending a near-drowning victim should keep in mind that hypoglycemia and hyperglycemia can cause further neurologic damage. Hyperthermia should be avoided and seizures controlled, with phenytoin being the preferred anticonvulsant. A postanoxic dystonic syndrome has been recognized in children. It appears 1 week to 36 months after the anoxic insult, and tends to worsen for several years. Dysarthria and dysphagia are common. Neuroimaging studies reveal putaminal lesions in the majority of such cases. Treatment is generally ineffectual. The pathophysiologic mechanism underlying this condition and the reason for its progression are totally unknown ( 37). The persistent vegetative state (PVS) after near drowning is being seen with increasing frequency owing to the resuscitative facilities of most emergency rooms. According to data compiled in California and reported in 1994, survival of children in PVS is dependent on their age. Median survival of infants younger than 1 year of age was 2.6 years; of infants between 1 and 2 years, 4.2 years; and children between 2 and 6 years, 5.2 years ( 38). The same group of workers, reporting in 1999, found that in the mid-1990s the mortality rate for infants in PVS was only one-third of those in the early 1980s. A smaller decrease in mortality rates was recorded for children ages 2 to 10 years (38a). In the experience of Heindl and Laub 55% of children who are in PVS as a result of an anoxic event became conscious within 19 months of the injury. The quality of life was fairly good for those who recovered from PVS; 9% recovered completely, and another 52% became independent in everyday life (39). After 9 months, less than 5% of children were able to recover from PVS (39). In the study of Ashwal and coworkers (38), children in PVS survive somewhat longer in institutions than at home; other studies have shown converse results ( 40). A more extensive consideration of the PVS can be found in Chapter 8. Hypoglycemia The neonate does not show any specific symptoms of hypoglycemia. Table 15.2 outlines the clinical picture of symptomatic hypoglycemia in term neonates, as recorded from a Scandinavian nursery (41). TABLE 15.2. Symptoms of neonatal hypoglycemia in 44 newborn patientsa Transient hypoglycemia has been observed in a relatively significant proportion of infants with intrauterine growth retardation, perinatal asphyxia, or other forms of perinatal stress (42,43), and in neonates born to mothers with diabetes or toxemia (44). The incidence of neonatal hypoglycemia is difficult to ascertain because of the different criteria used to define hypoglycemia and because of the varieties of feeding routines used in nurseries. Normal plasma glucose values during the first week of life have been published (45). With hypoglycemia defined as glucose levels of 20 mg/dL or less, the condition was identified in 5.7% of cases at the University of Illinois Hospital Nursery (46). The incidence is higher in low-birth-weight infants. Symptoms of hypoglycemia may appear as early as 1 hour after birth, particularly in infants who are small for gestational age, but generally they are delayed until 3 to 24 hours. In approximately 25%, hypoglycemia does not become symptomatic until after 24 hours (41). An inconstant relationship exists between blood glucose levels and hypoglycemic symptoms. Some infants with blood sugar levels between 20 and 30 mg/dL develop hypoglycemic symptoms, whereas others whose levels fall below 20 mg/dL can remain asymptomatic (47). Evoked potentials have provided evidence for the critical value at which hypoglycemia affects the brain. SSEPs and brainstem auditory-evoked potentials become abnormal in term infants when their blood sugar falls below 41.5 and 45.0 mg/dL, respectively ( 48). Visual-evoked responses remain normal at these levels. A rapid compensatory increase in cerebral blood flow resulting from recruitment of previously unperfused capillaries mediated by an increase in plasma epinephrine levels occurs at or below blood glucose values of 30 mg/dL ( 49,50 and 51). Magnetic resonance imaging (MRI) studies can show patchy hyperintensities in the occipital periventricular white matter. These lesions tend to resolve with prompt therapy ( 51a). From the point of view of a neurologist it therefore seems prudent that any blood glucose value of 45 mg/dL or less should be emergently corrected and followed closely to ensure normoglycemia. The clinical management of hypoglycemia in the neonates is beyond the scope of this text. The reader is referred to a flow diagram by Cornblath and Schwartz ( 52). It is difficult to know what the outlook is in terms of neurologic and cognitive deficits for neonates who develop symptomatic hypoglycemia. This is because of limitations of current definitions for neonatal hypoglycemia, our inability to determine at what glucose level hypoglycemia becomes symptomatic, and on the various other risk factors, which complicate the clinical course of hypoglycemic infants and confound every study on neurodevelopmental outcome ( 53). From a multitude of data derived from neonates without other major risk factors, who had severe hypoglycemia as a consequence of nesidioblastosis, it is clear that a significantly low plasma glucose level that persists over a prolonged period of time can indeed result in major brain damage. The risks of asymptomatic neonatal hypoglycemia are even more undefined, because low-birth-weight and stressed infants, the group with the highest incidence of hypoglycemia, are also subject to a variety of other prenatal and perinatal risks, notably hypoxic ischemic encephalopathy ( 54). When older infants and children develop symptomatic hypoglycemia, the condition presents with autonomic symptoms, which accompany a progressive impairment of neurologic function. The serum glucose level at which symptoms appear varies, but any child with a blood glucose level of 46 mg/dL or less is suspect for hypoglycemia (55). Autonomic symptoms are mainly caused by increased adrenaline