Neonatal and Pediatric Epilepsy Syndromes

Paul R. Carney

James D. Geyer

L. John Greenfield Jr

NEONATAL SEIZURES

Neonatal seizures are poorly classified and under-recognized, especially in critically ill neonates, and often difficult to treat. The immature brain is highly vulnerable to seizures, and seizure incidence is higher in the neonatal period than any other period of life.¹ Seizure incidence in term infants is 0.5-3 per thousand live births but up to 13% in low-birth-weight preterm infants.² Neonatal seizures are often the presenting clinical manifestation of underlying neurologic conditions such as hypoxic-ischemic encephalopathy (HIE), stroke, intraventricular or intraparenchymal hemorrhages, meningitis, sepsis, or metabolic disorders such as hypoglycemia, hypomagnesemia and hypercalcemia. Of these, HIE is the most common etiology, accounting for 50%-60% of patients with neonatal seizures, followed by intracranial hemorrhage (ICH), stroke, cerebral malformations and meningitis.²^,³ However, other disorders can have an early manifestation in the neonatal period such as neuronal migration disorders (eg, lissencephaly), TORCH infection, or catastrophic genetic epilepsies (early neonatal myoclonic encephalopathy, early infantile encephalopathy).

The neonatal brain is particularly vulnerable to seizure activity as a result of an imbalance of excitatory vs inhibitory circuitry. The imbalance favors excitation in order to facilitate important developmental processes that occur during the neonatal period, including synaptogenesis, apoptosis, progressive integration of neuronal circuitry, and synaptic pruning. The imbalance occurs anatomically and physiologically by an overexpression of NMDA receptors in the hippocampus and neocortical regions of the neonatal brain, as well as a delay in the maturation of the inhibitory system. In the developing brain, neurons in such regions as the hippocampus are excited rather than inhibited by the neurotransmitter GABA (normally the primary inhibitory neurotransmitter in the brain), due to differences in the expression pattern of chloride cotransporters. During infancy, the sodium/potassium/chloride cotransporter (NKCC1) predominates, which concentrates chloride in neurons, so that the opening of GABA_A channels results in the exit of negatively charged chloride from the cell, resulting in depolarization. In older children and adults, NKCC1 is replaced by the potassium/chloride cotransporter (KCC2), which extrudes chloride ions, so the opening of GABA_A channels causes chloride ions to rush into the neuron, resulting in hyperpolarization.

DIAGNOSIS OF SEIZURES

Video-EEG is the gold standard for distinguishing between seizures and other paroxysmal activities of the neonate. Prompt diagnosis and treatment can prevent neuronal cell death and brain injury. In addition to video-EEG monitoring, the workup for neonatal seizures should include a screen for infection including blood cultures and lumbar puncture, laboratory studies including glucose, electrolytes, arterial blood gas, liver function tests and ammonia, metabolic screening, TORCH titers, and drugs of abuse. Cranial ultrasound and other imaging modalities (head CT, MRI) are also helpful. Despite the advent of numerous anticonvulsants in the past 20 years, phenobarbital and fosphenytoin are still the first options to treat neonatal seizures. A trial of pyridoxine should be considered for any infant refractory to anticonvulsants.

NEONATAL SEIZURE SEMIOLOGIES

Neonatal seizures differ from those that occur in older children and adults and are often difficult to recognize and differentiate from either normal behaviors or abnormal movements that are not epileptic.¹ They do not fit well into the ILAE classification systems used for older children and adults. Several different classification systems have been proposed. Volpe’s classification² is based on clinical features only and divided into subtle seizures, clonic, myoclonic, and tonic, which are
discussed in more detail below. By contrast, Mizrahi and Kellaway⁴ proposed a system based on epileptic vs nonepileptic pathophysiology. Epileptic seizures include focal clonic, focal tonic, myoclonic, spasms, and electrographic (with no clinical correlate), while nonepileptic seizures include generalized tonic posturing and motor automatisms (similar to those considered subtle seizures in the Volpe classification).

In broad strokes, there are three types of clinical seizures in the neonate: tonic, clonic, and myoclonic. The first two have a simultaneous electrographic pattern, that is, abnormal EEG patterns occurring simultaneously with the clinical seizure behavior, an example of which is shown in Figure 12.1. Myoclonic seizures are not associated with an electrographic abnormality detected on EEG (other than motion artifact) and may be generated by subcortical structures. Subclinical seizures refer to electrographic seizure activity without clinical signs.

