Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter III.9. Neonatal Seizures
Lynn M. Iwamoto, MD

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This is a term female infant born to a 28 year old mother who is A+, serologies unremarkable, and group B strep (GBS) negative with no preexisting medical problems. Labor and delivery was notable for a tight nuchal cord. The infant was delivered vaginally. Brief oxygen blow by and tactile stimulation were required. Apgar scores were 7 (-1 tone, -2 color) and 9 (-1 color) at 1 and 5 minutes, respectively. Initial glucose screen was 40mg%. The infant had no respiratory distress and fed adequately overnight. Early in the morning on the second day of life, she has a 1 minute generalized tonic-clonic seizure. She is taken to the nursery and oxygen is administered. The rapid glucose is 60mg%. An IV is started and a loading dose of phenobarbital is given. She is then transferred to the NICU. She then has a second seizure, initially noted to start in the right arm which then becomes generalized. In retrospect, slight decreased fetal movements were noted, in utero.

Exam: VS T36.8, P140, R60, BP 90/50, birth weight 3300g. Length and head circumference are at the 50th percentile. She is in no respiratory distress, but she is sleepy. Head shows mild molding, no caput or cephalohematoma. No dysmorphic features are evident. Lungs are clear to auscultation. Heart regular without murmurs. Abdomen with normal umbilicus, no masses, no hepatosplenomegaly and normoactive BS. Normal female genitalia. Extremities are well perfused with good pulses. There is mildly decreased generalized tone. DTRs are 2+ and symmetric.

The infant requires a second dose of phenobarbital. Maintenance dosing is started. No further seizures are noted. Electrolytes and glucose are normal except for a bicarbonate level of 19. BUN, Cr, Ca, P, and Mg are normal. CBC is remarkable for a hemoglobin of 12 g/dl, hematocrit 36% (anemic for a newborn), normal WBC and differential, normal platelet count. A lumbar puncture is performed which shows normal CSF findings. An MRI scan shows an increased signal in the left hippocampus, suggesting ischemic injury. EEG shows moderate burst suppression.


Most neonatal seizures occur within the first few days of life, with an incidence between 1.8 and 3.5 per 1000 live births (1). The clinical manifestations of seizures in newborns differ significantly from that seen in older children and adults as the human neonatal brain is still in the process of organization and development. Premature infants have a higher frequency of seizures and their seizures are less organized (2).

Seizures in newborns can be classified as subtle, clonic, tonic, or myoclonic (3). Subtle seizures are often difficult to recognize, they occur more frequently in premature infants, and they are not always correlated with electroencephalographic seizure activity. Examples of subtle seizures include bicycling movements, autonomic dysfunction, horizontal eye deviation, and repetitive facial movements. Clonic seizures are slow, rhythmic movements. They can be focal or multifocal. Tonic seizures can be focal or, more commonly, generalized. They consist of sustained extension and/or flexion posturing. Lastly, myoclonic seizures are composed of rapid, flexion twitching or jerking movements. These seizures can be focal, multifocal, or generalized.

A clinical seizure results from excessive depolarization of neurons in the central nervous system. The pathophysiology of this excessive depolarization is unclear, but is thought to be related to energy production failure, membrane alteration, excess excitatory neurotransmitters, or deficit of inhibitory neurotransmitters (2). Hypoxemia, ischemia and hypoglycemia can result in significantly decreased energy production and increased release of glutamate, the principal excitatory neurotransmitter in the cerebral cortex. Hypocalcemia and hypomagnesemia cause increased depolarization by increasing sodium influx across the neuronal cell membrane. In addition, the inhibitory pathways are not well developed early in life.

Neonatal primary seizure disorders, epileptic syndromes, do occur, but at a very low frequency. The major etiologies of neonatal seizures include hypoxic-ischemic encephalopathy, intracranial hemorrhage, metabolic disturbances, intracranial infection, developmental defects, and drug withdrawal.

The most common cause of neonatal seizures is hypoxic-ischemic encephalopathy (HIE) brain injury. Asphyxial injury may occur in utero as a result of decreased uteroplacental perfusion, for example in abruptio placenta, cord compression, preeclampsia, or chorioamnionitis. Postnatally, conditions such as persistent pulmonary hypertension of the newborn, cyanotic congenital heart disease, sepsis, and meningitis can also result in hypoxic-ischemic brain injury. In those infants with HIE who have seizures, onset of seizures is generally within the first 24 hours after birth. However, the timing of onset is not a reliable indicator of the timing of the neurologic injury (4).