secretion. They include anxiety, palpitations, pallor, sweating, irritability, and tremors (55). During the initial stages, impaired neurologic function is manifested by dizziness, headache, blurred vision, somnolence, and slowed intellectual activity. Transient cortical blindness is seen only rarely ( 56). In fact, if permanent blindness accompanies hypoglycemia, one must consider the diagnosis of congenital optic nerve hypoplasia associated with hypopituitarism (see Chapter 4) (57). If hypoglycemia is prolonged, subcortical and diencephalic centers become inoperative. The brainstem, the area most resistant to hypoglycemia, is the last to be affected. Almost all children develop generalized or focal seizures during a severe hypoglycemic episode. With even more prolonged involvement, tonic extensor spasms and shallow respirations develop. The response to intravenous glucose is immediate in patients who have not progressed to brainstem involvement. In children who have experienced prolonged unconsciousness or repeated hypoglycemic attacks the prognosis for complete recovery is poor and approximately one-half of the patients remain mentally retarded (58). Not uncommonly, the clinician encounters a child whose first seizure occurred in the setting of suspected hypoglycemia, but who continues to experience seizures in the absence of hypoglycemia. Although prolonged hypoglycemia can indeed induce hippocampal damage and thus set up a seizure focus, we believe that isolated hippocampal damage is quite rare, and that, in the majority of such cases, both initial and subsequent seizures are unrelated to hypoglycemia. Transient hemiparesis or aphasia has been seen in diabetic children, often in association with documented hypoglycemia. The cause of these focal deficits is unclear, but they could reflect focal seizures followed by Todd's paralysis (59). Brain Death The Ad Hoc Committee on Brain Death from the Children's Hospital, Boston, has defined brain death: Brain death has occurred when cerebral and brainstem functions are irreversibly absent. Absent cerebral function is recognized clinically as the lack of receptivity and responsivity, that is, no autonomic or somatic response to any sort of external stimulation, mediated through the brainstem. Absent brainstem function is recognized clinically when pupillary and respiratory reflexes are irreversibly absent. . . . Particularly in children, peripheral nervous activity, including spinal cord reflexes, may persist after brain death; however, decorticate or decerebrate posturing is inconsistent with brain death ( 60). Recommendations made by a special task force appointed to set guidelines for determining brain death have been published ( 61). Although it is generally recognized that particular caution should be exerted when diagnosing brain death in small children, the task force further emphasized this age distinction by recommending different brain death criteria for infants between 7 days and 2 months of age, between 2 months and 1 year, and older than 1 year. The period of observation before declaration of brain death in the youngest group should be such that two examinations and EEGs to document electrocerebral silence are performed, separated by at least 48 hours. In the group from 2 months to 1 year of age, the interval between the two examinations and EEGs can be reduced to 24 hours. Furthermore, a repeat examination and EEG are not necessary in this group if radionuclide angiography demonstrates absent cerebral blood flow ( 62). In children older than 1 year, the task force recommended the period of observation be a minimum of 12 hours, unless corroborating tests added further support to the diagnosis of brain death. When the extent and reversibility of brain damage are difficult to assess because of the type of insult (e.g., hypoxic-ischemic encephalopathy), the observation period should be extended to at least 24 hours. Some authorities have challenged these recommendations and a survey of pediatric intensive care units shows substantial variability even within the same pediatric intensive care unit with respect to criteria used by clinicians for the diagnosis of brain death ( 63). In a clinical and neuropathologic study of brain death, Fackler and coworkers found no support for employing distinct brain death criteria for infants between 2 months and 1 year of age ( 64). Other investigators question the validity of relying on the EEG to confirm brain death, because EEG activity is occasionally seen after brain death ( 65). Conversely, phenobarbital levels above 25 to 35 µL can suppress EEG activity in neonates (66). The brainstem-auditory evoked response cannot be used as a confirmatory laboratory criterion of brain death. Its absence is not predictive of brain death and persistence of peak I has occasionally been seen in brain dead infants ( 67). Although complete absence of cerebral blood flow is considered irrefutable evidence of brain death, cerebral blood flow is extremely low in normal term or preterm newborns ( 10). We believe that as more sophisticated imaging techniques such as xenon-enhanced computed tomography (CT), single photon emission computed tomography (SPECT) (68), and positron emission tomography (PET) (69) are applied to the clinical evaluation of brain death in children, the criteria for making this diagnosis will become refined and perhaps simplified. An important aspect in diagnosing brain death is the documentation of apnea. During this procedure, it is vital to prevent hypoxemia. Administration of 100% oxygen for 10 minutes is recommended before withdrawal of respiratory support. A catheter should be inserted into the endotracheal or tracheostomy tube, and oxygen be continued at 6 L/minute during the test. The arterial pCO level should be allowed to increase to 60 mm Hg. Patients who are hypothermic or receiving medications 2 that suppress respiration cannot be reliably tested using this procedure ( 70). When diabetes insipidus is seen, it reflects midbrain