HISTORY OF PRESENT ILLNESS
The patient is a 10-day-old boy who was well until the day of admission when he had a sudden onset of left arm and leg shaking while sleeping. The episode lasted about 1 minute and was accompanied by eyelid fluttering. After spontaneous cessation of the episode, the infant continued sleeping but was aroused easily. He was brought to the emergency department for evaluation. He did not have fevers or cyanosis. There was no recent vomiting or diarrhea. His oral intake had been unchanged during the past several days, consisting exclusively of cow-milk-based formula every 2.5-3 h. The parents were uncertain about urine output since the maternal grandmother had cared for the infant the day prior to admission.
The infant weighed 3600 g, born by spontaneous vaginal delivery after an uncomplicated pregnancy. The infant required phototherapy briefly on the second day of life for hyperbilirubinemia with a peak total bilirubin level of 15.5 mg/dL. The mother had vaginal colonization with group B Streptococcus and received two doses of penicillin during labor. She also had a history of genital herpes simplex virus infection. Although no lesions were noted at delivery, she did develop lesions on the seventh postpartum day.
T 37.5°C; HR 124 bpm; RR 40/min; BP 75/45; SpO2 100% in room air
Weight 50th percentile; Length 25th percentile; Head Circumference 25th percentile
The infant appeared alert. There were no vesicles on the scalp or skin. His anterior fontanelle was open and flat. His conjunctivae were pink and anicteric. Red reflex was present bilaterally. There was no murmur on cardiac examination and femoral pulses were strong. The spleen tip was just palpable and there was no hepatomegaly. The Moro reflex was symmetric. The remainder of the examination was normal.
Complete blood count revealed 8800 WBCs/mm3 (16% segmented neutrophils, 70% lymphocytes; 11% monocytes; and 3% atypical lymphocytes); hemoglobin, 13.4 g/dL; and platelets, 511 000/mm3. Serum chemistries included sodium, 139 mmol/L; potassium, 5.5 mmol/L; chloride, 104 mmol/L; and bicarbonate, 28 mmol/L. The blood urea nitrogen and creatinine were normal. Serum alanine and aspartate aminotransferases were normal. Serum albumin was 3.3 g/dL. Examination of the cerebrospinal fluid revealed the following: WBCs, 12/mm3; RBCs, 1834/mm3; glucose, 45 g/dL; and protein, 124 g/dL. There were no bacteria on Gram stain.
COURSE OF ILLNESS
They infant was treated empirically with ampicillin, cefotaxime, and acyclovir while awaiting the results of CSF bacterial culture and CSF HSV PCR. An ECG (Figure 19-4) suggested a cause of the seizures, which was confirmed by additional blood tests in both the infant and his mother.
FIGURE 19-4. Electrocardiogram.
DISCUSSION CASE 19-2
Many neonatal seizures are idiopathic. The most common definable etiologic agents include asphyxia, intracranial infection, trauma, nontraumatic hemorrhage, strokes, metabolic disorders, central nervous system malformations, and maternal drug abuse. Seizures due to perinatal asphyxia typically occur within the first 24 hours of life. Common infectious causes in the first week of life include bacterial meningitis due to group B Streptococcus and Escherichia coli. Neonates with herpes simplex meningitis typically present during the second week of life but up to 40% develop symptoms within the first 5 days of life. Intracranial hemorrhage of any cause can provoke seizures. Neonatal seizures related to birth trauma with subsequent subarachnoid hemorrhage or subdural and epidural hematomas usually occur within the first 72 hours of life. Non-traumatic causes of intracranial hemorrhage including ruptured arteriovenous malformations and underlying disorders of coagulation can occur at any time. Metabolic disorders include hypocalcemia, hypoglycemia, and pyridoxine dependency. Neonatal hypocalcemia occurring after the third day of life is usually due to transient relative hypoparathyroidism. The immature neonatal parathyroid may be unable to handle an excessive phosphate load, particularly when the infant is fed a formula with a relatively low ratio of calcium to phosphorus. Rarely, prolonged phototherapy induces hypocalcemia. Phototherapy decreases melatonin secretion, which in turn decreases glucocorticoid secretion, which leads to an increase in bone calcium uptake with subsequent hypocalcemia. Multiple defects in urea cycle and organic acid metabolism may cause seizures during the neonatal period. Infants with these disorders usually have unexplained stupor, coma, and vomiting in addition to seizures. Infants born to mothers who have used heroin or metha-done may have seizures, although other symptoms such as poor feeding, diarrhea, sweating, jitteriness, and irritability are more common.
Bacterial cultures and HSV PCR of the CSF were negative. The ECG demonstrated QTc prolongation (QTc = 0.47 seconds) characteristic of hypocalcemia (Figure 19-4). The infant’s serum calcium was 6.6 mg/dL (normal range 8.8-10.1 mg/dL); ionized calcium, 0.83 mmol/L (normal range 1.00-1.17 mmol/L); phosphate, 10.6 mg/dL (normal range 4.8-8.2 mg/dL); and magnesium, 1.1 mg/dL (1.5-2.5 mg/dL). Additional testing included intact parathyroid hormone, 9.7 pg/mL (normal range 10-55 pg/mL); 25-hydroxy vitamin D, 7 ng/mL (normal range 5-42 ng/mL); and active vitamin D (1-alpha-25-dihydroxy-cholecalciferol) (1,25(OH)2D), 114 pg/mL (normal range 8-72 pg/mL). See Table 19-3 for the differential diagnosis of hypocalcemia in an infant. Although the mother was asymptomatic, her calcium level was elevated to12.8 mg/dL. The mother was subsequently diagnosed with hyperparathyroidism related to a parathyroid adenoma. The infant was diagnosed with transient neonatal hypoparathyroidism secondary to maternal hyperparathyroidism. The infant was initially treated with intravenous calcium gluconate followed by oral calcium and vitamin D supplementation, which were weaned over the subsequent 3 weeks.
