Chapter III.11. Neonatal Seizures
Richard Ho
October 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Lynn M. Iwamoto, MD. This current third edition chapter is a revision and update of the original authorís work.


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 pre-existing medical problems. Labor and delivery course 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 40 mg/dL. 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. A point of care glucose check results 60 mg/dL. An IV is started and a loading dose of phenobarbital is given. She is then transferred to the NICU. In retrospect, mother reports feeling slightly decreased fetal movements towards the end of pregnancy.

Exam: VS T 36.8, HR 140, RR 60, BP 90/50. Birth weight 3300g and current weight is 3100g. Length and head circumference are both 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 umbilical cord, no masses, no hepatosplenomegaly and normoactive bowel sounds. Normal female genitalia. Extremities are well perfused with good pulses. There is mildly decreased generalized tone. She is sleepy but responds to exam. Pupils are 2mm and reactive to light bilaterally. No abnormal posturing noted. Patellar deep tendon reflexes are 2+ and symmetric.

The infant has a second seizure, initially noted to start in the right arm which then becomes generalized. A second dose of IV phenobarbital is given. Maintenance dosing is started. No further seizures are noted. A renal function panel is unremarkable except for a bicarbonate level of 19 meq/L. CBC is only remarkable for a low for age hemoglobin of 12 g/dL, hematocrit 36% (anemic for a newborn). A lumbar puncture is performed which shows normal cerebral spinal fluid cell count, protein and glucose levels. A magnetic resonance imaging (MRI) scan of the brain shows an increased T2 signal in the left hippocampus, suggesting ischemic injury. EEG shows moderate burst suppression.


Neonatal seizures are seizures that occur within the first 28 days of life for full-term infants or before 44 weeks of gestational age (GA) for preterm infants. Neonatal seizures affect up to 1.5 to 3.5 per 1000 full term infants, and 10 to 130 per 1000 preterm infants (1). Studies have reported an upward trend of neonatal seizure occurrences as gestational age decreases (1,2). A study on the U.S. National Inpatient neonate population reported the highest occurrence of neonatal seizure at 24 weeks of GA, at 0.12%. After 33 weeks GA, newborns with neonatal seizures were more likely to have higher mortality rates and higher lengths of stay (2). While these seizures may be short lived, they can signify damage to the immature brain warranting urgent management and treatment.

Seizures in newborns can be classified as subtle, clonic, tonic, spasms, and myoclonic (3). Focal clonic, focal tonic, and generalized myoclonic seizures are typically epileptic seizures, hence, associated with electroencephalographic discharge, whereas, subtle, generalized tonic and multifocal myoclonic seizures are not typically true epileptic seizures, therefore not associated with discharge. Subtle seizures are often difficult to recognize; they are the most common form of seizures and occur more frequently in premature infants. Subtle seizures mimic normal behavior, examples including blinking or fluttering, horizontal eye deviation, mouthing, extremity movements (swimming, bicycling, stepping), autonomic dysfunction, and repetitive facial movements. Clonic seizures are repetitive, rhythmic movements that may involve multiple muscle groups and are migratory in nature. They can be focal or multifocal. These seizures may occur asynchronously or synchronously on one side of the body or simultaneous but asynchronously bilaterally. Tonic seizures can be focal or, more commonly, generalized. Focal tonic seizures consist of sustained extension and/or flexion posturing of a limb, trunk, or neck, whereas generalized tonic seizures are often associated with extension or flexion of the upper and lower extremities. Spasms are generalized jerks that last between 1 to 2 seconds and are usually associated with a brief generalized discharge. Lastly, myoclonic seizures are composed of rapid, flexion twitching or jerking movements. They may be differentiated from clonic seizures with the lack of rhythmic motion and the rapidity of the jerks (<50 msec). These seizures can be focal, multifocal, or generalized (3,4).

A clinical seizure results from excessive excitatory or decreased inhibitory neural discharges in the central nervous system. The primary factor of neonatal seizures is due to undeveloped brain that contain areas of immaturity, resulting in an imbalance of neuronal excitation and inhibition. Animal studies have shown an increased excitatory receptor density including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (3). GABA (gamma-aminobutyric acid) receptors are chiefly responsible for inhibitory signals in the mature brain, decreasing cellular membrane potential by regulation of chloride and potassium channels. Chloride gradients are reversed in the immature brain. There is a higher concentration intracellularly than extracellularly. Thus, contrary to the mature brain, the opening of the chloride channels in the immature brain results in depolarization instead of hyperpolarizing. This inhibitory pathway is developed after the excitatory pathway early in life, thus it is not well developed in neonates (3,5).

The major etiologies of neonatal seizures include hypoxic-ischemic encephalopathy, intracranial hemorrhage, intracranial infection, metabolic disturbances, congenital malformation developmental defects, and drug withdrawal. Neonatal epilepsy syndromes, do occur, but at a very low frequency (3,4,5).

The most common cause of neonatal seizures is hypoxic-ischemic encephalopathy (HIE) brain injury. Severe asphyxia may occur in utero as a result of decreased uteroplacental perfusion, examples include abruptio placenta, umbilical cord compression, preeclampsia, or chorioamnionitis. Postnatally, conditions such as persistent pulmonary hypertension of the newborn, cyanotic congenital heart disease, hypovolemic shock, sepsis, and meningitis can also result in hypoxic-ischemic brain injury. In those infants with HIE who have seizures, the onset of seizures is generally within the first 12 hours after birth; however, the timing of onset is not a reliable indicator of the timing of the neurologic injury (3-6).