death ( 71). Disorders of Acid–Base Balance Pathology Both pH and ionic concentrations within the CNS are controlled by the blood–brain barrier, which renders the brain relatively resistant to alterations in the electrolyte composition of serum. In disorders of acid–base balance, the blood pH correlates poorly with the presence or severity of neurologic symptoms. This is because cerebrospinal fluid (CSF) pH tends to fluctuate less than arterial pH, even with wide shifts in serum hydrogen ion concentrations. Resistance to shifts of systemic pH is most pronounced in metabolic acidosis, less evident in metabolic and respiratory alkalosis, and least effective in respiratory acidosis. Homeostatic factors maintaining + – the pH of CSF include alterations in cerebral blood flow, active transport of H and HCO , and carbon dioxide removal. These factors are reviewed by Plum and 3 Siesö (72). In respiratory acidosis, the pH of CSF deviates from normal as much as or more than arterial pH. This deviation often obscures the severity of acid–base disturbance and suggests measurements of CSF pH in encephalopathies associated with ion imbalance are preferable to those of blood pH. Clinical Manifestations The neurologic picture of acid–base disorders is nonspecific. Children become progressively more obtunded, finally delirious, and comatose. Seizures are rare. Often, the patient's clinical condition does not correlate well with either blood or CSF pH, although in patients with respiratory acidosis, neurologic symptoms are invariably present when the pH of CSF decreases below 7.25. Disorders of Electrolyte Metabolism Sodium and Potassium Disturbances of serum electrolytes can induce changes in the ionic composition of the intracellular and extracellular compartments of the brain. These changes can have major effects on the excitability of the neural membrane and on the processing and transmission of neuronal signals. The membrane potential depends in part on the ratio of intracellular and extracellular sodium and potassium concentrations. Major shifts in serum sodium concentrations disrupt cerebral function as a result of altered osmolality of the cellular compartments. A normal potassium level is essential for the maintenance of the membrane potential. In contrast to the ease with which fluctuations in serum sodium concentration affect intracerebral sodium, the concentration of extracellular potassium within the brain, as reflected by CSF levels, varies little, even with such major shifts as those induced by intravenous infusions of potassium or by the administration of corticosteroids. It is, therefore, uncertain what role potassium plays in the evolution of cerebral symptoms commonly associated with hyperkalemia or hypokalemia. The effect of potassium on muscular function is reviewed in Chapter 14. The reader is also referred to a review by Katzman and Pappius (73) for a full discussion of the pathogenesis of cerebral symptoms in electrolyte disorders and to a review by Strange on disorders of osmotic balance ( 74). Hyponatremia Low-sodium syndromes can result from an increase in body water with retention of a normal sodium store or can occur after reduction of sodium stores. The clinical conditions associated with hyponatremia are outlined in Table 15.3. TABLE 15.3. Clinic conditions producing abnormalities of sodium concentration In the experience of Arieff and colleagues, the most common cause for symptomatic hyponatremia in the pediatric population was administration of hypotonic fluids combined with extensive extrarenal loss of electrolyte-containing fluids ( 75). Oral water intoxication from increased intake of tap water during the summer months also induces symptomatic hyponatremia (76). Neurologic symptoms of hyponatremia include headache, nausea, incoordination, delirium, and, ultimately, generalized or focal seizures with apnea and opisthotonus (77,78). On autopsy, cerebral edema and transtentorial herniation are seen (75,76). Generally, severe neurologic symptoms with permanent residua do not develop at sodium levels above 130 mEq/L, unless plasma sodium has decreased rapidly. Some have advocated rapid correction of hyponatremia in a patient with neurologic symptoms using urea in conjunction with salt supplements and water restriction (79). A too rapid correction of hyponatremia has been thought to play a role in the development of central pontine myelinolysis ( 80), a frequently fatal disorder characterized clinically by confusion, cranial nerve dysfunction, and, in larger lesions, a “locked in” syndrome and quadriparesis. Pathologically, central pontine myelinolysis is characterized by symmetric destruction of myelin at the center of the pons. The pontile demyelination can be visualized by MRI ( 81). According to Brunner and colleagues, central pontine myelinolysis is more likely to develop when the initial sodium level is less than 105 mEq/L, when hyponatremia has developed acutely, and when sodium levels are corrected too rapidly (82). Other investigators have challenged the concept that this condition is related to the rate of correction of hyponatremia, and the optimal rate for correcting hyponatremia is still controversial ( 83). According to Keating and colleagues, an optimal rate of correction is 2 to 3 mEq/L per hour (76). Hypernatremia Increased concentration of sodium in body fluids elevates fluid osmolality and induces severe cerebral manifestations. Major causes for hypernatremia are outlined in Table 15.3. Luttrell and Finberg have delineated the factors responsible for neurologic symptoms. These are subdural hematomas, venous and capillary congestion, and hemorrhages, the last produced by shrinkage of the brain during dehydration ( 84). Neurologic symptoms can also occur in the absence of any structural alteration and are probably the direct result of hyperosmolality. Symptoms are caused by cerebral edema, which is particularly likely to occur with rapid rehydration and is caused by an elevated content of chloride and potassium in