Chapter 20. Toxic and Metabolic Encephalopathies

Metabolic disorders and disorders caused by exposure to a toxic agent portend a good prognosis, leading most of the time to a full recovery when recognized and treated promptly. Despite significant advances in critical care in the last 30 years, leading to improved survival of affected patients, little advance has been made in the treatment of acute neurological problems in the pediatric population. Metabolic disorders represent an exception to this statement, due to the development of new diagnostic techniques combined with a better understanding of the pathophysiology of such disorders, which have lead to the application of life-saving therapeutic tools and reducing the severity of brain injury. Examples include hemodialysis for the treatment of urea cycle disorders1 (eg, citrulinemia). In addition, significant advances in communication have made more readily available consultative expertise through academic centers worldwide. Access to the Internet has allowed most practitioners managing patients with a toxic or metabolic encephalopathy to maintain the highest standards of treatment, reduce injury, improve survival, and reverse changes in the penumbra zone of the affected areas of the brain.

This chapter is an approach to the different etiologies causing a metabolic derangement leading to a toxic or metabolic encephalopathy, and classified according to the age of the patient. Also, this chapter provides a wide overview of the pathogenesis, clinical approach, and treatment of patients affected with such disorders.

Toxic and metabolic encephalopathies refers to a group of disorders characterized by changes in the level of consciousness due to an exogenous or endogenous substance causing a metabolic derangement in the normal neuronal activity and leading to a transient or permanent damage of neuronal pathways (see Figure 20-1). The source of the injurious substrate can be from (1) a malfunctioning organ such as the liver or kidney, (2) an outside source such as a poisoning, or (3) deregulation of internal homeostasis as seen in primary or secondary electrolyte disturbances. Either pathway leads to compromise of autoregulation of the blood-brain barrier or internal brain homeostasis. Several etiologies are included in this syndrome and classified in two groups: congenital and acquired disorders.2 Causes of acquired disorders are listed in Table 20-1 and include exogenous poisoning (eg, methanol, ethanol, and ethylene glycol), diabetes mellitus, uremia, and late-onset congenital enzymatic deficiencies. Causes of congenital disorders leading to a toxic metabolic encephalopathy can be divided into early and late onset, based on the clinical presentation, and include organic acidurias, congenital glycosylation disorders, and neurotransmitter deficiencies3 (Table 20-2). For better understanding, definitions of several terms used when describing patients with altered mental status have been summarized in Table 20-3.

In the newborn, differential diagnosis considerations include two categories: disorders of glucose/ion metabolism and genetically programmed congenital errors of the metabolism. Disorders of glucose/ion metabolism are generally correctable if suspected and diagnosed promptly. Three important disorders in this category are (1) salt-wasting syndromes, (2) congenital hypothyroidism, and (3) vitamin D-dependent rickets. There are two different groups of genetically programmed congenital errors of metabolism that we classify based on clinical presentation: (1) acute-onset neurological derangement and (2) static encephalopathies of prenatal onset such as peroxysomal disorders. Several classifications have been attempted to better grade the severity of the symptoms. We have developed our own classification based on clinical findings and degree of impairment (Table 20-4).

Disorders of Glucose and Ion Metabolism

Disorders of glucose and ion metabolism should be considered in the differential diagnosis of patients with altered level of consciousness. Under normal circumstances, glucose is the main source of energy for the brain. The brain is extremely susceptible to hypoglycemia. This is due to the fact that brain glucose is only 25% of the total blood glucose. Besides, there are no significant sources of stored glucose in the form of glycogen, as happens in cardiac or skeletal muscle. The central nervous system better tolerates hyperglycemia than hypoglycemia. However, hyperglycemia can cause significant neurological symptoms.

After having a load of glucose, the pancreas releases large amounts of insulin that regulate the glucose metabolism. Several other mechanisms are triggered after food ingestion, including storage of glucose in the liver as glycogen (glycogenosis). The human body has enough glycogen to maintain the blood glucose concentration between 80 and 100 mg/dL for 24 to 36 hours after having a last meal. Then, generation of glycogen (gluconeogenesis) takes over as the main mechanism for glucose control. Alanine and glutamate as well as lactic and pyruvic acid are well-known substrates for energy formation in this setting. The liver is the main organ involved in the process of maintaining glucose during starvation. After the hepatic sources for glucose have been depleted, the kidneys and other organs could contribute up to 50% of basal glucose. This explains why several organs are clinically involved during the severe hypoglycemic stage.