Electrographic seizures in neonates are typically required to last at least 10 seconds, and paroxysmal discharges shorter than 10 seconds are termed “BIRDS”—brief interictal rhythmic discharges. These are of uncertain significance but tend to correlate with the presence of seizures and can predict a poor neurodevelopmental outcome.¹^,⁵ Most neonatal seizures are self-limited and last 2-3 minutes.

Subtle Seizures

Subtle seizures are more common in premature infants. As the name suggests, the seizures may be difficult to identify, with only faint clinical signs including tonic horizontal eye movements, sustained eye opening, chewing, or apnea. In some cases, there may be “boxing” arm movements (brief flapping movements at the shoulder with extension at the elbow). These seizures may have limited EEG changes correlating with the seizure activity.⁶^,⁷^,⁸^,⁹

Clonic Seizures

Clonic seizures typically present as rhythmic, slow movements with a frequency of 1-3 Hz. Focal clonic seizures involve one side of the body, and the infant is not clearly unconscious. Multifocal clonic seizures involve several body parts, often in a migrating pattern. Generalized clonic seizures are rarely observed in newborns because of the incomplete myelination of the brain.⁶^,⁷^,⁸^,⁹

Tonic Seizures

Focal tonic seizures result in sustained posturing of the limb, trunk, or neck. These seizures are usually accompanied by ictal patterns on EEG. Generalized tonic seizures exhibit tonic extension of all limbs (mimicking decerebrate posturing) or tonic flexion of upper limbs and tonic extension of lower limbs (mimicking decorticate posturing). There are no EEG changes in 85% of cases, suggesting that generation of focal seizures involves a cortical region too small to generate signals detected by scalp EEG or that subcortical structures are involved.⁶^,⁷^,⁸^,⁹

Myoclonic Seizures

Focal myoclonic seizures usually involve flexor muscles of an upper extremity. Often, there are no EEG changes. Conversely, generalized myoclonic seizures exhibit bilateral jerks of both upper and lower limbs and may resemble infantile spasms. These generalized seizures are more likely to have EEG changes.⁶^,⁷^,⁸^,⁹

REVIEW

12.1: Which of the following is not true about neonatal EEG abnormalities?

a. Burst suppression or low-voltage EEGs suggest severe neurologic dysfunction

b. Asymmetry may reflect a focal cortical lesion or scalp edema

c. The most common etiology of neonatal seizures is meningitis

d. Myoclonic seizures may have no EEG correlate

e. Generalized seizures may mimic decorticate or decerebrate posturing

View Answer

12.1: c. The most common etiology of neonatal seizures is hypoxic ischemic encephalopathy (HIE).

NEONATAL STATUS EPILEPTICUS

Neonatal status epilepticus (NSE) refers to a state of prolonged clinical or subclinical seizure activity lasting longer than 30 minutes. In addition, a criterion in which 50% of a 1-hour EEG demonstrates electrographic seizures (ie, a total of 30 minutes of seizure activity within 1 hour) has been suggested to represent a more realistic definition of status epilepticus during the newborn period. This is particularly important as several authors have reported that up to 40%-80% of the total number of neonatal seizures can in fact be subclinical electrographic sequences.¹⁰ Therefore, it is important that continuous bedside video-EEG be performed when NSE is suspected.

Seizures are almost always of focal onset and any region of the neonatal brain can be involved. Ictal onset may migrate between different brain areas, a phenomenon called fast intraictal activation. Typically, the EEG will demonstrate multiple ictal morphologies (Fig. 12.2).

A variety of systemic and brain derangements can cause NSE (see Table 12.1). As for self-limited seizures, the most important cause of NSE is HIE, which may be present in 50%-60% of the cases. Seizures usually manifest in the first

12-24 hours of life. Focal cerebral infarctions, ICH, or subdural hematomas can also be the cause of NSE in up to 20% of cases. In patients with a germinal matrix hemorrhage with parenchymal involvement, there is a 50% risk of NSE.

FIGURE 12.1. Focal seizure in a 2-day-old neonate with SCN2a mutation, born at 39 weeks gestational age. Note limited lead placement. Seizure activity is predominantly at T4 with lesser amplitude at C4. (Figure generously provided by Dr. Mark Schomer.)

FIGURE 12.2. Same infant as in Figure 12.1. Sustained seizure lasting 10 minutes. Discharges are now bilateral with a left temporal emphasis. (Figure generously provided by Dr. Mark Schomer.)