the brain ( 85,86). Hypernatremia is generally seen in infants younger than 6 months of age. All have clear evidence of dehydration. Patients have varying degrees of impaired consciousness and hyperpyrexia. Approximately one-third experience generalized convulsions and spasticity. Focal neurologic abnormalities, notably hemiparesis, are seen in approximately 10% of patients. Finberg found subdural hematomas in many of his hypernatremic infants ( 87). In some, neurologic symptoms, notably seizures, do not appear until 24 to 48 hours after the start of fluid therapy. These symptoms have been ascribed to cerebral edema and a lowered convulsive threshold developing with rehydration of the brain (85). The mortality of children who develop neurologic symptoms with hypernatremia ranges from 10% to 20%. Approximately one-third of survivors have permanent sequels, notably seizures, spasticity, and mental retardation (88). Chloride Hypochloremia A syndrome marked by anorexia, lethargy, failure to thrive, muscular weakness, and hypokalemic metabolic alkalosis was seen in infants who ingested a chloride-deficient formula for the preceding 1 or more months (89,90). Serum chloride as low as 61 mEq/L and arterial pH values as high as 7.74 were recorded (89). Usually, urinary chlorides were completely absent. Impaired growth of head circumference was documented in the majority of cases. Rehydration and chloride supplementation reversed all symptoms and resulted in a marked acceleration of motor milestones and in complete or partial recovery of the decelerated skull growth. Developmental testing in some of these children at 9 to 10 years of age indicated that children who had received this formula had significantly lower scores on the Wechsler Intelligence Scale for Children (WISC) and significantly higher risks for receptive and expressive language disorders ( 91). We have recognized a clinical picture of an expressive language delay, coupled with visuomotor deficits and an attention deficit disorder that often assumes the overfocused pattern (see Chapter 16). When the defect is more severe, the language and visuomotor problems can expand to a picture of generalized mental retardation, and the attention disorder can exhibit autistic features (92). A similar condition has been seen in nursing infants whose mothers' milk was for unknown reasons deficient in chloride ( 93). Calcium Calcium is the major extracellular divalent cation. Both high and low serum calcium levels are associated with neurologic symptoms. Total calcium in serum is found in three forms: protein bound, and therefore nondiffusible (30% to 55% of total); chelated (i.e., diffusible but nonionized; 15% of total); and ionized (remaining percentage). Generally, the appearance of neurologic symptoms correlates well with levels of ionized calcium of 2.5 mg/dL or less. The concentration of CSF calcium is normally approximately one-half that of serum calcium and represents the result of a secretory process, rather than the movement of diffusible and ionized calcium from the serum. Changes in the CSF concentration are relatively small, although large alterations in serum calcium values overcome homeostatic mechanisms ( 73). Hypocalcemia The clinical picture of hypocalcemia and its causes varies with the age of the affected child. Some of the syndromes that produce hypocalcemia are outlined in Table 15.4. TABLE 15.4. Conditions producing hypocalcemia, hypomagnesemia, and neurologic symptoms Hypocalcemia was one of the more common causes of seizures during the neonatal period. The condition can be defined as a level of serum calcium below 7 mg/dL or of ionized calcium below 3.5 mg/dL. It is commonly seen in the preterm neonate or in the stressed term neonate ( 106). Two forms of neonatal hypocalcemia are encountered. One occurs during the first 2 days of life in premature and critically ill term infants. It is also seen in infants who have suffered perinatal asphyxia and in infants of mothers with insulin-dependent diabetes. As many as 50% of very-low-birth-weight infants have serum calcium levels below 7 mg/dL ( 107). The exact mechanism of this form of hypocalcemia is still obscure. Impaired vitamin D metabolism also has been excluded as a pathogenetic factor. Increased levels of calcitonin have been suggested as an etiologic factor in the hypocalcemia of prematurity, but not in that seen in infants of diabetic mothers ( 108). Decreased end-organ responsiveness, decreased calcium intake and absorption, and respiratory alkalosis are also believed to play a role ( 107). Less often, maternal hyperparathyroidism, congenital absence of the parathyroid glands, or disturbed renal function induce neonatal hypocalcemia (see Table 15.4). The second form of neonatal hypocalcemia is the classic neonatal tetany (late hypocalcemia), whose mechanism was first elucidated by Bakwin in 1937 ( 109). It occurs between the fifth and tenth days of life and results in part from intake of cow's milk, which induces an increased phosphate load. In this form of hypocalcemia, hyperphosphatemia and hypomagnesemia are commonly present (97). Additionally, low circulating parathyroid hormone levels are seen. With the widespread use of low-phosphate milk formulas this condition has virtually disappeared. In the series of Lynch and Rust, congenital heart disease was seen in 47% of infants with hypocalcemic seizures, and prematurity in 13%. Maternal hyperparathyroidism, idiopathic hypoparathyroidism, and DiGeorge syndrome were other causes. In 20% of infants there was no obvious cause for the seizures (110). Neonatal hypomagnesemia has been recorded in association with hypocalcemia resulting from maternal hyperparathyroidism ( 106). It can also be the result of a selective malabsorption of magnesium (108) (see Table 15.4). Hypocalcemic seizures can be focal, multifocal, or generalized. In the series of Lynch and Rust, multifocal clonic seizures were the most common. True tonic seizures or tonic-clonic (grand mal) attacks are unusual, and