The mean cerebral blood flow is 50 mL/100 g of brain tissue. This flow provides large amounts of glucose to the brain if the peripheral glycemia is between 5 and 6 mmol/L. A cerebrospinal glucose transporter protein maintains appropriate CSF glucose level. Once in the brain, the glucose is metabolized into ATP by two main pathways: glycolisis and the Krebs cycle. Detailed review of both processes is beyond the scope of this chapter. However, faulty glycolitic mechanisms are responsible for significant systemic and neurological symptoms. A congenital disorder characterized by seizures and developmental delay has been identified—glucose transporter deficiency. In this disorder, cerebrospinal fluid (CSF) glucose is low due to a faulty glucose transporter protein. A ketogenic diet appears to be one of the main therapeutic tools available for better seizure control in this population. However, a ketogenic diet does not appear to modify other aspects of the disorder, such as developmental delay. Genetic testing is available for patients suspected to have glucose transporter deficiency.

Hypoglycemia

The most common causes of hypoglycemia are (1) overuse of glucose, as seen in carnitine deficiency, sepsis, prediabetic state, and oral hypoglycemic abuse; (2) underproduction of glucose, as seen in enzymatic disorders6 (glucose-6-phosphatase deficiency, glycogen phosphorylase deficiency, glycogen synthetase deficiency, pyruvate carboxylase deficiency, and phosphoenolpyruvate carboxykinase deficiency); and (3) hormonal imbalances (eg, growth hormone). Maternal use of hypoglycemic medications or neonatal sepsis are the most common causes in the newborn period. Salycilate overdose and alcohol intoxication should be ruled out in the teenage population. There are three hypoglycemic syndromes: acute, subacute, and chronic.

1. Patients presenting in the acute state are usually restless and complain of dizziness or nervousness. Most of the time, patients presenting with an acute hypoglycemic state have a past history of diabetes mellitus. The most common cause of hypoglycemia in this group of patients is due to overdose of insulin or oral hypoglycemic medications. Symptoms usually resolve with a loading dose of IV glucose.

2. The subacute syndrome is characterized by obtundation, slowness of thought process, and amnesia. It is not uncommon to find hypothermia. The diagnosis is confirmed by checking the blood glucose during one of the episodes.

3. Chronic hypoglycemia is an uncommon situation, and when suspected, an insulinoma or excessive use of antihyperglycemic medications should be considered. Unlike the two prior groups, patients with chronic hypoglycemia usually do not respond to boluses of intravenous glucose.

Hyperglycemia

The most common cause of hyperglycemia in the pediatric population is diabetic ketoacidosis (DKA). This condition is usually triggered by an infection in an otherwise well-controlled diabetic type I patient, or can present as new-onset hyperglycemia in an otherwise previously healthy patient, prompting a visit to the emergency room due to obtundation or other changes in the level of consciousness. In addition to polyurea and polydipsia, symptoms include anorexia, nausea, vomit, dehydration, and coma. This is a disorder of severe deficit of insulin. In the absence of insulin, the body's peripheral glucose uptake and glycogen formation are inhibited, leading to excessive lypolisis, glycogenolysis, and hyperglycemia. Treatment with insulin enhances entry of glucose in to the cell, glycogen formation, and reduction of the rate of ketone body formation. Supportive treatment is based on the judicious correction of hypernatremia and dehydration. An excessively rapid correction of hypernatremia and hyperosmolarity may lead to cerebral edema. It is believed that a clinically silent form of cerebral edema may be present in most cases of DKA. When clinically indicated, further evaluation, including placement of an intracranial pressure monitor, should be considered to better guide therapy. The treatment of cerebral edema in this particular setting is based in decreasing the elevated intracranial pressure, including intubation, mechanical ventilation, elevation of the head, hyperoxygenation, and measures aiming to avoid Valsalva maneuvers such as treating constipation and avoiding excessive gag or suction stimuli to the throat or the trachea. The use of manitol to facilitate osmogenic diuresis is one of the pharmacologic tools available when treating patients with cerebral edema.

Disorders of Sodium Metabolism

When hyponatremia is confirmed, serum osmolarity must also be checked, since hyponatremia and hypoosmolarity are both frequently associated. Causes include renal loss (renal disease, adrenal insufficiency), gastrointestinal losses (diarrhea, vomit), sequestration (peritonitis), hemodilution, sickle cell disease, hyperosmosis, hyperglycemia, and inappropriate secretion of anti-diuretic hormone (SIADH). In addition to hyponatremia, the diagnosis of SIADH should be suspected in the normovolemic or hypervolemic patient with documented normal renal function.

Water restriction is usually the treatment for mild cases. More severe cases require hypertonic solutions and diuretic treatment. Excessive overcorrection may lead to hypernatremia and central pontine myelonolisis (CPM). This last disorder is characterized by acute demyelination of the pontine structures due to fast correction of hyponatremia. Patients with CPM develop a myriad of symptoms including changes in sensorium, lower cranial nerve palsies, and diffuse weakness. Serial and frequent serum electrolytes monitoring and avoidance of excessive administration of hypertonic, hypernatremic solutions are needed to prevent this irreversible and permanent complication. Brain MRI typically show areas of demyelination in the mamillary bodies and around the fourth ventricle (see Figure 20-2).

