20 Seizures in the Neonate

Adam L. Hartman¹ and Frances J. Northington²

¹ Divisions of Epilepsy and Pediatric Neurology, Neurosciences Intensive Care Nursery, Johns Hopkins Medicine Baltimore, MD, USA
² Division of Neonatology, Neurosciences Intensive Care Nursery, Neonatal Research Laboratory, Johns Hopkins Medicine, Baltimore, MD, USA

Introduction

Seizures are common during the neonatal period, occurring at a rate of approximately 2/1000 live births. Although the neonate with seizures may have an otherwise normal appearance, seizures reflect the presence of central nervous system pathology, such as hypoxic–ischemic injury. The presence of a seizure in a neonate should be considered an urgent condition requiring close monitoring and a thorough diagnostic evaluation for treatable and life-threatening conditions.

SCIENCE REVISITED

In the developed nervous system, GABA is considered an inhibitory neurotransmitter. However, in immature neurons, GABA can lead to depolarization (rather than hyperpolarization) due to reversals of the chloride gradient. It has been posited that this depolarizing effect of GABA contributes to the propensity for seizures during the neonatal period and may complicate treatment with drugs that target the GABAergic system.

Clinical features

Electroclinical seizures

The clinical features of neonatal seizures may involve focal clonic activity (unifocal or multifocal), focal tonic activity (which may involve limbs, trunk, or sustained ocular deviation), myoclonic activity, or spasms (either flexor, extensor, or both). Myoclonus may be either epileptic or nonepileptic, making it one of the more challenging semiologies to evaluate.

TIPS AND TRICKS

At the bedside, the most straightforward way to differentiate a seizure from other adventitious movements is to determine whether the suspicious activity can be provoked or, conversely, can be easily suppressed (i.e., by gently restraining the affected limb). In both cases, the likelihood of a seizure is decreased.

Classically, the EEG during neonatal seizures is associated with rhythmic sharp or sharply contoured slow activity that evolves from higher to lower frequencies, sometimes followed by postictal slowing (i.e., a typical ictal evolution). One variant that may be missed by automated EEG detection systems is low-amplitude, low-frequency activity with a typical ictal evolution. Most neonatal seizures last less than 5 min and originate in the central or temporal regions. According to one convention, in order to be labeled a seizure, ictal EEG changes must have a duration greater than 10 s. Some neonates have bursts of epileptiform activity that are brief in duration (i.e., >10 s), referred to as “brief rhythmic discharges” or BRDs. Although not typically treated as seizures, BRDs may be an indicator of other types of underlying pathology, including periventricular leukomalacia.

Electrographic seizures

It is not uncommon in the setting of a neonatal encephalopathy to observe on brain monitoring periods of abnormal activity that have a typical electrographic ictal evolution without clinical changes. These “electrographic-only” seizures typically portend a poor long-term outcome or death. There are a number of conditions associated with these “electrographic-only” seizures. The most obvious is that the neonate has been paralyzed (i.e., for ventilation) and is not capable of manifesting motor activity. The second reason is that the neonate has been sedated to the point that motor and/or autonomic changes have been masked (i.e., electroclinical dissociation). The third and most concerning reason is that the initial injury prevents the expected clinical manifestations from occurring. Occasionally, these circumstances may occur in combination.

Neonatal epilepsy syndromes

Although the distinction is rarely considered initially, there are both malignant and benign neonatal epilepsy syndromes. The malignant epilepsy syndromes include early infantile epileptic encephalopathy (EIEE, also known as Ohtahara syndrome) and early myoclonic encephalopathy (EME). The EEG in both syndromes shows a burst–suppression pattern. At the bedside, the distinction between these two syndromes is not always clear, and both share a poor prognosis in terms of seizures, development, and survival. Neonates with EIEE typically have frequent tonic spasms (i.e., hundreds per day) that may occur during the awake or asleep states. Myoclonic and partial seizures also can occur. The most common associated pathology is structural brain lesions, including hemimegalencephaly, porencephaly, and malformations of cortical development. Some patients have mutations in STXBP1, CDKL5, ARX, and other genes. Neonates with EME typically have recurrent myoclonic seizures but also can have focal seizures or tonic spasms. The most common associated pathologies are inborn errors of metabolism, including glycine encephalopathy and organic acidurias. Because of some overlap in signs and symptoms, with either electroclinical presentation, extensive genetic and metabolic testing is typically performed. In both EIEE and EME, the mortality rate is high in early infancy and survivors have poor neurodevelopmental outcomes. Seizures are highly resistant to treatment.

Fortunately, not all neonatal epilepsy syndromes are malignant. Benign familial neonatal seizures (BFNS), also known as “third-day fits,” are associated with mutations in KCNQ2 and KCNQ3. In most patients, seizures are focal or generalized and there may be associated apnea. The interictal EEG usually is normal. The ictal EEG shows a voltage decrement followed by spikes or slowing (either focal or generalized). Focal epileptiform activity is seen rarely. Other types of seizures may occur later in life.

CAUTION!

Not all patients with mutations in KCNQ2 have a benign course, although a malignant course is rare. Recently, mutations in KCNQ2 were found in neonates with treatment-resistant seizures. Unlike in “typical BFNS,” in this syndrome tonic seizures are prominent and the EEG has a burst–suppression pattern. Although the seizures may cease, many of the patients in the study were found later to have motor and intellectual disabilities.

The syndrome of benign idiopathic neonatal seizures (BINS) also is known as “fifth-day fits.” The seizures associated with this rare syndrome can include multifocal clonic seizures that may occur in clusters or be associated with apnea. Tonic–clonic seizures have been reported as having episodes of eye deviation and oral-motor movements. The interictal EEG may be normal but occasionally shows a pattern known as theta pointu alternant, which consists of theta-range activity with intermixed sharp activity (this may be asynchronous between hemispheres). Importantly, this pattern is nonspecific and may be seen in BFNS and in patients with seizures of other etiologies. Another variant, benign familial neonatal–infantile seizures, is associated with a positive family history of similar seizures. Seizure onset usually is at 2–3 months of age but can occur as early as 2 days of life. The seizure semiology usually is focal onset with secondary generalization, but apnea and cyanosis have been reported. This syndrome is associated with mutations in SCN2A, PRRT2, and ASC-1 genes (and possibly others), but seizures resolve after the first year of life.

Diagnosis

The goal of finding an underlying cause for neonatal seizures is to make a diagnosis with therapeutic or prognostic implications (Figure 20.1). Underlying causes of neonatal seizures include hypoxic–ischemic injury, infection (congenital or perinatal), metabolic abnormalities (both acute and inborn errors of metabolism), genetic abnormalities, hemorrhage, infarction, cortical dysgenesis, drug withdrawal, and neonatal epilepsy syndromes.

At a minimum, all neonates with seizures should have a neonatal montage EEG. The American Clinical Neurophysiology Society has released a guideline on continuous electroencephalography monitoring in neonates, citing continuous video–EEG monitoring as the gold standard for characterization of abnormal paroxysmal events. Many institutions also use amplitude-integrated EEG (aEEG) for prolonged monitoring if video–EEG resources are limited.

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