the latter seizure type was not encountered by Lynch and Rust ( 110). In the interictal period, infants generally are alert, and seizures without apparent loss of consciousness are not uncommon (97). Jitters were encountered in 35% of hypocalcemic infants in the 1971 series of Cockburn and coworkers (97), and in 27% of infants in the series of Lynch and Rust (110). An increased extensor tone is relatively common, as are increased deep tendon reflexes and ankle clonus. In contrast to neonates suffering from seizures owing to nonmetabolic causes, persistent focal neurologic deficits are not observed. The classic signs of tetany seen in the older child are usually absent. Carpopedal spasm was rare, stridor owing to laryngospasm, and Chvostek's sign (a brief contraction of the facial muscles elicited by tapping the face over the seventh nerve) was not noted in any of the hypocalcemic infants reported by Keen ( 111). The EEG is frequently abnormal. It can demonstrate electroencephalo-graphic seizures ( 110). The treatment of seizures caused by neonatal tetany consists primarily of the administration of calcium salts (see the section on neonatal seizures in Chapter 13). The long-term outlook of infants who have experienced seizures owing to late hypocalcemia is generally good and in the absence of subsequent neurologic insults the majority develop normally (97,110,111). Calcium deposition in necrotic areas of brains of stressed neonates has been related to the transient elevations of ionic calcium after parenteral administration of calcium gluconate ( 112). In older infants and in children, neurologic symptoms of hypocalcemia include tetany and seizures. Tetany is characterized by episodes of muscular spasms and paresthesias mainly involving the distal portion of the peripheral nerves. Episodes appear abruptly and are precipitated by hyperventilation or ischemia. No alteration of consciousness occurs. Carpopedal spasm and laryngospasm are the two most frequent examples of tonic muscular spasms. Chvostek's sign is not diagnostic of tetany, because it is seen in healthy infants. Seizures can occur in the absence of tetany and are occasionally focal. Headaches and extrapyramidal signs are less common and are confined to older children or adults with hypoparathyroidism (113). In this condition, CT scans can show symmetric bilateral punctate calcifications of the basal ganglia, although only 50% show an association between this finding and the occurrence of extrapyramidal signs ( 113). Pseudohypoparathyroidism is characterized by obesity, moon-shaped facies, mental retardation, cataracts, short, stumpy digits, enamel defects, and impaired taste and olfaction. Calcifications of the basal ganglia are seen in approximately one-third of instances. The condition is seen more commonly in females and is caused by an inability of renal tubules to respond to parathormone ( 103). In neonates undergoing gastrostomy for various reasons, vitamin D malabsorption can lead to hypocalcemic seizures. This condition is treated by parenteral administration of vitamin D (114). Tetanic seizures also can result from sodium phosphate enemas (115). Hypercalcemia Aside from hyperparathyroidism, which is rare, hypercalcemia of childhood takes two forms: mild hypercalcemia and the hypercalcemia elfin-facies syndrome (Williams syndrome) (see Chapter 3). Patients with mild idiopathic hypercalcemia usually show a sudden failure to thrive between 3 and 7 months of age. The condition is probably the result of excess vitamin D intake and is reversible with restriction of calcium and vitamin D intake. Williams syndrome is covered in Chapter 3. Neonatal hypercalcemia also is seen in the presence of subcutaneous fat necrosis and blue diaper syndrome. The latter is a rare familial disease in which hypercalcemia is associated with a defect in the intestinal transport of tryptophan. The blue diaper results from the oxidation of indican, a tryptophan derivative (116). Neurologic symptoms are generally absent, although optic nerve hypoplasia has accompanied this condition. Magnesium Since the 1970s, it has become apparent that a number of symptomatic infants with combined hypocalcemia and hypomagnesemia respond only to the administration of magnesium (117). This condition, termed congenital hypomagnesemia, is marked by recurrent tetany or convulsions, which commence during the first few weeks of life and respond to administration of magnesium but not calcium. Blood magnesium levels can be as low as 0.04 mmol/L, as contrasted with mean normal levels of 0.8 mmol/L, with hypomagnesemia being defined as levels below 0.65 mmol/L (118). Although boys are overrepresented in reported cases, this condition is now believed to be transmitted as an autosomal recessive disorder (119), and in one extended Bedouin family it has been mapped to the long arm of chromosome 9 (9q) (120). The condition is caused by a selective defect in magnesium absorption in the small intestine ( 121). This is believed to result from a defect in a receptor or ion channel (120). Symptomatic hypocalcemia also occurs and is believed to be secondary to impaired synthesis or secretion of parathyroid hormone, or end-organ unresponsiveness to parathormone as a result of diminished activity of magnesium-dependent enzymes. When treated early and consistently, the outcome is good in terms of neurodevelopment, but untreated children can die or experience permanent brain damage (119). Congenital hypomagnesemia is distinct from primary familial hypomagnesemia, whose gene has been mapped to the long arm of chromosome 3 (122). Hypomagnesemia also is seen in infants of diabetic mothers and in small-for-date infants. It has been described in conjunction with maternal hypoparathyroidism, neonatal hepatic disease, and increased loss of magnesium, as might occur after repeated exchange transfusions. In older infants or children, low plasma magnesium levels are encountered in malabsorption syndromes, prolonged diarrhea, rickets, protein energy