Seizures - Case 19-3: 8-Month-Old Boy
Seizures - Case 19-3: 8-Month-Old Boy: Excerpt from Pediatric Complaints and Diagnostic Dilemmas
I. History of Present Illness
An 8-month-old boy was well until 1 week before admission, when he was found by
his mother having a
“seizure.” He had shaking and jerking of all extremities that did not stop when his
extremities were held. He did not respond to touch or stimulation. There was no
cyanosis. The episode lasted approximately 15 minutes. By the time Emergency
Medical Services personnel arrived, the patient was alert and feeding on a
bottle. He was not taken to the hospital. His last feeding had been
approximately 3 hours before the event. Two days later, he was evaluated by his
primary physician, who performed the following laboratory evaluations: glucose
(during feeding), 121 mg/dL; alanine aminotransferase (ALT), 73 U/L; aspartate
aminotransferase (AST), 93 U/L;
γ-glutamyl transferase (GGT), 28 U/L; and cholesterol, 423 mg/dL. These
laboratory studies were repeated 2 days later, with similar results except the
glucose was 16 mg/dL. Head CT and EEG were normal. He was hospitalized for
additional evaluation.
II. Past Medical History
The patient was born at 38 weeks' gestation with a birth weight of 3,400 g. His delivery was complicated by
meconium aspiration. He was treated with supplemental oxygen and empiric
antibiotics for 3 days. He also had hypoglycemia requiring intravenous dextrose
and bottle feedings every 1.5 hours. This resolved, and he was discharged home
on the fourth day of life. At 3 months of life, he had been diagnosed with
otitis media and received oral antibiotics. There was no family history of
seizures or mental retardation.
III. Physical Examination
T, 36.2°C; RR, 20/min; HR, 90 to 110 bpm; BP, 120/55 mm Hg; SpO2, 100% in room air
Height, 25th percentile; weight, 10th percentile; head circumference, 25th
percentile
On examination, he was thin but playful and interactive. The anterior fontanel
was open and flat. His pupils were symmetrically reactive to light. The heart
sounds were normal, and the lungs were clear to auscultation. His abdomen was
slightly protuberant, with a liver edge that was firm and palpable 6 cm below
the right costal margin. The spleen tip was just palpable below the left costal
margin. There was no ascites or palpable abdominal mass. The infant was
circumcised and had normal male genitalia. The neurological examination was
normal. He was able to sit without support and maintained good head control.
Deep tendon reflexes were 2+ and symmetric. The gag reflex was intact. There
were no hyperpigmented or hypopigmented skin lesions.
IV. Diagnostic Studies
Serum chemistry values included sodium, 137 mmol/L; potassium, 5.5 mmol/L;
chloride, 100 mmol/L; bicarbonate, 13 mmol/L; calcium, 10.5 mg/dL; phosphorous,
6.5 mg/dL; and serum glucose 20 mg/dL. The cholesterol and triglyceride
concentrations were 465 and 4,070 mg/dL, respectively. Hepatic function tests
included AST, 125 U/L; ALT, 155 U/L; GGT, 564 U/L; total bilirubin, 0.6 mg/dL;
and albumin, 4.0 g/dL. Serum and urinary ketones were present. The WBC count,
hemoglobin, and platelet count, as well as prothrombin and partial
thromboplastin times, were normal. Blood, urine, and stool cultures were
obtained.
V. Course of Illness
The patient underwent a fasting study that revealed the diagnosis within
approximately 4 hours.
Discussion: Case 19-3
I. Differential Diagnosis
This infant had seizures related to hypoglycemia. Hypoglycemia in an infant,
defined as a blood glucose concentration of 40 mg/dL or less, warrants
immediate treatment followed by appropriate investigation. Many inborn errors
of metabolism responsible for hypoglycemia manifest during the first year of
life, whereas milder defects of glycogen degradation and gluconeogenesis
manifest in childhood only after prolonged periods of fasting. Causes of
hypoglycemia in an infant include hyperinsulinism, hormone deficiency, and
defects in branched-chain amino acid metabolism, fatty acid oxidation, and
hepatic enzymes.
Urinary ketones are absent or low in children with hyperinsulinism and fatty
acid oxidation defects who present with hypoglycemia. Hypoglycemia secondary to
hyperinsulism most commonly appears during the first year of life. It is
usually associated with islet-cell dysplasia and rarely with islet-cell
adenomas. Insulin is elevated (greater than 5
µU/mL), and injection of glucagon elicits a rapid rise in blood glucose levels.
