Metabolic Encephalopathies

Metabolic Encephalopathies

Edward R. B. McCabe

Many of the metabolic disorders include among their clinical features abnormalities of the central nervous system (CNS). A significant portion of these disorders can be treated to prevent progression of the encephalopathy. Because of the potential for treatment, arriving quickly at a definitive diagnosis is extremely important so that appropriate treatment may be instituted promptly. Rapid and definitive diagnosis also allows the family to plan realistically for their child’s future, even if a specific treatment is not available. Genetic counseling is much more accurate and informative when the diagnosis is known, and ensuring that family members have this information while they still are in their childbearing years is important. A delay in the diagnosis until a subsequent pregnancy or birth of an affected sibling occurs is particularly unfortunate.


Hypoglycemia is a common, treatable, and often preventable cause of encephalopathy in children. Glucose is a critical substrate for energy production in the brain; when its availability is interrupted, significant CNS dysfunction results. The signs and symptoms of CNS dysfunction include convulsions and coma, but they may be less severe, involving confusion, irritability, listlessness, headache, eye rolling, and agitation. Night terrors also may accompany hypoglycemia in some patients. In addition, affected children may evidence hunger, tachycardia, or sweating, the last being especially noticeable on the brow and hands, which may be cold and clammy to the touch. Although the heart depends on fatty acids for its primary energy supply, glucose represents an important substrate; therefore, cardiomegaly with or without overt cardiac failure may be associated with hypoglycemia. Symptoms in neonates and young infants may include poor feeding, a weak or high-pitched cry, limpness, cyanosis, and vomiting. Signs and symptoms should resolve rapidly with normalization of the blood glucose level, unless the episode has been sufficiently profound or prolonged to result in dysfunction extending beyond the hypoglycemic episode. In such cases, the possibility of developing long-term sequelae is significant.

Hypoglycemia has been defined classically as a whole-blood glucose level of less than 20 mg/dL or a serum or plasma glucose level of less than 25 mg/dL in preterm or low-birth-weight infants during the first week of life; a blood glucose level of less than 30 mg/dL or a serum glucose level of less than 35 mg/dL in full-sized or term neonates from birth to 72 hours; and a blood glucose level of less than 40 mg/dL or a serum glucose level of less than 46 mg/dL thereafter. Other physicians suggest that these definitions represent population norms rather than physiologically acceptable glucose concentrations and that a blood glucose level of less than 40 mg/dL or a serum glucose level of less than 45 to 50 mg/dL should be considered hypoglycemia regardless of the age of the individual. The differential diagnosis of hypoglycemia is extensive, but the history and clinical assessment can be helpful in narrowing the possibilities (Table 412.1). Specific diagnostic testing is recommended for these disorders to tailor management, prevent recurrences, and treat the hypoglycemia effectively.

The primary complication of hypoglycemia is irreversible CNS damage. The goal of diagnosis and treatment is to prevent acute and chronic hypoglycemia, with its attendant CNS compromise. A severe acute insult may result in respiratory compromise and death from status epilepticus or coma. The clinician must carry out the diagnostic evaluation with care and discretion so as to prevent hypoglycemia. For example, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency may be diagnosed by the measurement of octanoylglycine and other organic acids using tandem mass spectrometry (MS/MS) (e.g., as part of the newborn screen) without risk to the patient, whereas a fast or a fat challenge may lead to significant hypoglycemia and the risk of developing sequelae.


