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Inborn Errors of Metabolism
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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.
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Inherited metabolic disorders characterized by encephalopathy are the following:
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Pyruvic dehydrogenase deficiency
Pyruvate carboxylase deficiency
Disorders of hepatic glycogenolisis or gluconeogenesis
Respiratory chain disorders
Ornithine carbamoylase deficiency
Glycogen storage disease
Carnitine deficiency
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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.
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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.
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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
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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
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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
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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.
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Disorders of Sodium Metabolism and Osmolality
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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.
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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).
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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