Children with disorders of fatty acid metabolism can present with hypoglycemia
and profound disturbance of consciousness that may not improve when the plasma
glucose is normalized. In addition to hypoketonemia, they have high plasma free
fatty acid concentrations, elevated ALT and AST, rhabdomyolysis,
cardiomyopathy, and cerebral edema.
The presence of urinary ketones usually suggests hormone deficiency, glycogen
storage disease (GSD), or defects in gluconeogenesis. Hypoglycemia is a common
presentation for infants with panhypopituitarism, isolated growth hormone
deficiency, and absolute (adrenal hypoplasia, Addison
's disease, adrenal leukodystrophy) or relative (congenital adrenal hyperplasia)
glucocorticoid deficiency. Midline defects such as cleft lip or palate, optic
dysplasia, and microphallus suggest anterior pituitary hormone deficiency.
Hyperpigmentation associated with Addison
's disease rarely occurs in young children. Addison's disease is occasionally associated with hypoparathyroidism (hypocalcemia).
Severely compromised adrenal function, as in congenital adrenal hyperplasia,
may lead to serum electrolyte disturbances or ambiguous genitalia.
Children with branched-chain ketonuria (maple syrup urine disease) excrete
urinary ketoacids that impart the characteristic odor of maple syrup.
Clinically, these infants have frequent hypoglycemic episodes, lethargy,
vomiting, and muscular hypertonia. GSDs are inherited autosomal recessive
defects that are characterized by either deficient or abnormally functioning
enzymes involved in the formation or degradation of glycogen. Hepatomegaly,
growth failure, hyperlipidemia, and hyperuricemia are common clinical features.
Other disorders to consider include galactosemia, especially in children with
hepatosplenomegaly, jaundice, and mental retardation; and
fructose-1,6-diphosphatase deficiency, in children with hepatomegaly due to
lipid storage but only mildly abnormal liver function studies.
II. Diagnosis
After 4 hours, the child's glucose concentration was 16 mg/dL; lactate, 32 mg/dL (normal range, 5 to 18
mg/dL); and uric acid, 14.2 mg/dL (normal range, 2 to 7 mg/dL). He received
intravenous glucagon (30
µg/kg), after which the blood glucose concentration was 22 mg/dL and the lactate
level was 44 mg/dL. He then received oral glucose, which increased his blood
glucose concentration to 65 mg/dL and decreased the lactate concentration to 24
mg/dL.
These findings suggested type IA glycogen storage disease (von Gierke disease). Liver biopsy demonstrated increased glycogen content and deficient
glucose-6-phophatase (G6P) enzyme activity (2 nmol/min per milligram of
protein; normal range, 20 to 70 nmol/min per milligram of protein).
III. Incidence and Epidemiology
The GSDs, or glycogenoses, comprise several inherited diseases caused by
deficiency in one of the enzymes that regulate the synthesis or degradation of
glycogen. The end result is abnormal accumulation of glycogen in various
tissues. GSD type I has an estimated incidence of 1 in 200,000 births. GSD IA
is caused by deficiency of the enzyme G6P, which catalyzes the breakdown of
stored glycogen into glucose for use by the body. At least 56 different
mutations in the gene for G6P (chromosome 17q21) have been found in patients
with GSD IA. Failure of the G6P transporter (GSD IB) or of the microsomal
phosphate transporter (GSD IC) also ultimately impair G6P activity. The three
types of GSD result in similar clinical and biochemical disturbances. G6P is
expressed in the liver, kidneys, and intestines.
IV. Clinical Presentation
GSD type I is characterized by severe hypoglycemia occurring within 3 to 4 hours
after a meal. Although symptomatic hypoglycemia may appear soon after birth,
most patients are asymptomatic as long as they receive frequent feeds that
contain sufficient glucose to prevent hypoglycemia. Symptoms of hypoglycemia
appear only when the interval between feedings increases, such as when the
child begins to sleep through the night or when an intercurrent illness
disrupts normal feeding patterns.
Patients may have hyperpnea from lactic acidosis. Untreated patients have poor
weight gain and growth retardation. Most patients have a protuberant abdomen
and hepatomegaly due to glycogen deposition and fatty infiltration. Social and
cognitive development are normal unless the infant suffers neurologic
impairment after frequent hypoglycemic seizures. Xanthomas may appear on the
extensor surfaces of the extremities and buttocks. Older children develop gout.