malnutrition or other forms of chronic malnourishment, and hypoparathyroidism (117,123). Diagnosis of the Metabolic Encephalopathies In most instances, the differential diagnosis of the metabolic encephalopathies rests on the clinical history and on laboratory examinations. The clinical and EEG pictures tend to be nonspecific and usually reflect dulling of consciousness and a diffuse cerebral disorder. The examining physician, therefore, must go through the differential diagnosis of impaired consciousness in an infant or child. A history obtained quickly but competently is the first requirement for the differential diagnosis of coma. The physician must determine if loss of consciousness occurred without warning or was preceded by other symptoms, such as an upper respiratory infection, gastrointestinal disturbances, headaches, or unsteady gait. If the onset of unconsciousness was sudden, one has to consider acute poisoning, trauma, postictal stupor, or, less likely, an intracranial or subarachnoid hemorrhage. Trauma and acute subdural and extradural hemorrhages secondary to trauma are unlikely in the absence of external injuries and retinal hemorrhages and in the presence of a normal CT scan, whereas a normal CSF virtually excludes a subarachnoid hemorrhage. Focal neurologic signs are the rule in an intracerebral hemorrhage. Poisoning is often difficult to exclude, particularly in a toddler, and warrants gastric lavage and blood screening for toxins in all undiagnosed cases of coma. Making a diagnosis of postictal stupor is difficult after an unobserved convulsive attack unless one can elicit a history of a seizure disorder. Obstruction of the ventricular system by an intraventricular tumor, and hemorrhage arising from a hemangiomatous malformation within the brainstem are rare causes for sudden loss of consciousness. When loss of consciousness is preceded by an illness, the diagnosis of metabolic encephalopathy, acute meningitis, encephalitis, or increased intracranial pressure must be considered. Examination of the eye grounds for papilledema, neuroimaging studies, blood chemistries, and a lumbar puncture are required to distinguish among the various entities. It is hazardous to arrive at a diagnosis of encephalitis in a patient who has normal CSF. Rather, one must consider other conditions. Acute toxic encephalopathy and Reye syndrome are two entities, which are now relatively uncommon. They were characterized by vomiting, seizures, and prolonged loss of consciousness. Because they have been postulated to have a viral cause, they are considered in Chapter 6. NEUROLOGIC COMPLICATIONS OF PULMONARY DISEASE In the past, neurologic problems in children with lung disease were encountered relatively infrequently, but with the recent advent of improved management for both acute and chronic pulmonary disease, and hence prolonged survival, such disorders are being recognized increasingly. Extracorporeal membrane oxygenation (ECMO) is being used in most medical centers to treat neonates with uncontrollable respiratory failure ( 124). This invasive, technically complicated procedure is designed to functionally bypass the lungs. It requires systemic anticoagulation and generally necessitates ligation of the right common carotid artery, the right internal jugular vein, or both. Even though there is a compensatory response anatomically mediated through the circle of Willis, approximately one-fourth of infants demonstrate focal parenchymal lesions on postECMO MRI (125). As a rule, these are right-sided ischemic lesions, and contralateral hemorrhagic lesions consistent with hyperperfusion of the left cerebral hemisphere. In the experience of Mendoza and her group, 83% of ischemic lesions involved the right side and 70% of the hemorrhagic lesions occurred solely or predominantly on the side opposite the carotid ligation ( 126). These abnormalities are demonstrable on head ultrasound studies performed during the course of ECMO ( 127). Additionally, there is a significant incidence of left hemiparesis and left focal seizures. These deficits, seen during the neonatal period, however do not always translate into focal functional disabilities in later life. The neurodevelopmental outcome of infants who had been placed on ECMO has been surveyed in several centers. Most studies record a handicap rate of approximately 20% to 30% (128,129). The underlying diagnosis necessitating ECMO is in part a predictor of the outcome. Children who required ECMO because of meconium aspiration have higher developmental indices than those whose underlying diagnosis was sepsis ( 129), whereas children who develop bronchopulmonary dysplasia after ECMO fare less well (130). Serial plasma lactate concentrations obtained during the procedure may help predict the developmental outcome ( 131), as may the degree of abnormality seen on neuroimaging (132). The major causes of handicap are spastic quadriparesis, seizures, impaired cognitive functioning, and language delay (128). Additionally, approximately 20% of children have abnormal hearing, most commonly a sensorineural hearing loss ( 133,134). This figure, obtained by testing brainstem auditory-evoked potentials on ECMO-treated infants at the time of hospital discharge, may be falsely low, and at least in some infants hearing loss appears to have a delayed onset and to be progressive (135). The sensorineural hearing loss seen in children postECMO treatment parallels an incidence of 37% of generally bilateral sensorineural hearing loss in children with persistent fetal circulation who are not treated with ECMO. Although prolonged hyperventilation has been implicated in this deficit, other factors are probably operative ( 136,137). Theophylline is commonly used in the nursery for the treatment of apnea and in older children for asthma and other pulmonary conditions. The major neurologic complication of theophylline therapy is the appearance of seizures, which are seen in all age groups, and are generally accompanied by elevated theophylline