Metabolic Disorders Diagnostic Comments
Primary disorders of carbohydrate metabolism
Glycogen storage disease Hepatomegaly and fasting hypoglycemia with:
   IA. Glucose-6-phosphate deficiency    Prominent short stature, lactic acidemia
   IB. Glucose-6-phosphate translocase deficiency    Neutropenia
   III. Debrancher deficiency    Elevated red blood cell glycogen
   VI. Hepatic phosphorylase deficiency    Frequently a milder course
   IXA. X-linked hepatic phosphorylase kinase deficiency    Mild course
   IXB. Autosomal hepatic and muscle phosphorylase kinase deficiency    Mild course
   IXC. Autosomal hepatic phosphorylase kinase deficiency    More severe than IXA and B, and may include hepatic cirrhosis
Fructose-1,6-diphosphatase deficiency Profound hypoglycemia and acidemia
Hereditary fructose intolerance
   Fructose-1-phosphate aldolase deficiency Jaundice and hepatomegaly develop after child begins sucrose-fructose intake; hypoglycemia and hypophosphatemia with fructose load
Galactosemia (galactose-1-phosphate uridylyl transferase deficiency) Hypoglycemia rare, except with significant galactose load, and more frequently a consequence of liver disease
Glycerol intolerance Hypoglycemia associated with fat ingestion or glycerol challenge; includes patients with fructose-1,6-diphosphate deficiency
Disorders of amino acid and organic acid metabolism
Organic acidemias, including maple syrup urine disease, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, glutaric acidemia, acetoacetyl-CoA thiolase deficiency, and others Hypoglycemia associated with acidemia and, in some cases, with a “Reye-like” syndrome with hyperammonemia, and cerebral edema
Congenital lactic acidoses Lactic acidemia with disturbance of gluconeogenesis or energy metabolism
Biotinidase deficiency Hypoglycemia associated with complex organic acidemia, ataxia progressing to seizures and coma, alopecia, and rash
Disorders of fat metabolism
MCAD, LCAD, VLCAD, LCHAD deficiency Fasting, hypoketotic hypoglycemia associated with dicarboxylic acidemia; seen among patients with sudden infant death syndrome and acute life-threatening episodes
Endocrine disorders
Hyperinsulinism Postprandial and post-glucose infusion hypoglycemia; may be caused by increased islet-cell mass (as with islet cell adenoma and nesidioblastosis) or functional hyperresponsiveness (as with leucine hypersensitivity); may be exogenous, as in diabetics who receive too much insulin or individuals with Münchhausen or Münchhausen-by-proxy syndrome
Infant of a diabetic mother A specific form of hyperinsulinism found in large-for-gestational-age neonates with a history of maternal diabetes mellitus
Hypopituitarism Hypothalamic or pituitary hormonal deficiencies resulting in the inability to mount a normal glycemic response to stress or to tolerate starvation; may include deficiencies of growth hormone, adrenocorticotropic hormone, or thyroid hormone
Adrenal insufficiency Seen with the congenital adrenal hyperplasias and congenital adrenal hypoplasias and with adrenal medullary unresponsiveness
Limited substrate availability
Malnutrition History of limited intake of protein or calories; signs and symptoms of kwashiorkor or marasmus
Ketotic hypoglycemia Fasting, ketotic hypoglycemia; frequently preceded by intercurrent illness; also known as accelerated starvation; typically seen between ages 1 and 7 years
Infectious and postinfectious
Sepsis Hypoglycemia in all age groups; particular vigilance essential in neonatal period, when signs and symptoms of hypoglycemia may be subtle
Reye syndrome History of chickenpox or flu-like illness; aspirin is an important risk factor; inherited metabolic diseases represent an increasing proportion of cases
Neonatal Must seek underlying etiology, especially sepsis, maternal diabetes; limited substrate availability renders neonates particularly vulnerable
Shock Must consider hypoglycemia as possibly contributory in any individual with shock until glycemic status is determined
Liver disease Must consider metabolic and nonmetabolic disorders as underlying etiologies
Toxic Includes exogenous insulin, sulfonylureas, salicylates, propranolol, L-asparaginase, and others
LCAD, long-chain acyl-CoA deficiency; LCHAD, long-chain hydroxy acyl-CoA deficiency; MCAD, medium-chain acyl-CoA dehydrogenase; VLCAD, very long-chain hydroxy acyl-CoA deficiency.