Hyperosmolarity

Hyperosmolarity should be suspected in diabetic patients or in an otherwise healthy person presenting with severe dehydration and acute intracranial bleeding. Bleeding occurs due to tearing of the bridging vessels at the level of the dural sinuses. The deficit of water should be estimated carefully and replacement therapy should be started promptly, bearing in mind that a fast correction may lead to brain swelling. In general, it is recommended to attempt correction by the oral route, aiming to replace the deficits slowly.

Disorders of Calcium Metabolism

This group of disorders is usually associated with a deficient parathyroid gland function. In normal circumstances, about 50% of the serum calcium is bound to protein and therefore considered metabolically in quiescent form. The other 50% is ionized and therefore metabolically active. Hyperthyroidism may be associated with hypercalcemia and should be part of the differential diagnosis when evaluating patients with idiopathic hypercalcemia. Symptoms of hypercalcemia range from altered consciousness, weakness, and nausea and vomitting to coma. The most common causes of hypercalcemia are sarcoidosis, thiazide diuretics, vitamin D intoxication, and excessive calcium intake. Treatment includes hydration, diuresis, and supportive treatment.

Hypothyroidism is usually associated with hypocalcemia. Clinically, patients complain of paresthesias around the mouth and fingers, cramps, headaches, and seizures. The presence of positive Chvostek and Trousseau signs documented in the physical examination should raise the index of suspicion. Chovstek sign consists of tapping the thenar region and looking for a spasmodic contracture of the hand. Trousseau sign is usually elicited in the hypocalcemic patient when the cuff of a blood pressure monitoring device is applied to the arm and inflated above the diastolic pressure until a tonic contracture of the arm is present. Both findings are indicative of hypocalcemia. Treatment is based in administration of calcium to correct the deficit.

Hypothyroidism can also present clinically as idiopathic intracranial hypertension, formerly known as pseudotumor cerebri. Postural headaches, sixth cranial nerve palsy, and blunted optic disk borders are typical findings. Optic disk edema is a common finding. Figure 20-3 shows blunting of the optic disc borders and elevation of retinal blood vessels. Patients may complain of having blurry or double vision and early morning headaches. The pathophysiology of benign increased intracranial pressure syndrome is not well understood, but a mismatch between excessive CSF production by the choroid plexus and deficient CSF reabsorption mechanisms has been postulated. The diagnosis is suspected when the patient has a focal neurological exam such as optic disk edema or sixth cranial nerve palsy and has a normal brain MRI.The spinal tap is both diagnostic and therapeutic. An opening spinal pressure above 25 ml H20, within the right clinical setting, is confirmatory. Then, drainage of cerebro-spinal fluid is the treatment of choice. The aim is to drain enough CSF to bring the closing pressure to half the opening pressure. A comprehensive list of etiologies causing idiopathic increased intracranial pressure is given in Table 20-5. In nearly 60% of the cases, the cause is not established (idiopathic). When established, the treatment should be aimed to treat the cause. Early diagnosis and treatment should be established promptly to prevent further injury to the optic nerve and subsequent permanent blindness. Carbonic anhydrase inhibitors such as acetazolamide are usually the first line of therapy by decreasing the production of CSF. Other potential options are loop diuretics such as furosemide or corticosteroids such as prednisone. Patients with idiopathic intracranial pressure that fail medical treatment should be referred to the neurosurgeon for a decompressive procedure of the optic nerves such as optic nerve fenestration. Consultative expertise obtained from a neuro-opthalmologist should also be sought to better guide the therapy.

Toxic and metabolic encephalopathy should be considered in the differential diagnosis of patients with altered mental status. Patients may present with a myriad of symptoms including lethargy, obtundation, stupor, or coma. Lethargy is defined as an inability to maintain arousal. Obtundation is characterized by significant altered level of consciousness that is responsive at least to verbal stimuli. Stupor is a more significant abnormal level of consciousness in which patients are only responsive to pain. Coma implies full unresponsiveness to any type of stimuli (Table 20-6). Patients with toxic encephalopathy present with the acute onset of symptoms. Changes in sensorium, cognitive decline, jaundice, headaches, anemia, and seizures are usual common clinical scenarios. More focal neurological findings are seen in selected cases. For example, patients with homocystinuria are at increased risk of stroke and therefore may present with acute, new onset hemiparesis or visual complaints. The differential diagnosis is listed in Table 20-7.

