Hypocalcemic Seizures in Neonates
A case of a 2-week-old infant who presented to the emergency department (ED) with rapid eye blinking and jerking in the absence of physical abnormalities is presented. Hypocalcemia and hypomagnesemia were detected. This case represents the common presentation, therapy, and outcome of neonatal hypocalcemia. It is of particular interest to ED physicians because most of the time the etiology of neonatal seizures can be diagnosed in the ED and appropriate therapy can be immediately instituted.
Neonatal seizures occur within the first 2 weeks of life. Even though the threshold for seizure is high in the neonatal period, neonatal seizures are quite common. The overall incidence is 1 in 200 live births. Neonatal seizures tend to be brief, because immature neurons are unable to sustain repetitive activity for long periods of time and to be focal or multifocal. Parents invariably rush their child with seizure to the emergency department (ED) for immediate treatment. Specific cause can be determined only in about 70% of cases. Infants commonly present with subtle symptoms, more often than with clonic or tonic convulsion. Recognization of these symptoms is important for making the diagnosis and initiation of appropriate treatment in the ED.
A 2-week-old infant was brought to the ED by her mother, who stated that the child had been well until 2 days earlier, when she began having episodes of rapid eye blinking, trembling, and jerking occurring several times a day, each episode lasting approximately 1 minute. All four extremities were involved symmetrically; each episode was followed by a brief period of sleep. There was no associated skin color change or respiratory difficulty, and there was no history of trauma, fever, vomiting, or diarrhea.
The child had continued to feed well on iron-fortified formula. Past medical history showed that the infant had been the 3-kg product of a 38-week gestation in a 43-year-old gravida 8, para 6 mother. Pregnancy and delivery were complicated by hypertension, gestational diabetes, and a cesarean section delivery for oligohydramnios and breech presentation. The child did well at birth however, with Apgar score of 9 and 9. Family history was significant for seizure disorder in the father.
Initial physical examination showed a well-developed, well-nourished, alert infant in no acute distress. The vital signs were rectal temperature, 99.4?F; heart rate, 160; respiratory rate, 58; and blood pressure, 82/56 mm Hg. Examination of the head, eyes, ears, nose, and throat was normal; the lungs were clear to auscultation; the cardiac examination was unremarkable, with normal pulses; and the abdominal examination was also normal. The neurological examination showed normal cranial nerve function, normal motor function, and no localizing signs. The infant was irritable with an incessant cry. While in the ED the child was noted to have several brief episodes of seizure activity that consisted of rapid eye blinking and jerking of all four extremities, followed by a short postictal period.
The child remained stable, and blood was obtained for serum chemistries and complete blood count (CBC). The serum sodium was 143 mEq/L (143 mmol/L), potassium 5.0 mEq/L (5.0 mmol/L), chloride 103 mEq/L (103 mmol/L), bicarbonate 26 mEq/L (26 mmol/L), calcium 5.2 mgm/dL (1.25 mmol/L), phosphorous 10.1 mg/dL (3.26 mmol/L), and magnesium 1.0 mg/dL (4.1 mmol/L). The rest of the chemistries and CBC were normal. The child was admitted to the hospital for further evaluation and treatment of her hypocalcemia. She was started on oral calcium replacement therapy over the next 3 days, and became symptom free with the correction of her serum calcium. The parathyroid levels were normal. At discharge she was seizure-free and was much less irritable. The calcium level was 9.9 mg/dL (2.5 mmol/L). Calcium supplements were discontinued 1 week later, and the child has done well subsequently.
Overall prognosis of seizure in the newborn period depends on the underlying cause (Table 1) .The infant in this case presented with seizure activity of unknown etiology. The most common cause of seizures in the newborn period is hypoxic-ischemic encephalopathy; seen in full-term infants, onset is usually within the first 24 hours of life.  Congenital anomalies of the central nervous system, pyridoxine deficiency, or drug withdrawal cause seizures in the early neonatal period, as early as within the first 2 hours of life.   Although seizures are not common among drug withdrawal infants, they have been observed in those severely affected. The usual withdrawal signs includes tremulousness, tachypnea, vomiting, diarrhea, and fever.  Electrolyte disturbances, including hypoglycemia and hypocalcemia, are commonly seen in association with infants of diabetic mothers and may result in early-onset seizures. Infections are the most common cause of neonatal seizures in the late first week and during the second week of life.
