5
CHAPTER
Neonatal Seizures
William B. Gallentine
Seizures occur frequently in the newborn period, more commonly than in any other time period across the lifespan. They have been associated with increased mortality, adverse neurodevelopmental outcome, and increased risk of epilepsy later in life. Frequently, seizures in neonates are only detected by EEG as clear clinical behavior is often absent. This, along with the high rate of nonepileptic paroxysmal behaviors, makes continuous EEG monitoring imperative in the management of these patients. It is important to delineate the underlying etiology of neonatal seizures, as this often carries the greatest implications in regard to prognosis. It is very important to recognize that some etiologies do have specific disease-altering therapies, which can have profound impacts on outcome. Although these disorders are relatively rare, care should be taken not to miss them as the consequences in terms of neurologic sequelae can be great. Overall, current therapeutic options for neonatal seizures are quite limited. As such, there is a significant need for further studies in this area.
DIFFERENTIAL DIAGNOSIS
There are many paroxysmal nonepileptic behaviors that can occur in the neonate, which may be misinterpreted as clinical seizure activity. Table 5.1 provides a list of behaviors that may mimic seizures along with their distinguishing features. Continuous EEG monitoring is helpful in clarifying the nature of these events and prevents overtreating with antiepileptic drugs. In a child that is stable and not having clear epileptic events, if EEG can be obtained in a timely manner, delaying treatment for EEG confirmation is reasonable. Clinical behaviors that have a high correlation with electrographic seizure activity include recurrent rhythmic focal clonic activity and tonic gaze deviation, with or without associated nystagmus. Generalized tonic posturing is rarely associated with electrographic seizure activity, but often mistaken for seizure. Apnea associated with tachycardia is much more likely to be associated with seizure, rather than that of bradycardia. Although apnea is much more likely to be nonepileptic in etiology, it can be a sole seizure manifestation. Because these behaviors can be so difficult to clinically distinguish from seizure activity, continuous EEG monitoring is essential for activity characterization. Ultimately, less than half of the behaviors initially concerning for seizures in the neonatal intensive care unit are confirmed to be seizures by EEG.
EPIDEMIOLOGY AND RISK FACTORS
The true incidence of neonatal seizure has been difficult to estimate and varies greatly depending on the study. Traditionally, seizure incidence was reported based upon clinically observed abnormal behavior, without EEG. This premise has proven to be flawed, as it is now well known that many of the seizures occurring in this patient population are electrographic only. Thus, studies using clinical observation have grossly underestimated the true incidence. There is also a high rate of nonepileptic events that may be mistaken for clinical seizures without EEG confirmation. Prospective studies using continuous EEG monitoring are currently lacking and are needed to define the true incidence. Clinical seizure activity has been reported in 0.95–5.0/1000 and 13.5–57.5/1000 very-low-birth weight live births (1). Risk factors associated with seizures in neonates are listed in Table 5.2 (1,2).
EEG background patterns have proven to be a powerful tool in predicting both seizures and outcome in critically ill neonates. As it is important to recognize the normal EEG changes occurring every few weeks in the preterm infant in order to provide accurate background assessment, the normal maturation of the preterm infant EEG is discussed in Table 5.3. Mild (excessive discontinuity) to severe (burst suppression) EEG background abnormalities have been shown to be predictive of electrographic seizures (Table 5.2) (2). In general, isolated spikes and sharps in the neonatal EEG are not predictive of neonatal seizures, and only represent diffuse brain dysfunction.