TABLE 12.1 Etiologies of neonatal status epilepticus

Hypoxic-ischemic encephalopathy

Intracranial hemorrhage

Bacterial and nonbacterial meningitides

Water and electrolyte disturbances

Inadvertent scalp injections with local anesthetics

Disorders of cortical migration

Neurometabolic disorders

Meningitis is the second most common cause of NSE. Bacterial meningitides such as Escherichia coli, Listeria monocytogenes, and group-b streptococcal infections are the three most common etiologies. Nonbacterial meningitides including toxoplasma, herpes, coxsackie, rubella, and cytomegalovirus can also cause NSE.

Metabolic and electrolyte disturbances such as hypoglycemia, hyponatremia, hypocalcemia, or hypomagnesemia are the third most common cause. NSE may present within the first 3 days of life. The duration of the metabolic disturbance and the time elapsed to start treatment are prognostic factors for the development of NSE. The neonate usually has other warning signs such as jitteriness, irritability,
or stupor. Risk factors for hypoglycemic NSE are infants of diabetic mothers, small for gestational age, HIE, infection, or ICH. Neonatal hypocalcemia, usually accompanied by hypomagnesemia, can also cause NSE. Seizures stop once the deficit is corrected with IV infusions of calcium and magnesium. The abnormality is due to suboptimal phosphorus/calcium or phosphorus/magnesium ratio. DiGeorge syndrome and congenital hypoparathyroidism are less common causes of hypocalcemia and subsequent NSE.

Hyponatremia secondary to meningitis, ICH, HIE, inappropriate secretion of antidiuretic hormone (SIADH), or excessive water intake (diluted formula) or hypernatremia secondary to dehydration or sodium bicarbonate intoxication are also causes of NSE. Seizures may occur during correction of hypernatremia if hypotonic solutions are used due to iatrogenic intracellular edema.

Inadvertent scalp injections with local anesthetics during paracervical, pudendal, or epidural blocks for episiotomy are a rare cause of NSE. These accidents are commonly confused with HIE. However, anesthetic-induced NSE should be suspected if the following signs are present: pupils dilated and fixed to light, absent oculocephalic reflex, needle marks in scalp, and clinical improvement in 24-48 hours. The diagnosis can be confirmed with blood or cerebrospinal fluid drug levels.

Disorders of cortical neuronal migration are a less common cause of NSE, occurring in only 5%-10% of cases. Cortical dysgenesis, lissencephaly, pachygyria, and polymicrogyria are the most common. These inherited disorders are often called catastrophic epilepsies since the patients are frequently intractable to medical interventions. Neurometabolic disorders may present in the neonatal period with prolonged seizures and NSE. Nonketotic hyperglycinemia is an autosomal recessive disorder manifested by lethargy and pharmacoresistant seizures, secondary to a deficit of a glycine cleavage enzyme in CSF. The diagnosis is confirmed by documenting hyperglycinemia in CSF and serum. Despite significant advances in the understanding of this disorder, therapies are still limited to the use of sodium benzoate, which binds to glycine and forms hippurate, or dextromethorphan, which weakly inhibits excitatory N-methyl-D-aspartate receptors coactivated by glycine and glutamate. Antiepileptic drugs (AEDs) have a limited role, but benzodiazepines may be helpful. The prognosis in general is poor. Other neurometabolic disorders include sulfite oxidase deficiency, multiple carboxylase deficiency, multiple acyl-Co-A dehydrogenase deficiency, pyruvate dehydrogenase deficiency, cytochrome C oxidase deficiency, and peroxisomal disorders such as adrenoleukodystrophy or Zellweger disease.

Pyridoxine dependency is a rare cause of NSE, with fewer than 200 cases reported to date. The onset of symptoms is intrauterine, and the EEG shows generalized and multifocal interictal patterns. The patients usually do not respond to conventional AED therapy. However, cessation of seizures and other symptoms occurs within minutes after intravenous administration of 50-100 mg of pyridoxine. Although the pathophysiology is not well understood, it has been postulated that pyridoxine deficiency affects the metabolism of glutamate and causes abnormalities of brain formation such as hypoplasia of corpus callosum, brain atrophy, and poor myelination patterns. Pyridoxine is essential to produce the cofactor pyridoxal-5-phosphate that is required by the enzyme glutamic acid decarboxylase (GAD). GAD transforms glutamate into GABA; hence, the lack of pyridoxine results in reduced GABA synthesis. CSF from these infants shows low GABA and high glutamate levels. Lifetime pyridoxine supplementation at a dose of 5-10 mg daily can help prevent seizures.