levels, although seizures have been observed at levels of 21 to 23 µg/mL (138,139). Seizures can be focal or generalized. When they are focal, one should suspect an underlying focal cerebral lesion. Theophylline-induced seizures are often difficult to control with anticonvulsants, and in some instances a toxic encephalopathy and permanent brain damage can ensue (140). Seizures are best avoided by careful monitoring of serum theophylline levels, and it would appear wise not to use the medication for the treatment of reactive airway disease in children who have an abnormally low seizure threshold. In the past, a progressive degenerative disease of the CNS was seen in premature infants with bronchopulmonary dysplasia or other forms of severe and chronic lung disease who were receiving ventilatory support. This condition involved the cerebral cortex, brainstem, or basal ganglia ( 141). With improved control of the respirator variables, which affect mechanical ventilation, this entity is no longer encountered. A distinctive neuromuscular syndrome has been encountered in children who had been on prolonged ventilatory support and nondepolarizing neuromuscular blocking agents. The condition is more common in the adult population and has been termed critical illness neuromuscular disease (142). Several overlapping syndromes are subsumed under that term. Some patients suffer from an axonal motor neuropathy, whereas in others a defect at the neuromuscular junction or a myopathy can be documented by electrophysiologic studies or biopsy (143). The clinical picture is similar and is highlighted by an inability of most such patients to be weaned from a respirator. Neurologic examination discloses a quadriparesis with absent or reduced reflexes, a neuropathic or myopathic electromyography result (EMG), and normal or only slightly elevated creatine kinase levels. Nerve conduction studies on patients with the axonal polyneuropathy show a mild slowing of motor velocity, and a muscle biopsy shows grouped atrophy. In critical illness myopathy there is a type II muscle fiber atrophy ( 144). The cause or causes for the clinical picture are obscure (145). Intravenous immune globulin has been suggested, but even without treatment affected children improve over the course of ensuing weeks or months. The neurologic picture in chronic pulmonary disease (e.g., in advanced cystic fibrosis) results from hypoxia combined with carbon dioxide retention, and, to a lesser degree, from chronic respiratory acidosis. Children develop progressively deepening lethargy that, often with the onset of a respiratory infection, progresses to coma. Approximately 14% show papilledema, the consequence of increased intracranial pressure owing to chronic carbon dioxide retention, which induces dilatation of the cerebral vasculature (146). Seizures are rare. With evolution of the encephalopathy, asterixis and multifocal myoclonus become prominent. Asterixis consists of sudden flapping movements of the palms at the wrists (liver flap), most easily elicited when the arms are outstretched and the hands dorsiflexed. During coughing paroxysms, such as are seen in cystic fibrosis, the most common neurologic complaints are lightheadedness and headache. Visual disturbances, paresthesias, tremor, and speech disturbances are occasionally encountered ( 147). All symptoms are reversible. NEUROLOGIC COMPLICATIONS OF GASTROINTESTINAL AND HEPATIC DISEASE Hepatic Encephalopathy When the liver is damaged by acute or chronic disease, a characteristic set of neuropsychiatric symptoms develops termed hepatic encephalopathy (HE). The etiology of HE is still debated, but it is probably the consequence of systemic shunting of gut-derived constituents, caused by the impaired extraction by the failing liver (148,149). Pathology and Pathogenesis The morphologic changes in the brain are dominated by astrocytic alterations. The principal microscopic abnormalities include enlargement and increase in the number of protoplasmic astrocytes. These cells (Alzheimer II cells) are astrocytes with an enlarged, pale nucleus, and a marked diminution in glial fibrillary acidic protein. They are found throughout the cerebral cortex, basal ganglia, brainstem nuclei, and Purkinje layer of the cerebellum. They are most prominent in the chronic forms of liver disease and in patients dying after prolonged periods of coma ( 150). Neuronal changes are generally not seen. Less often, central pontine myelinolysis has been noted in children with hepatic failure (151). According to current consensus HE is multifactorial (152,152a). The two most important factors in its pathogenesis are increased plasma and brain concentrations of ammonia and increased GABAergic neurotransmission. Ammonia has been known to be neurotoxic for several decades. When astrocyte cultures are exposed to ammonia, they are transformed to Alzheimer II cells. From a neurophysiologic point of view, ammonia enhances neuronal inhibition, either by acting directly on the GABA receptor complex and increasing selectively the binding A of agonist ligands, or by promoting astrocytic synthesis of substances that activate the GABA receptor complex (152). A However, approximately 10% of patients with HE have normal or only moderately elevated blood ammonia levels ( 153), and electrophysiologic experiments have shown that at the ammonia concentrations seen in hepatic failure, (0.5 to 2 mM), ammonia blocks the formation of hyperpolarizing inhibitory postsynaptic potentials, thus impairing postsynaptic inhibitory processes and increasing excitatory neurotransmission ( 154). These effects contrast with the clinical picture of hepatic coma, making it evident that hyperammonemia is not solely responsible for HE. Increased GABA-mediated neurotransmission contributes significantly to the manifestations of HE. Primarily studied in chronic liver disease, GABAergic transmission is probably also affected in acute HE. Several mechanisms have been proposed. These include an increased availability