TABLE 5.1 Differential Diagnosis of Paroxysmal Nonepileptic Behaviors in the Neonate
BEHAVIOR | CLINICAL FEATURES |
Jitteriness (recurrent tremors in extremities) | Occurs in sleeping and active awake infants (most pronounced in crying infants) in the first 3 days of life. Diminishes with passive flexion. Stimulus sensitive. Excessive jitteriness may be associated with hypoxic–ischemic encephalopathy (HIE), hypoglycemia, hypocalcemia, sepsis, and drug withdrawal. |
Benign neonatal sleep myoclonus | Occurs in normal infants. Rapid migrating jerks involving the distal extremities occurring only in sleep, resolving with arousal. Can be quite intense, and occur for long periods during sleep, leading to misdiagnosis of status epilepticus. EEG is normal. Occurs in the first few days of life and resolves at 4 months. |
Hyperekplexia (startle disease) | Excessive startle, with generalized rigidity, sometimes with tonic spasms with associated apnea, and even secondary hypoxic seizure. Can be triggered by nose tapping. Caused by genetic mutation in the presynaptic glycine receptor gene (GLRA1). Increased risk of sudden infant death syndrome. |
Cardiac arrhythmia | Often accompanied by cyanosis. |
Gastroesophageal reflux (Sandifer’s syndrome) | Opisthotonic posturing in association with feeding. Improves with treatment of reflux. |
Brainstem release phenomena | Decerebrate or decorticate posturing often occurring in neonates with diffuse HIE, with no EEG correlate. |
Other “normal baby movements” | Eye rolling, dysconjugate eye movement, hiccups, sucking, chewing, tongue thrusting. |
TABLE 5.2 Neonatal Seizure Risk Factors
Low birth weight <1500 grams Male sex Advanced maternal age >40 years Maternal history of gestational diabetes Evidence of perinatal hypoxia: fetal distress, placental abruption, cord prolapse Maternal intrapartum fever or infection Maternal substance abuse Moderate-to-severe EEG background abnormalities: excessive discontinuity, burst suppression, very low voltage or isoelectric |
Source: From Refs. (1,2).
ETIOLOGIES
A list the etiologies of neonatal seizures and neonatal epilepsy syndromes are provided in Tables 5.4 and 5.5. The most common causes include hypoxic–ischemic encephalopathy (HIE) (40%–60%), intracranial hemorrhage (7%–18%), ischemic stroke (6%–17%), congenital brain malformations (3%–17%), and CNS infections (2%–14%) (1). Although relatively uncommon, metabolic disturbances (3%–5%) such as hypoglycemia, hypocalcemia, hypomagnesaemia, and hyper/hyponatremia should be assessed for, as these are easily treated, and in some cases may result in secondary brain injury if left untreated (1). Withdrawal seizures from maternal drug use may also be a precipitant, including prolonged exposure to cocaine, alcohol, narcotics, and tricyclic antidepressants. Inborn errors of metabolism are an overall relatively rare cause of neonatal seizures, but should be suspected in patients without one of the more common etiologies, especially in those patients refractory to standard therapies. There are several vitamin-responsive epilepsies (pyridoxine, folinic acid, biotin, and pyridoxal-5-phosphate) encountered in this age group that are important to recognize as supplementation often results in improved seizure control. Glucose transporter deficiency (CSF/serum glucose ratio ≤0.45) is also crucial to diagnose as these patients have a relative shortage of CNS glucose to use as fuel. This typically results in epileptic encephalopathy with severe cognitive impairment, unless placed on the ketogenic diet, which has been very successful in treating both seizures and improving cognitive outcomes.
DIAGNOSTIC EVALUATION
In a neonate with suspected seizures, the first step is assessing for any life-threatening emergencies that would need to be addressed. This includes assessment for readily treatable metabolic causes (glucose, calcium, magnesium, sodium, and hypoxia), as well as assessment for infectious etiologies with blood work and lumbar puncture. In patients where seizure suspicion is high, performing some form of urgent neuroimaging (head ultrasound will suffice in most cases) to assess for neurosurgical emergencies is strongly recommended. The next step in the diagnostic evaluation is confirming that seizures are actually present with EEG. The American Clinical Neurophysiology Society (ACNS) has published high-risk clinical scenarios for which continuous EEG monitoring for seizure detection should be considered (Table 5.6) (3).
As 80% to 85% of patients have HIE, ICH, cerebral brain malformation, or CNS infection, etiology can be determined in most patients with neuroimaging and lumbar puncture (1). Once seizures have been controlled and the patient stabilized, MRI is the neuroimaging method of choice. If MRI is normal and there is no evidence of infection or acute metabolic disturbance, performing evaluation for inborn errors of metabolism and genetic disorders is warranted. Magnetic resonance spectroscopy (MRS) may be helpful in diagnosing mitochondrial and creatine disorders. Summary of the diagnostic work up is provided in Table 5.7.