Drug Overdose

Toxic exposure to a drug, whether accidental or intentional, should always be suspected in the patient presenting with altered mental status or in coma. Accidental poisoning is commonly seen in the toddler who finds readily available bottles of medications in the surroundings. Intentional poisoning due to a suicidal plan is most often seen in the teenage patient. The most common toxic substances abused are alcohol, salycilates, acetaminophen, benzodiazepines, barbiturates, and antidepressants. Serum screening tests are the best way to confirm an overdose. Patients with suspected ethylene glycol toxicity would have the history of antifreeze exposure. The blood level predicts the toxicity. Similar situations occurs with acetaminophen, digoxin, lithium, salicylates, and theophylline. Methanol poisoning is a special consideration. Patients have the history of consumption of alcohol that has been fraudulently altered. Symptoms include blindness and coma. Methanol is metabolized by the enzyme alcohol dehydrogenase into formaldehyde, a more deleterious byproduct, causing a wide range of demyelinating effects in the nervous system. The optic nerve is particularly sensitive to the effects of formaldehyde and therefore blindness is a common complication. Treatment is aimed to block the alcohol dehydrogenase. IV alcohol is available as a first-line therapy in such patients.

Congenital Inborn Errors of Metabolism

Maple Syrup Urine Disease

Maple syrup urine disease is an autosomal recessive disorder of the metabolism of amino acids due to absence or faulty functioning of the branching-chain alpha ketoacid dehydrogenase enzyme and leading to toxic accumulation of alpha-amino acids valine, leucin, and isoleucin. There are five different forms, but the neonatal presentation has the worst prognosis. Patients present with changes in level of consciousness after the first week of life.8 Then, seizures, hypotonia, and poor oral intake are present. Brain imaging will demonstrate edema of the white matter. Ketoacidosis, hypoglycemia, and ketonuria are typical laboratory findings. Histopathology evaluation shows spongiform degeneration of white matter. The diagnosis is suspected when high levels of valine, leucin, and isoleucin are found during an acute exacerbation. Measurement of enzyme activity in fibroblasts is diagnostic. During acute crisis, treatment is supported by removal of the excessive concentration of amino acids using hemodialysis or peritoneal dialysis. Long-term treatment includes a valine-restriction diet, avoidance of catabolic stress, and good nutritional support.

Organic Acidopathies

Branched-chain amino-acidopathies are autosomal recessive disorders of the metabolism of propionate and methyl malonate and their cofactors biotin and cobalamin. Onset of clinical symptoms ranges from the neonatal period to early infancy, and includes various forms of hypoglycemia, metabolic acidosis, hyperamonemia, seizures, and coma.9 Other features include growth failure, abnormal liver function test, neutropenia, thrombocytopenia, and cardiovascular collapse. The pathogenesis of this disease is due to accumulation of a substrate in the toxic ranges. Lack of energy production is the result of a deficient supply of highly efficient energetic compounds for gluconeogenesis and limited availability of free CoA for mitochondrial fatty acid oxidation. The diagnosis is suspected when a neonate or a young child presents with metabolic acidosis, hypoglycemia, hyper-amonemia, and ketosis. Further enzymatic testing using skin fibroblast cultures can confirm the diagnosis. The treatment consists of glucose administration, protein restriction, and cardiovascular and respiratory support in the critical care settings. Cofactor supplementation is useful to reverse the pathogenic process. Carnitine and glycine supplementation will improve clearance of the toxic metabolites.

The presentation of a delirious child to the emergency room should prompt expeditious and organized evaluation due to the potential for deterioration if not diagnosed and treated promptly. The diagnosis should be based on a carefully obtained history and detailed physical and neurological examinations as well. A systematic approach is a must in order to avoid missing an important part of the differential diagnosis. The following questions should be entertained:

1. Timing of the onset of symptoms

2. Provoking or precipitating factors

3. History of toxic ingestions or availability of medications or other substances potentially injurious (eg, prescription medications for other adults living in the same household where the child has been lately seen)

4. Significant past medical history (migraines, epilepsy)

5. Travel history

6. Infectious contacts with a history of encepha-lopathy

7. Any genetic or metabolic disorders in the family.

The physical exam should be complete, including the vital signs and general appearance of the patient. Findings that should be sought during the physical and neurological exam include the following:

1. Glasgow coma scale score (Table 20-6)

2. Presence of raccoon eyes (suggests injury to the anterior fossa)

3. Presence of retro-auricular bleeding or oozing bloody material per auditory canal (suggests injury to the middle fossa)

4. Nose bleeding or drainage of spinal fluid by nose (injury to the anterior fossa)

5. Scalp tenderness

Clinical History

Children with altered mental status required prompt assessment and treatment because of the risk of rapid deterioration if intervention is not well organized, adequate, and fast. The clinical history is the cornerstone for the correct diagnosis of a delirious child. A diagnostic algorithm has been provided in Figure 20-4 as an attempt to better guide the diagnostic approach when assessing a patient with suspected toxic or metabolic encephalopathy. The following pertinent questions should be considered when assessing a patient with altered mental status:

1. Prior events leading to the current presentation

2. History of accidental drug exposure, including prescribed or over-the-counter medications available in the home's cabinets