TABLE 19-3. Differential diagnosis of neonatal hypocalcemia.
INCIDENCE AND EPIDEMIOLOGY OF TRANSIENT NEONATAL HYPOPARATHYROIDISM
Hyperparathyroidism has a prevalence rate of 0.15% with a peak incidence between 30 and 50 years of age. Approximately 80% are due to a solitary adenoma that requires resection and 15% are due to chief cell hyperplasia. Maternal symptoms are not apparent until the serum calcium level exceeds 12-13 mg/dL. However, even mild maternal hypercalcemia leads to chronic fetal hypercalcemia, which in turn suppresses fetal PTH production. After birth, calcium levels decrease but PTH production cannot be rapidly increased. In this condition, neonatal hypoparathyroidism is transient, lasting only several days to several weeks. Eventually, as the parathyroids become more active, increasing PTH levels stimulate vitamin D production and extra calcium absorption from the plentiful supply in the gut. Clinically detectable hypocalcemia develops in 15%-25% ofinfants born to mothers with hyperparathyroidism. As in this case, neonatal seizures or tetany often lead to a search that identifies a maternal parathyroid adenoma.
CLINICAL PRESENTATION OF TRANSIENT NEONATAL HYPOPARATHYROIDISM
Signs of hypocalcemia usually develop within the first 3 weeks of life. Signs of neonatal hypocalcemia are often nonspecific and may be seen in a variety of other conditions. Tremors and jitteriness are most commonly seen. Other signs include irritability, hyperreflexia, facial twitching, carpalpedal spasm, seizures, cyanosis, and, rarely, laryngospasm. More importantly, other disorders that can present with hypocalcemia should be considered. Features of 22q11 deletion syndromes include cleft palate, micrognathia, ear anomalies, bulbous nasal tip, and conotruncal heart defects. Findings associated with Albright hereditary osteodystrophy (pseudohypoparathyroidism type Ia) include round face, short distal phalanges of the thumbs, subcutaneous calcifications, and a family history of developmental delay and dental hypoplasia. Sensorineural deafness, renal dysplasia, and mental retardation are also associated with syndromes that include hypoparathyroidism.
Serum calcium and ionized calcium. Both calcium and ionized calcium levels are low with symptomatic hypocalcemia.
Serum albumin. Since approximately 45% of serum calcium is protein bound, low serum albumin levels lead to low serum calcium levels but normal ionized levels. Symptoms of hypocalcemia develop only when ionized calcium is low. The following correction factor approximates whether a low measured serum calcium level is due solely to hypoalbuminemia: Corrected serum calcium = measured serum calcium + [(Normal serum albumin - measured serum albumin) × 0.8].
When the corrected serum calcium is less than normal (<8.8 mg/dL), the ionized calcium may also be low, increasing the likelihood of symptomatic hypocalcemia. In this patient, the corrected serum calcium was calculated as follows: [6.6 mg/dL + (4.0 mg/dL - 3.3 mg/dL) × 0.8] = 7.1 mg/dL = Corrected calcium.
Serum magnesium. Magnesium deficiency can lead to neonatal hypocalcemia through functional hypoparathyroidism and pseudohypoparathyroidism. In most cases, it is seen in neonates born to magnesium-deficient mothers, such as those with poorly controlled diabetes mellitus. In magnesium deficiency, magnesium replenishment leads to increases in both calcium and PTH levels. In hypoparathyroidism of any other cause, magnesium administration does not lead to changes in the calcium and PTH levels.
Serum phosphorus. Phosphorus levels are elevated with both phosphate-induced neonatal hypocalcemia and with hypoparathyroidism.
Serum PTH. PTH levels are low with hypoparathyroidism. However, in phosphate-induced neonatal hypocalcemia, serum PTH is appropriately elevated.
Active vitamin D. Levels of 1,25(OH)2D are low with hypocalcemia due to vitamin D deficiency but normal or high with underlying hypoparathyroidism.
Other tests. Infants who were treated with bicarbonate or other alkali to correct acidosis can develop very significant hypocalcemia, therefore, an arterial blood gas should be considered. A chest radiograph can document a normal thymic shadow in neonates when 22q11 deletion syndromes are a concern. When neonatal risk factors for hypocalcemia are absent, consider measuring maternal serum calcium, phosphorus, and PTH levels.
Emergency treatment for neonatal hypocalcemia consists of intravenous 10% calcium gluconate infusion with continuous electrocardiographic monitoring. Additionally, 1,25-dihydroxycholecalciferol (vitamin D3; calcitriol) should be given. Once the QTc interval on ECG is normal, therapy can be continued with oral calcium and vitamin D2 (ergocalciferol), which is less costly than calcitriol. Serum calcium levels should be measured frequently in the early stages of treatment to determine the appropriate dosing. If hypercalcemia occurs, therapy should be discontinued and resumed at a lower dose after the serum calcium level has returned to normal. When maternal hyperparathyroidism is the cause of neonatal hypoparathyroidism and hypocalcemia, supplementation with calcium and vitamin D analogs is only required for 3-4 weeks.
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