V. Diagnostic Approach
Fasting study. In GSD, the liver is not able to release sufficient glucose from hepatic stores
to meet peripheral tissue demands. The consequence of this
“fasting state” is hypoglycemia, which causes lipolysis and protein breakdown. Therefore, in
GSD, hypoglycemia is accompanied by elevated lactic acid, elevated uric acid,
and metabolic acidosis. The serum insulin level is low, but serum and urinary
ketones are markedly elevated. Glucagon does not significantly alter the
glucose level and actually increases the lactic acid level. An oral glucose
load increases serum glucose and decreases lactic acid. At the time of
hypoglycemia, serum should be collected for determinations of insulin,
C-reactive peptide, growth hormone,
β-hydroxybutyrate, lactate, and free fatty acids. Urine may be analyzed for
organic acids, ketones, and reducing substances. This combination of studies
allows diagnosis of GSD as well as exclusion of other disorders that manifest
with hypoglycemia.
Liver function tests. Mild elevations of AST and ALT occur.
Lipid profile. Markedly elevated serum triglycerides, free fatty acids, and apolipoprotein
C-III are seen. Infants with triglyceride levels greater than 1,000 mg/dL are
at high risk for development of acute pancreatitis. Despite the
hypertriglyceridemia, the risk for cardiovascular disease is not increased.
Complete blood count. Neutropenia develops with GSD IB but not with GSD IA.
Bleeding time. Although this test is not routinely performed, most children with GSD type I
have impaired platelet function due to systemic metabolic abnormalities. This
bleeding tendency, manifested by recurrent epistaxis and prolonged bleeding
after surgery, resolves with correction of the metabolic abnormalities.
Urinalysis. Glucosuria and proteinuria indicate proximal renal tubular dysfunction that
improves with correction of metabolic abnormalities.
Abdominal ultrasound. Hepatic adenomas occur in the majority of patients by the second decade of life
but may be noted before puberty. Women also usually have polycystic ovaries, a
finding whose clinical significance remains unclear.
Other studies. Measurement of G6P enzyme activity in a fresh liver biopsy specimen can be used
to diagnose GSD IA. Molecular analysis to identify mutations on the G6P gene is
a reliable alternative to liver biopsy.
VI. Treatment
Treatment consists of providing a continuous dietary source of glucose to
prevent hypoglycemia. When hypoglycemia is prevented, the biochemical
abnormalities and growth improve and liver size decreases. Infants require
frequent feedings, approximately every 2 to 3 hours during the day and every 3
hours at night. A variety of methods can be used to provide a continuous source
of glucose at night in older children, including intravenous dextrose infusion,
continuous intragastric feeding via a nasogastric or gastrostomy tube, and the
use of low glycemic index foods such as cornstarch. Orally administered
uncooked cornstarch seems to act as an intestinal reservoir of glucose that is
slowly absorbed into circulation. It has been used successfully in infants as
young as 8 months of age and may obviate the need for continuous intragastric
infusion of formula overnight. It can be mixed with water, formula, or
artificially sweetened fluids in 4- to 6-hour intervals overnight. The optimal
schedule requires validation by serial glucose monitoring. Allopurinol and
lipid-lowering agents are used for severe uric acid and lipid abnormalities.
Hepatocyte infusion and liver transplantation may be curative, but the
long-term complications in children with GSD are not yet known.
VII. References
1. Lee PJ, Patel A, Hindmarsh PC, et al. The prevalence of polycystic ovaries in
the hepatic glycogen storage diseases: its association with hyperinsulinism.
Clin Endocrinol 1995;42:601–606.
2. Rake JP, ten Berge AM, Visser G, et al. Glycogen storage disease type Ia:
recent experience with mutation analysis, a summary of mutations reported in
the literature and a newly developed diagnostic flow chart.
Eur J Pediatr 2000;159:322–330.
3. Sperling MA, Finegold DN. Hypoglycemia in the child. In: Sperling MA, ed. Pediatric endocrinology. Philadelphia: WB Saunders, 1996;265–279.
4. Willi SM. Glycogen storage diseases. In: Altschler SM, Liacouras CA, eds. Clinical pediatric gastroenterology. Philadelphia: Churchill Livingstone, 1998:377–383.
5. Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Endocrinol Metab Clin 1999;28:801–823.
Book Source Details
- Book Title: Pediatric Complaints and Diagnostic Dilemmas
- Author(s): Samir S Shah MD; Stephen Ludwig MD
- Year of Publication: 2003
- Copyright Details: Pediatric Complaints and Diagnostic Dilemmas, Copyright © 2003 Lippincott Williams & Wilkins.
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