Seizures due to intracranial hemorrhage may also be associated with hypoxic-ischemic or traumatic injury since these events are frequently associated with each other. Onset of seizures due to subarachnoid hemorrhage or subdural hemorrhage is usually the second or third day of life, while those due to germinal matrix-intraventricular hemorrhage present after the third day (2).

CNS infections can also be associated with neonatal seizures. Congenital infections with viruses (cytomegalovirus, rubella, herpes, and others) or toxoplasmosis can cause severe encephalopathic disease. Seizures also often occur in neonates with acute intracranial bacterial infections, most commonly Escherichia coli and group B streptococcal menigitis.

Metabolic disturbances such as hypoglycemia, hypocalcemia, and hypomagnesemia are associated with neonatal seizures. Newborn infants who are premature and infants of diabetic mothers (large for gestational age, or small for gestational age) are most at risk for hypoglycemia. Those infants who are of low birth weight, born to diabetic mothers, or who have suffered hypoxic-ischemic injury are also at risk for hypocalcemia. Hypomagnesemia often accompanies hypocalcemia. Other metabolic abnormalities associated with seizures include local anesthetic intoxication, hyponatremia, and inborn errors of metabolism (2,5).

Diagnostic evaluation includes glucose, electrolytes, calcium, magnesium, and phosphorus in order to identify an immediately correctable metabolic condition. Spinal fluid analysis is performed to identify a potential bacterial infection. CT and magnetic resonance imaging (MRI) can delineate the brain anatomy with high sensitivity and resolution (MRI better than CT). Lesions of hypoxic-ischemic injury can be identified within the first 2-3 days after the asphyxial event (6). The electroencephalogram (EEG) is used to confirm the presence of seizure activity and to define the background electrical activity which is valuable in estimating prognosis.

Treatment of neonatal seizures should focus on the primary etiology as well as direct seizure control. Neonates are less likely to incur seizure related injury. Phenobarbital is often used as the first line anticonvulsant, followed by phenytoin and lorazepam. Oral phenytoin is poorly absorbed from the infant GI tract.

Prognosis varies as a function of primary etiology and gestational age of the infant. The background EEG activity is also correlated with outcome in both term and preterm infants. Infants with a normal background activity are less likely to have neurological sequelae as opposed to those with moderate to severe abnormalities such as burst-suppression pattern, voltage suppression, and electrocerebral silence (2).


Questions

1. True/False: Neonatal seizures are always the tonic-clonic type.

2. Which of the following conditions is LEAST likely to be associated with neonatal seizures?
. . . . a. E. coli meningitis
. . . . b. syndrome of inappropriate diuretic hormone
. . . . c. transient tachypnea of the newborn
. . . . d. umbilical cord prolapse

3. True/False: Oral phenytoin is often used as a first line anticonvulsant. Why or why not?

4. Facial twitches are an example of what kind of seizures?
. . . . a. tonic-clonic
. . . . b. myoclonic
. . . . c. clonic
. . . . d. subtle

5. True/False: Neonates have an immature inhibitory neurotransmitter system.

6. Which of the following would be LEAST helpful in the immediate diagnostic evaluation of an infant with a neonatal seizure?
. . . . a. brain ultrasound
. . . . b. serum glucose level
. . . . c. cerebral spinal fluid gram stain
. . . . d. serum calcium level


References

1. Mizrahi EM. Neonatal seizures and neonatal epileptic syndromes. Neuro Clinics 2001;19:427-463.

2. Volpe JJ. Neonatal Seizures. In: Neurology of the Newborn, 3rd edition. WB Saunders Company, Philadelphia, 1995, pp. 172-207.

3. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics 1989;84:422-428.

4. Ahn MO, Korst LM, Phelan JP, Martin GI. Does the onset of neonatal seizures correlate with the timing of fetal neurologic injury? Clin Pediatr 1998;37:673-676.

5. Scher MS. Seizures in the newborn infant. Clinics in Perinatol 1997;24:735-772.

6. Leth H, Toft PB, Herning M, Peitersen B, Lou HC. Neonatal seizures associated with cerebral lesions shown by magnetic resonance imaging. Arch Dis Child 1997;77:F105-F110.


Answers to questions

1. false

2. c

3. false, since it is poorly absorbed from the infant GI tract.

4. d

5. true

6. a


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