3. Travel history to rural areas

4. Symptoms of systemic illness such as rash, jaundice, malaise, bony tenderness, joint pain, diffuse pain, or fever

5. Prior intercurrent illness (vomiting, diarrhea, cough, runny nose, congestion)

6. History of seizures, migraines

7. Other family members with similar symptoms

8. History of trauma

9. Symptoms suggestive of increased intracranial pressure such as headaches, blurry vision, vomiting, changes in personality, or changes in the level of consciousness

Physical Exam

The physical exam should be tailored according to the patient's age, and should look for the following signs:

1. Complete vital signs, including oxygen saturation

2. Testing of mental status (orientation in time, place, and person; short- and long-term memory; affect, counting, paraphrasing errors; fund of knowledge)

3. Signs of child abuse or neglect (poor hygiene, old fractures, retinal hemorrhages, hematomas, or other skin manifestations of physical abuse)

4. Signs of meningitis such as neck rigidity, Kernig sign (pain and resistance to extending the knees with the leg flexed), or Brudzinski sign (spontaneous flexion at the hips when passively flexing the neck)

5. Careful eye exam looking for papilledema

6. Judicious cranial nerve examination looking for nystagmus, size and reactivity of the pupils to direct and consensual light stimuli, internuclear opthalmoplegias, cranial nerve paresis, facial asymmetry, facial weakness, poor palate elevation, poor gag, poor sucking response, corneal reflex, swallowing, and coughing (see Figure 20-5)

7. Testing of motor strength looking for hemiplegia, hemiparesis, or other focal neurological features

8. Plantar response and deep tendon reflexes

9. Frontal release signs such as palmo-mental reflex (look for oral movements, upon hand stroking), sucking response

Inborn Errors of Metabolism

Patients may present with an acute decompensation or with a more protracted clinical syndrome. Seizures are a very common symptom, especially in the neonatal period.10 Sepsis is the most important differential diagnosis that always should be considered and ruled out in patients with neonatal seizures. Bacterial etiologies should be always considered when assessing an unconscious or poorly responsive baby. Group B streptococcal sepsis is one of the most feared infections in the neonatal period. There are two syndromes: early (less than 2 weeks of age) and late (older than 2 weeks of age). Presenting symptoms and signs are fever or hypothermia, lethargy, seizures, bulging fontanel, and tachypnnea. The patient rapidly deteriorates into septic shock. However, features that help distinguish sepsis from a congenital metabolic disorder are the presence of hyperamonemia, hypoglycemia, and acidosis.

Inherited metabolic disorders characterized by encephalopathy are the following:

1. Pyruvic dehydrogenase deficiency

2. Pyruvate carboxylase deficiency

3. Disorders of hepatic glycogenolisis or gluconeogenesis

4. Respiratory chain disorders

5. Ornithine carbamoylase deficiency

6. Glycogen storage disease

7. Carnitine deficiency

Patients with glycogen storage diseases present clinically with hypoglycemic encephalopathy and lactic acidosis. Glucose 6-phosphatase deficiency (type I glycogenosis) is an autosomal recessive disorder. Glucose 6-phosphatase catalyzes the final steps of gluconeogenesis and glycogenosis to produce glucose. Its role is of the utmost importance to maintain glucose homeostasis. Accumulation of its precursor, glucose 6-phosphate, leads into lactic acidemia. Diagnosis is based on determination of enzymatic levels in hepatic tissue, since enzyme is not present in skin fibroblasts. Acute decompensation requires judicious glucose maintenance through intravenous fluids. Long-term treatment requires nocturnal infusions of enteral glucose and frequent, daytime, highly enriched carbohydrate meals.

Fructose 1–6 biphosphatase deficiency is another autosomal recessive disorder presenting clinically as metabolic encephalopathy, lactic academia, and hypoglycemia. This disorder is due to defective gluconeogenesis. In addition to the brain, the liver is also involved. Therefore diagnosis is similar to that for type I glycogenosis. Treatment includes glucose supplementation, sucrose supplementation, and fructose restriction.

Pyruvate dehydrogenase complex deficiency is a disorder of congenital lactic acidemia.11 Several enzymes could be affected in this disorder. E1 component defect is the most common enzymatic disorder in this group and is inherited as an X-linked dominant trait. Clinically, there is evidence of intrauterine growth retardation, brain dysgenesis (partial and complete agenesis of the corpus callosum), and facial dysmorphology. Fulminant lactic acidosis is a presenting form in the neonatal period. Survivors may develop necrotic changes, and cavitations in the cerebral cortex, basal ganglia, and brainstem.12 Palliative treatment is based on the use of a ketogenic diet, carnitine supplementation, and thiamine.13

Pyruvic carboxylase is a critical pathway in the generation of citric acid during gluconeogenesis. A faulty pyruvic carboxylase enzyme produces marked substrate deficiency for the neurotransmitter pool needed for the synthesis of glutamate and GABA. Severe lactic acidosis, citrullinemia, and hyperamonemia are common findings during acute exacerbations. Diffuse atrophy, both cortical and subcortical, or cystic encephalomalacia, are common radiographic and hystopathologic findings due to neuronal death and arrested myelination.14,15