Seizures due to intracranial hemorrhage may also be associated with hypoxic-ischemic or traumatic injury since these events are frequently associated with each other. Intracranial hemorrhages include subarachnoid hemorrhage, subdural hemorrhage, and germinal matrix intraventricular hemorrhage (3-6). Infants with vascular events such as arterial stroke or venous sinus thrombosis can also present with seizures and can be diagnosed with neuroimaging (3).

Infection accounts for 5% to 10% of neonatal seizures. Bacterial meningitis, most commonly Escherichia coli and group B streptococcal, or nonbacterial meningitis including TORCH infections (toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex virus) can cause severe encephalopathic disease (3,4,6).

Metabolic disturbances such as hypoglycemia, hypocalcemia, hypomagnesemia, imbalances of sodium, inborn disorders of metabolism, and pyridoxine dependency are associated with neonatal seizures. Newborn infants who are premature, infants of diabetic mothers (large for gestational age, or small for gestational age), and infants with hypoxic ischemic encephalopathy are most at risk for hypoglycemia and hypocalcemia. Hypomagnesemia often accompanies hypocalcemia. Hyponatremia is often due to inappropriate antidiuretic hormone secretion or water intoxication. Other metabolic abnormalities associated with seizures include local anesthetic intoxication, pyridoxine dependency disorders, and inborn errors of metabolism. Seizures due to disturbance in organic acid or amino acid metabolism are often associated with hyperammonemia or acidosis. Diagnosis often requires a full metabolic workup (3-6).

Malformation developmental defects can be attributed to 5% to 10% of neonatal seizures. Examples include lissencephaly, focal cortical dysplasia, tuberous sclerosis, Sturge-Weber syndrome, and Aicardi syndrome. Dysplasia or agenesis of regions of the brain could lead to subsequent infantile spasms (3,4,5). Drug withdrawal secondary to chronic maternal use of narcotics, sedatives and anti-depressants can also be associated with neonatal seizures in the first 3 days of life (3).

The diagnostic evaluation to rule out metabolic condition includes serum electrolytes, amino acids (ammonia, acyl carnitine, lactate pyruvate), urine organic acids (sulfocysteine and alpha-aminoadipic acid semialdehyde), and CSF (neurotransmitter metabolites, glucose, protein, cells, amino acids, lactate). A thorough family history is imperative to rule out inborn defects of metabolism, as most conditions are passed down in an autosomal recessive or X-link recessive fashion. 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 yields greater diagnostic information and it avoids radiation to the developing neonatal brain. 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 (3,5). Some cases of neonatal seizures can be correctly diagnosed with thorough prenatal and postnatal history and physical exam.

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. Lorazepam is often used for acute cases of neonatal seizures. It exerts its anticonvulsant in less than 5 minutes. Phenobarbital is often used as the first line long-acting anticonvulsant for neonatal seizures, followed by fosphenytoin and phenytoin. The only random clinical trial comparing the efficacy of phenobarbital and phenytoin for neonatal seizures has not found one to be superior than the other. Fosphenytoin is often preferred over phenytoin due to its water solubility and can be safely administered IV or IM, minimizing injury to muscles. Phenytoin is not absorbed from the neonatal GI tract making it impractical for long term outpatient use. About 45% of neonates respond to phenytoin or phenobarbital when used first line and 15% respond to the second agent. Other medications used include levetiracetam and topiramate (3,4,5).

Prognosis varies as a function of the primary etiology and gestational age of the infant. The background EEG activity is strongly correlated with outcome in both term and preterm infants (3). Infants with a normal background activity are less likely to have long term neurological sequelae as opposed to those with moderate to severe abnormalities such as multifocal electrographic discharges, prolonged electrographic seizures, and electrographic seizures that have spread to the contralateral hemisphere (3,5,7). Advancements in obstetrics and intensive neonatal unit has increased prognosis of neonatal seizures. Morality rate has greatly decreased from 40% to 20% (3).


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

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

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

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

5. Which of the following brain imaging studies would be the most sensitive in identifying intracranial abnormalities in the newborn such as congenital malformation, infarction, and hemorrhage?
   a. brain MRI
   b. brain ultrasound
   c. brain CT


References
1. Han JY, Moon CJ, Youn YA, Sung IK, Lee IG. Efficacy of levetiracetam for neonatal seizures in preterm infants. BMC Pediatr. 2018;18(1):131. doi:10.1186/s12887-018-1103-1
2. Padiyar S, Nusairat L, Kadri A, Abu-Shaweesh J, Aly H. Neonatal seizures in the U.S. National Inpatient Population: Prevalence and outcomes. Pediatr Neonatol. 2020;61(3):300-305. doi:10.1016/j.pedneo.2019.12.006
3. Mikati MA, Tchapyjnikov D. Chapter 611: Seizures in Childhood. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp: 3111-3116.
4. Niranjana N, Gospe SM. Chapter 65: Neonatal Seizures. In: Gleason CA, Juul SE (eds). Averyís Diseases of the Newborn. Tenth edition. 2018, Elsevier, Philadelphia, PA. pp: 961-970.e4
5. Ziobro J, Shellhaas RA. Neonatal Seizures: Diagnosis, Etiologies, and Management. Semin Neurol. 2020;40(2):246-256. doi:10.1055/s-0040-1702943
6. Soul JS. Acute symptomatic seizures in term neonates: Etiologies and treatments. Semin Fetal Neonatal Med. 2018;23(3):183-190. doi:10.1016/j.siny.2018.02.002
7. Ramantani G, Schmitt B, Plecko B, et al. Neonatal Seizures-Are We there Yet? Neuropediatrics. 2019;50(5):280-293. doi:10.1055/s-0039-1693149


Answers to questions
1.False, 2.False, since it is poorly absorbed from the infant GI tract, 3. D, 4. True, 5. A


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