To avoid repeated hypoglycemic episodes, if a definitive diagnosis has not been made, and the risk of spontaneous or challenge-induced hypoglycemia exists, the diagnostic plan should be worked out well ahead of time so that the necessary information may be obtained if the child becomes symptomatic. A secure intravenous line should be in place in any hospitalized patient who is at risk for developing iatrogenic or spontaneous hypoglycemia, and the blood glucose should be measured at an appropriate frequency to attempt to anticipate and prevent symptomatic episodes and their sequelae.

The treatment of an acute hypoglycemic episode involves the rapid restoration of normoglycemia to supply this substrate to the CNS. If venous access is readily available, the most rapid and effective therapy is the administration of intravenous glucose delivered at a rate of 0.5 to 1.0 g/kg, or 2 to 4 mL/kg of a 25-g/dL (25%) dextrose solution given at a rate of 1 mL/minute. The glucose infusion should continue at a rate of 8 to 10 mg/kg/minute, with frequent measurement taken of the blood glucose concentration and necessary adjustments made in the infusion rate to maintain a normal blood glucose level. If hypoglycemia persists despite increasing glucose infusion rates, hyperinsulinism should be considered. After the blood glucose level has stabilized and feeding has been reinitiated, the infusion rate may be decreased slowly but never discontinued abruptly. Even in the absence of pathologic hyperinsulinemia, the insulin level will rise physiologically in response to the administration of glucose; therefore, the glucose infusion must be tapered slowly (by decrements of 4 to 6 mg/kg/minute at 4- to 6-hour intervals) to prevent rebound hypoglycemia.

Hypoglycemia is a medical emergency and, if percutaneous venous access is not achieved rapidly, a cutdown should be performed by someone who is skilled in this technique; alternatively, in the young child, interosseous access should be considered. Additional supportive measures, including endotracheal intubation, may be necessary.

For the child with milder hypoglycemia, oral glucose may be beneficial, but care must be taken to protect against aspiration if the child is becoming obtunded. Glucagon (0.03 to 0.30 mg/kg, up to a maximum total dose of 1 mg intramuscularly) may be given, but with the knowledge that if it is effective, the benefit may be only transient. For patients with certain glycogen storage diseases, ketotic hypoglycemia, and other disorders in which glycogen has been depleted or is unavailable, it may have a minimal effect or none at all. Diazoxide, an antihypertensive agent that also suppresses insulin release, may be useful in certain patients with hyperinsulinemia. The usual starting dosage of diazoxide is 8 to 12 mg/kg/day, given orally in divided doses every 8 to 12 hours, but the dose may range between 5 and 20 mg/kg/day. Marked hypertrichosis is a prominent side effect that should be discussed with the parents at the time the drug is started because it may become objectionable enough to them to interfere with compliance. The hypertrichosis is reversible when the drug is discontinued. Hemoglobin A1c may be used to monitor the magnitude of hyperglycemic excursions. Small, frequent feedings are useful for many patients with hypoglycemia, although the composition of the feedings differs according to the underlying disorder. Feedings may be supplemented with a slow-release glucose in the form of uncooked cornstarch, starting at 1.6 g/kg every 4 hours for children younger than 2 years of age and 1.75 to 2.50 g/kg every 6 hours in older children. Water or diet drinks are the preferred vehicles for suspension of the uncooked cornstarch (weight-to-volume ratio, 1:2) because these liquids avoid other sugars, which is important for certain hypoglycemic disorders, and do not contain natural amylases, such as may be present in some natural juices.

Home glucose monitoring may be valuable for many patients because of the variable course and response of any individual. With proper education and oversight, home monitoring will provide reassurance to patients and families and can reduce the risk of developing hypoglycemia.