Respiratory chain disorders have in common a defective oxidative phosphorylation pathway. External opthalmoplegia, cardiomyopathy, lactic acidosis, and encephalopathy are common features. Treatment is symptomatic.16,17

Medium-chain acyl-CoA dehydrogenase deficiency is an autosomal recessive disorder of the beta-oxidation of fatty acids. Carnitine has two functions: carrying long-chain fatty acids into the mitochondria and modulation of acyl-CoA and esterification of toxic acyl-CoA byproducts. The process of transferring fatty acids inside the inner mitochondrial layer requires the conversion of acyl-CoA and the presence of carnitine palmytoil transferase. If the carnitine concentration is low, toxic levels of acyl-CoA accumulate, leading to mitochondrial dysfunction and poor energy generation. Clinical symptoms include poor exercise tolerance or recurrent episodes of hypoglycemia during acute stress (eg, infection). Poor tolerance to brief periods of hypoglycemia is also a common feature. Proximal weakness is another presenting feature. Although it is less frequent, cardiomyopathy could be a first presenting symptom. Cardiovascular collapse and sudden infant death syndrome (SIDS) have also been reported. However, medium-chain acyl-CoA dehydrogenase deficiency is not an important cause of SIDS. The diagnosis is suspected when low levels of ketone bodies are found in urine during an acute exacerbation along with an elevated concentration of aspartate aminotransferase, aspartate amino transferase, and lactate dehydrogenase levels. Enzyme deficiency analysis is available. Genetic testing and mutation analysis confirm the diagnosis.

Disorders of Sodium Metabolism and Osmolality

Hypernatremia may be secondary to excessive overhydration with hypertonic solutions or due to excessive water loss during dehydration. It could be seen during periods of acute gastroenteritis, vomiting, and diarrhea. Excessive use of hypertonic solutions could cause iatrogenic hypernatremia.

Nonketotic hyperglycemic coma and diabetic ketoacidosis (DKA) are two complications seen in patients with diabetes mellitus. Nonketotic hyperglycemic coma is an unusual disorder in children and therefore will not be discussed in this chapter. Diabetic ketoacidosis is the most common complication of poorly controlled diabetes mellitus. It could also be seen in children with undiagnosed symptomatic hyperglycemia. An intercurrent infectious illness or poor compliance with insulin therapy are the most common triggering factors. Symptoms include polydypsia, lethargy, polyurea, polyphagia, and dehydration. A progressive change in the level of consciousness rapidly ensues, leading to coma if no intervention is provided promptly. Several degrees of cerebral edema are almost universally seen in patients presenting emergently with diabetic ketoacidosis. The mortality rate is 10%, and judicious correction of hyperglycemia, acidosis, and hyponatremia are indicated to improve survival. The diagnosis is established by the presence of hyperglycemia (blood glucose level above 400), acidosis (pH below 7.25 and serum bicarbonate less than 15 mmol/L), and the presence of serum and urine ketones. The treatment is targeted to correct hyperglycemia and fluid deficit during 48 hours. The sodium deficit should be calculated and corrected by half during the first 12 hours of treatment. The other half of the sodium deficit is corrected in the remaining 36 hours. The other issue is to avoid excessive administration of hypotonic fluids because of the risk of worsening the subsequent and ongoing cerebral edema, leading eventually to a brain herniation syndrome if not recognized and treated aggressively. Venous sinus thrombosis and intracranial hemorrhage are also potential complications seen in patients with DKA, and brain imaging should be considered in patients with focal neurological signs. Computed brain tomography taken at 24 hours and at 72 hours after the onset of the symptoms demonstrate an area of infarct in the territory of the left Middle Cerebral Artery (see Figure 20-6).

Hypoglycemia is usually due to insulin overdose. In the neonate, hypoglycemia is due to poor glucose regulation. Sepsis should be suspected in the neonate with symptomatic hypoglycemia. Certain inborn error of the metabolism could initially present with hypoglycemia. However, it is not clinically symptomatic until serum glucose levels drop below 50 mg/dL. Dizziness and tremors progressing to delirium, syncope, and loss of consciousness are the usual presenting symptoms. The diagnosis should be suspected in the jittery or obtunded neonate. Also the diagnosis should be considered in the older patient with a history of diabetes mellitus and presenting with significant altered mental status. Bedside glucometers are readily available for easy and fast diagnosis. Final confirmation is achieved by immediately testing peripheral blood glucose in a recently drawn serum sample. If the patient is symptomatic, IV fluid replacement with a dextrose solution should be administered promptly.