Neonatal seizures differ considerably from seizures observed in older children because the newborn infant is less able to sustain organized, generalized epileptiform discharges. A seizure is defined clinically as a paroxysmal alteration in neurological function, ie, motor, behavioral, and/or autonomic function. This definition includes both clinical phenomena that correlate temporally with seizure activity recorded by surface electrodes and therefore clearly epileptic, as well as sterotypic paroxysmal abnormal behaviors that are not associated clearly with electrographic seizures (nonepileptic seizure-like events [NESLES])  (Table 1) . About 65% of neonatal seizures belong to the latter category.  The epileptic seizure is the result of an abnormal discharge of a population of neurons in the brain that may result in a clinical seizure (Table 2) .
The clonic movements are rhythmic and occur at a slow rate of one to six times per second and often are multifocal or migratory, and erroneously may be thought to be a generalized seizure. Focal tonic seizures may present as a sustained deviation of the eyes with or without head deviation and asymmetric posturing of the limbs or trunk.
Motor automatism has an inconsistent association with electroencephalogram (EEG) seizure discharges. It has a poor association with EEG in full-term or newborn but greater association in premature infants. It is the most common seizures observed in the newborn period. In the full-term infant, it manifests as peddling, swimming, and stepping behavior. In premature infants it manifest as simple subtle seizure with eye, mouth, and tongue movement. An isolated episode of apnea is rarely an epileptic seizure, although apnea is seen frequently in epileptic seizures in association with other clinical signs.
TABLE 2 — Causes of Neonatal Seizures
It is important to differentiate clonic seizure from tremors and clonus. The former is slow, rhythmic activity that cannot be stopped by restraints, whereas infants with tremors and clonus have rapid, irregular motor activity that ceases with restraint and change in posture of the limb. Also, tremor and clonus can be induced by various tactics, such as touching the infant or making a loud noise nearby.
The evaluation of neonatal seizures (Table 3) includes checking serum glucose, calcium, magnesium, and sodium; a search for infection including CBC and cultures of blood, urine, and cerebrospinal fluid (CSF); CSF protein, glucose, and cell count; TORCH antibody titers (which give serological information about in utero infections with toxoplasmosis, rubella, cytomegalovirus, and herpes); and serum pH. Other studies depending on the individual case may include head ultrasound, computed tomography, blood ammonia, liver enzymes, blood and urine amino acids and organic acids, and urine-reducing substances.
Treatment of neonatal seizures should first focus on maintaining an adequate airway and ventilation and providing cardiovascular support and stopping the seizure. The seizures in this infant were short and did not compromise the airway; also the cardiovascular status was normal. An immediate bedside glucose test will rule out hypoglycemia, and pulse oximetry will allow constant monitoring of oxygenation status. In the presence of normal blood sugar and adequate oxygenation, aggressive intervention to terminate such brief seizure activity is not warranted because it is not associated with permanent deficits. Attention should instead be centered on determining the underlying etiology, while continuing to monitor the patient closely. In the presence of prolonged or more compromising seizures, phenobarbital (15 to 30 mg/kg loading dose) is the usual first choice in this age group.   Peak concentration is reached within 90 minutes to 6 hours after the injection. Phenytoin sodium is an alternative, followed by diazepam and valproic acid. Diazepam is not better than phenobarbital. Its short duration of action makes it a poor drug for maintenance. Furthermore, one of the main side effects is respiratory depression, which is most likely to occur in infants receiving a combination of diazepam and phenobarbital. Intractable seizures unresponsive to usual therapy may result from a congenital pyridoxine deficiency and may respond to vitamin B-6 replacement. 
Neonatal hypocalcemia is classified by time of onset and by etiology (Table 4) . Several normal events that occur in the normal neonate must be understood to properly evaluate hypocalcemia in this group of patients. During pregnancy a hyperthyroid state exists in the mother. Calcium and inorganic phosphorus are transferred across the placenta against a concentration gradient as evidenced by higher levels of calcium and phosphorus in cord blood compared with maternal blood. Neither parathyroid hormone nor calcitonin crosses the placenta. In the fetus serum calcium levels are comparable with those seen in older children and adults. In normal newborns this gradually decreases after birth to a level that is lower than that found in older infants and children at 2 to 3 days of age, and then slowly returns to normal adult level by 5 to 10 days of age. The decline in the calcium in the newborn period is greater in infants who are not fed or who receive cow’s milk than in breast-fed infants, and greatest in infants who are premature, asphyxiated, and have a diabetic mother.  Serum parathyroid hormone levels are low at birth, and gradually increase over the first 48 hours to normal levels in response to the decrease in serum calcium level. At the same time serum calcitonin levels increase sharply to a peak at 12 to 24 hours of life, and then slowly decrease over the next week to level off at concentrations above adult normals.  Infants are able to convert vitamin D to 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D (calcitrol) in normal fashion at birth. 
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