With severe and prolonged hypoglycemia, permanent encephalopathy is not an unusual event, particularly in young children. Learning disability, attention deficit disorder, developmental delay, ataxia, spasticity, or seizures may be seen. Seizures associated with normal blood glucose concentrations should be treated with the usual anticonvulsant medications. The family of a child with sequelae should be counseled regarding infant stimulation and special education. Most families have concerns regarding the genetic risk of recurrence, although they may not voice their concerns to the physician; therefore, this topic should be addressed with all families.


Menkes Syndrome

Menkes syndrome, also known as kinky-hair disease or steely hair disease, is an X-linked disorder characterized by progressive neurologic deterioration beginning in the first 4 to 8 weeks of life, with apathy, somnolence, feeding difficulties, and myoclonic seizures. Many of these patients are born prematurely, fail to thrive, and have hypothermia. Patients also can be seen with sepsis. Their muscle tone varies from hypotonia and flaccidity to hypertonia and spasticity. The descriptive names for this disorder derive from the dull, hypopigmented, sparse, and kinky appearance of the hair (resembling steel wool). Microscopically, pili torti and monilethrix with friable, short hair are present. The child’s face typically is pale, with pudgy cheeks, a prominent vermilion border (described as a “cupid’s bow” mouth), and microcephaly. The arteries are tortuous, with defective, fragmented elastic fibers. Generalized or focal cerebral and cerebellar degeneration may be present and may result from the vascular abnormalities. Low serum copper concentrations, low circulating ceruloplasmin levels, and decreased hepatic and brain copper content are observed.

Copper absorption from the intestine is deficient in Menkes syndrome, and elevated copper content in the intestinal mucosa, kidney, spleen, lung, muscle, pancreas, and placenta has suggested defective copper transport. The copper level is increased in cultured fibroblasts. The gene responsible for Menkes syndrome maps to Xq12–q13 and codes for the adenosine triphosphatase (ATPase), Cu2+-transporting, alpha polypeptide (ATP7A). ATP7A is a copper-binding P-type ATPase that is involved in the transport of copper and homeostasis.

Although progression followed by death in infancy or during the toddler years is a typical occurrence, individuals with milder forms of this disorder have been described. Patients with the occipital horn syndrome have allelic mutations in ATP7A and also have cutis laxa, bladder diverticula with occasional rupture, skeletal abnormalities, and mild mental retardation.

Treatment with copper in the form of copper histidinate has been reported to prevent progression of the neurodegeneration, but this treatment remains experimental, with considerable question existing with regard to its general efficacy in patients with this disease. If it has any possibility of being effective, treatment with copper must be initiated as early as possible in patients with Menkes syndrome.

Wilson Disease

Wilson disease, or hepatolenticular degeneration, is a disorder with a variable clinical presentation, but typical features
include neurologic manifestations, hepatocellular disease, Kayser-Fleischer rings of the cornea, a low serum ceruloplasmin level, and increased concentrations of copper in the serum, urine, and liver. Two neurologic forms are recognized, although their signs and symptoms overlap. Commonly, the dystonic form is associated with liver disease in children, and symptoms include rigidity progressing to contractures. Choreiform or athetoid movements are manifestations of the lenticular degeneration. The pseudosclerotic form is typified by tremors and adult onset, with a longer-term progression than that of the dystonic form. The neurologic dysfunction associated with Wilson disease primarily is motor, with no sensory component. Psychiatric manifestations may be seen, may be the primary complaint, and may be diagnosed as schizophrenia. Frequently, deterioration in school performance, alterations of mood, and acting out are not recognized as manifestations of organic disease in these patients and are attributed to problems of preadolescent and adolescent socialization. Even if neurologic features are subtle or absent, the presence of Kayser-Fleischer rings by gross visual or slit-lamp examination provides valuable clinical information. The corneal rings are present in virtually all patients with neurologic or psychiatric symptoms but only in two-thirds or fewer of those with hepatic abnormalities.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Metabolic Encephalopathies

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