Hyponatremia can be due to two different causes: (1) sodium loss or (2) water retention due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). This complication can be seen in head trauma, meningitis, or intracranial hemorrhage. Clinically, the patient is obtunded or lethargic. Hyponatremia is the hallmark of SIADH. In this disorder, there is an excessive secretion of antidiuretic hormone (ADH), leading to water retention and causing secondary hyponatremia and hypoosmolarity. As a consequence, there is less fluid filtered into the glomeruli. Urine osmolality is high but not higher than plasma osmolality, and this is an important diagnostic key. Therefore, urine and serum osmolality and serial urine sodium levels should be routinely checked in patients with hyponatremia to confirm the diagnosis. Treatment involves fluid restriction by as much as 50% of the daily recommended allowance.

Sodium loss due to vomiting, diarrhea and dehydration may cause significant disturbances in the level of consciousness leading to hyponatremia and encephalopathy. The patients are usually lethargic. Symptoms may rapidly progress to seizures and coma. The diagnosis is confirmed by measuring serum and urine sodium concentrations. The treatment is targeted to slow correction of hyponatremia up to 130 mEq/L but no more than 0.5 mEq/L per hour for the first 48 hours, using a sodium chloride solution. Fast correction could lead to central pontine myelinolisis, a permanent injury due to coagulation necrosis of the pontine structures.

Hypernatremia can be iatrogenic or due to dehydration. Excessive administration of hypertonic and hypernatremic solutions may lead to iatrogenic hypernatremia, and if this is not recognized, could lead to significant brain injury or death. In addition, patients with vomiting and diarrhea can develop hypernatremic dehydration, especially if there is a restriction of fluid intake. Symptoms are irritability, lethargy, seizures, and coma. Treatment is aimed to correct the hypernatremia slowly. The patient is usually symptomatic when the serum sodium level is above 160 mmol/L. Rapid hypernatremia correction could lead to excessive water retention and cerebral edema with all the potential complications including transtentorial or uncal herniation and death. Therefore, it is recommended to correct the intravascular volume deficit slowly with the use of hyponatremic or normo-natremic solutions. Patients with hypernatremic dehydration are at higher risk for other complications such as venous sinus thrombosis. This complication should be ruled out in the patient with focal neurological signs. Magnetic resonance venography is a useful brain imaging procedure available to exclude this condition.

Renal Disorders

Acute uremic encephalopathy is a complication seen in patients with renal disease. The patient develops symptoms during several days in the setting of abnormal kidney function and elevated creatinine levels. Usually the patient has the history of hemolytic uremic syndrome, or acute renal insufficiency. Lethargy, irritability, and lack of coherence are common symptoms. The physical exam is significant for asterixis, fasciculations, and cramps. Without intervention, patients may develop seizures and become comatose. The diagnosis is suspected when the patient present with acute renal failure and significant acute mental status changes. The severity of the abnormal kidney function does not correlate with the abnormalities of the central nervous system. Elevated ammonia levels, hyperkalemia, and hypercalcemia may contribute to the symptoms. Electroencephalography (EEG) shows diffuse slowing and disorganization of the background and periodic triphasic waves. Measures aimed to correct the electrolyte abnormalities, such as hemodialysis, are the cornerstone of treatment of this population. Prognosis is usually good once the kidney function has normalized

Chronic uremic encephalopathy is a common complication in patients with end-stage renal disease. Patients develop symptoms during weeks or months, and typically have other complications such as hyperthyroidism, hypercalcemia, hyperostosis, and growth failure. Common neurological symptoms are progressive developmental delay in all four domains (fine motor, gross motor, speech, and social). Other common early findings are fine tremors, hyperreflexia, and hypotonia. The symptoms may progress to diffuse myoclonus and fasciculation. Nerve conduction velocities are prolonged. The EMG shows slow amplitude potentials. The EEG shows diffuse slowing of the background activity and multifocal epileptiform discharges. Symptoms may progress to a vegetative state through the years and eventually death. Treatment is aimed to correct the electrolyte abnormalities. Long-term hemodialysis is the most important intervention available to treat the patients.

Hypertensive encephalopathy is a neurological emergency characterized by sudden and uncontrolled high blood pressure above the limits of cerebral blood flow autoregulation. Headaches, nausea, vomiting, and dizziness are common symptoms. Then, visual complaints and progressive changes in the level of consciousness ensue. However, due to the lack of specificity of such complaints, other differential diagnosis should be considered including uremic encephalopathy, meningitis, and sepsis. The patient's blood pressure will be high, and the treatment should be aimed to control the hypertensive crisis with antihypertensive medications. If not controlled, the patient may develop focal neurological signs and seizures. Other findings in the neurological exam are optic disk edema and retinal hemorrhages. Emergent brain imaging is indicated to rule out intracranial hemorrhage in the presence of a new onset focal neurological sign. Brain MRI will show areas of increased signal intensity in the occipital regions, which is indicative of cerebral edema. The patient should be admitted to the critical care unit, where appropriate therapy is started with intravenous antiepileptic medications for seizure control and antihypertensive medications for aggressive blood pressure control. In addition, measures to diminish cerebral edema and to treat elevated intracranial pressure should be considered, if clinically indicated.