of GABA in synaptic clefts, the result of ammonia-induced abnormalities in glial function, leading to decreased GABA reuptake, increased levels of benzodiazepine receptor agonists ( 155), loss of presynaptic feedback inhibition of GABA release caused by a decrease in the number of GABA receptors, or increased transfer of GABA from blood to brain (154). B Studies in both animal models and humans with HE have demonstrated transient improvement in mental status after administration of flumazenil, a benzodiazepine antagonist (156). The exact mechanism for improvement is unclear; it has been suggested that several, mostly unidentified endogenous or food-derived benzodiazepine-like substances act as ligands for the receptor ( 157). Additional metabolic disturbances may contribute to the evolution of HE. High levels of ammonia can increase glutamine synthesis. Although glutamine itself is not neurotoxic, its metabolite alpha-ketoglutarate is. Furthermore, the increased synthesis of glutamine depletes the available amounts of alpha-ketoglutarate, reducing the concentration of high-energy phosphates, and slowing the reactions in the Krebs tricarboxylic acid cycle. Decreased oxygen consumption and glucose metabolism are probably secondary to HE rather than causative (152). Evidence for the synergistic role of other neurotoxins such as mercaptans, short-chain fatty acids, and phenols, and the generation of false neurotransmitters such as octopamine is currently less strong (152). Additionally, liver failure induces profound multisystem disturbances, which, in turn, can further impair neurologic function (158). Clinical Manifestations HE can occur in two forms: acutely, as in fulminant hepatic failure, and as a chronic, progressive encephalopathy. In children, acute hepatic failure is primarily responsible for clinically important HE. The most common predisposing causes are acute infectious hepatitis, ingestion of drugs (e.g., valproic acid, acetaminophen, isoniazid, halothane) or toxins (e.g., mushroom poisoning) (159), or Wilson disease (160). In infancy, galactosemia, fructosemia, or tyrosinemia can present as fulminant hepatic failure (see Chapter 1). In the past, Reye syndrome and hemorrhagic shock syndrome presented with fulminant liver failure (see Chapter 6). The onset of the encephalopathy usually coincides with a deterioration of the general clinical condition. The principal signs and symptoms of hepatic coma are related to disorders of consciousness. The stages of HE are outlined in Table 15.5. It is of the utmost importance that the first signs of encephalopathy are recognized. Because the first evidence of encephalopathy can be outbursts of violent agitation or uncharacteristic behavior, the early stage of HE is frequently misdiagnosed. The progression from stage I to stage IV can be exceedingly rapid. Hyperventilation can develop during stages II and III and can lead to alkalosis, low serum pCO , and a 2 further deterioration of mental status. A fine tremor and more characteristically coarse flapping movements, termed asterixis, can be present in stages I and II, respectively, whereas decorticate and decerebrate postural responses accompany stage IV of HE. Choreic movements, a fluctuating rigidity of the limbs, dystonia, and periods of noisy delirium are particularly frequent in children ( 161). TABLE 15.5. Signs and symptoms of hepatic encephalopathy Cerebral edema is a prominent part of the clinical picture of acute HE and is the principal cause of death, with brainstem herniation found in up to 80% of patients dying in fulminant hepatic failure (162). The cause of cerebral edema is unknown, and it is believed to be both vasogenic and cytotoxic, with the latter being more important. In vasogenic edema, there is a toxin-induced breakdown of the blood–brain barrier, with leakage of serum proteins through the capillary endothelium into the brain parenchyma. The cytotoxic aspects of cerebral edema result from an impaired cellular osmoregulation, which results in intracellular accumulation of fluids, mainly within astrocytes (163). Although severe liver disease is a prerequisite for the appearance of HE, ascites, jaundice, edema, or hepatomegaly do not invariably accompany the neurologic involvement. In fact, frequently, as irreversible liver failure supervenes, previously elevated serum transaminase levels decrease rapidly, the coagulopathy worsens, the initially enlarged liver shrinks, and the total bilirubin climbs while the conjugated portion decreases. In a majority of patients, the EEG shows paroxysmal and diffuse bursts of high-voltage slow-wave activity, a pattern that is not specific for HE but is highly indicative of one of the metabolic encephalopathies. Triphasic waves, characteristic for HE, are common in adults but rare in children. Clinical or EEG evidence of seizures is associated with a poor outcome (164). Treatment and Prognosis The advent of successful liver transplantation has revolutionized the management, treatment, and prognosis of children with liver failure and HE ( 165). Liver transplantation now offers a success rate of between 55% and 89% (166). Therefore, the child with HE requires meticulous medical management until either the liver resumes adequate function or a replacement organ is found. Management of the precipitating event, dietary protein restriction, avoidance of constipation, and alteration of the intestinal flora are the major aspects of the therapeutic regimen ( 167). The therapeutic value of flumazenil, a benzodiazepine antagonist, appears to be minimal in the pediatric population (168). Response to flunazenil is transient; the medication may precipitate an anaphylactic reaction. For a comprehensive discussion of the therapy of hepatic failure, the interested reader is referred to reviews by Jalan ( 149), Sherlock (153), and Devictor (169). The neurologist involved in the treatment of the child in HE should consider that neurologic symptoms can result from six complications: hypoglycemia, sepsis,