Endocrine Disorders

Hashimoto encephalopathy is a disorder characterized by recurrent encephalopathy. Patients will present with headaches, obtundation, stupor, and intractable seizures. The neurological examination may show focal signs early in the disease that can be easily confused with transient ischemic attacks. The child is euthyroid, but further serologic testing will show elevated titers of anti-thyroid antibodies such as anti-thyroglobulin and anti-microsomal antibodies. Spinal fluid analysis will reveal elevated protein with a normal cell count and opening pressure. Treatment with corticosteroids is helpful in controlling the acute exacerbation and for the long term as well. It is important to look for a secondary autoimmune disorder, since frequently patients will have evidence of other organ involvement.

Adrenal insufficiency can be a lethal cause of encephalopathy in children. The patient may have the history of sepsis, adrenal gland bleeding, or abrupt corticosteroid withdrawal such as seen in patients receiving prednisone for myasthenia gravis or Duchenne muscular dystrophy. Vomiting, malaise, and lethargy, progressing to unresponsiveness and coma, are common findings. Treatment involves aggressive fluid replacement therapy, close monitoring of electrolyte imbalances, and corticosteroid replacement.

Hypocalcemic seizures are one of the manifestations of hypoparathyroidism. The symptoms may be present as early as in the neonatal period or during early infancy. It is important to check total and free calcium, magnesium, and vitamin D levels in an otherwise healthy baby presenting with new-onset seizures. The patient may present with focal seizures, and hypocalcemia is usually recognized during serologic screening. Antiepileptic medications do not have a role in the treatment of hypocalcemic seizures. Treatment is heavily supported in correcting hypocalcemia with calcium supplementation.

Hypercalcemia can cause agitation, mania, or psychosis but will not cause obtundation or coma. Patients will complain of weakness and the physical exam will reveal findings indicative of myopathy. Changes in mental status will be noticed with serum calcium levels above 11 mg/dL. Seizures are not presenting symptoms in patients with hypercalcemia.

Undiagnosed hyperthyroidism can present clinically as a thyroid storm. The patients will have significant changes in the personality such as mania, agitation, delirium, and paranoia. Other symptoms include diarrhea, vomiting, weight loss, and cardiac arrhythmias. Thyroid storm is a life-threatening disorder that requires fast intervention. The patients may quickly become obtunded and comatose.

Hypothyroidism may present with constipation, cold skin, and menstrual irregularities. The patient's physical exam is significant for psychomotor slowing and cognitive deficits. Focal neurological findings are lower cranial nerve neuropathies and ataxia. Other manifestations of central nervous system disease are seizure and coma. The peripheral nervous system is also affected, and peripheral neuropathy or myopathy are common findings. Thyroid replacement therapy is the cornerstone in the treatment of this population.

Patients with severe liver dysfunction, as a rule, will have a varying form of hepatic encephalopathy.18 The most common causes are viral hepatitis with marked liver involvement, Reye disease due to ingestion of aspirin, or accidental poisoning (eg, acetaminophen).19 The pathophysiology of encephalopathy is due to the severe liver dysfunction with subsequent release of several toxins from the portal circulation to the systemic circulation and causing end-organ symptoms. High excretion of branched-chain amino acids that work as false neurotransmitters and elevated serum ammonia concentrations are particularly important in the pathogenesis of the encephalopathy.20 A second syndrome affecting the posterior columns of the spinal cord due to deficient vitamin E can also be seen in patients with liver dysfunction. Ataxia, areflexia, and gaze paresis are the most common symptoms. Patients with liver failure will present with abdominal pain, jaundice, acholia, and dark urine. Early symptoms of hepatic encephalopathy are changes in the affect and obtundation. Asterixis, a tremor of the hands that is elicited by stroking the fingers with the hand extended and the wrist flexed, is seen at this stage. The symptoms may worsen if the patient developed other complications such as gastrointestinal bleeding, bacterial infection, sepsis, excessive protein ingestion, or using hepatotoxic medications. Then, symptoms may progress to seizures, coma, and decerebrate posturing.21 Serologic test results typical of liver failure are hyperbilirubinemia, elevated transaminases, prolonged prothrombin time, hyperammonemia, and hypoalbuminemia. The EEG will show lack of a dominant posterior rhythm, diffuse slowing and attenuation of the background, and triphasic waves. In mild cases, treatment is supportive until regeneration and normalization of liver function are achieved. More severe cases require supportive treatment until a liver transplant is available.22 Measurements aiming to minimize liver injury and removal of excessive ammonia levels are also recommended, and include dietary modifications, bowel enemas, and avoidance of hepatotoxic drugs.23