Glucose transporter deficiency is another neurometabolic disorder characterized by pharmacoresistant NSE and developmental delay. The diagnosis is confirmed by documenting low CSF glucose and lactate with normal serum glucose levels. The ketogenic diet has a major role in seizure control. This therapy provides a source of energy that bypasses the glucose transporter. However, the ketogenic diet does not appear to prevent developmental delay, and patients will demonstrate variable degrees of cognitive impairment.

Finally, drug withdrawal should always be considered as a potential cause of NSE in the appropriate clinical setting. Intrauterine exposure to methadone, barbiturates, propoxyphene, tricyclic antidepressants, cocaine, and alcohol can result in withdrawal syndromes shortly after birth. Treatment of these withdrawal symptoms involves conventional AEDs to manage NSE, with additional therapy depending on the agent involved.

REVIEW

12.2: Which of the following is true about neonatal status epilepticus?

a. Neonatal status consists of seizure activity lasting at least 20 minutes.

b. Seizures usually have focal onset with multiple ictal morphologies.

c. The most common cause of neonatal status is intracranial hemorrhage.

d. Nonketotic hyperglycinemia is an autosomal dominant cause of resistant seizures.

e. Pyridoxine deficiency is a common cause of neonatal status.

View Answer

12.2: b. Neonatal status is defined as seizure activity lasting at least 30 minutes. The most common cause of neonatal status is HIE. Nonketotic hyperglycinemia is autosomal recessive. Pyridoxine deficiency is rare, with only about 200 cases reported.⁶³

NEONATAL AND CHILDHOOD EPILEPSY SYNDROMES WITH BENIGN PROGNOSIS

Benign Familial Neonatal Seizures

Benign familial neonatal seizures occur as a genetic disorder with an autosomal dominant inheritance pattern associated with chromosome 20q13.3. In some families, they are associated with specific mutations in the KCNQ2 and KCNQ3 M-type potassium channels.¹¹ The seizures typically start on day of life 2 or 3.
The neonate may have as many as 10-20 seizures per day. The syndrome is usually self-limited and benign, but ˜10% of cases progress to an AED-requiring seizure disorder. Neurologic development is normal.⁶^,⁷^,⁸^,⁹

Benign Idiopathic Neonatal Convulsions (5th Day Fits)

Fifth-day fits usually begin on day of life 4-6. The seizures are typically multifocal clonic seizures and are frequently associated with apnea. The interictal EEG shows “théta pointu alternant” in 60% of patients, with the remainder showing normal background activity or discontinuous background with focal or multifocal abnormalities.¹ Ictal recordings show unilateral or generalized rhythmic spikes or slow waves.¹ The seizures usually last for <24 hours. Fifth-day fits progress to status epilepticus in 80% of cases.⁶^,⁷^,⁸^,⁹ The etiology is unclear, but they have been attributed to neonatal rotavirus infection,¹² exposure to hexachlorophene handwash,¹³ and other causes. The syndrome now appears to be rare. The outcome is generally good, but there is risk of mild neurologic impairment.

Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus begins during the 1st week of life. The seizures are usually bilateral myoclonic jerks that last for several minutes and occur only during NREM sleep. The EEG is normal or slow. Seizures worsen with the administration of benzodiazepines. The seizures usually resolve within 2 months, and neurologic outcome is normal.⁶^,⁷^,⁸^,⁹

Benign Myoclonus of Early Infancy

Benign myoclonus of early infancy has an onset at age 3-9 months, but it can occur much earlier. The seizures resemble infantile spasms, but the EEG is normal. The seizures usually occur while the patient is awake. The seizure disorder may continue for 1-2 years, but neurologic outcome is normal.⁶^,⁷^,⁸^,⁹

Febrile Seizures

Febrile seizures occur in 2%-5% of infants and children between 6 months and 5 years of age, associated with fever without evidence of intracranial infection or other identifiable etiology. The risk of recurrence in children younger than 6 months is 4% but increases to 30% in children between ages 6 months and 3 years and drops back to 6% in children older than 3.

Febrile seizures can be divided into simple or complex depending on the duration of seizure, seizure type, and number of seizures during a 24-hour period (see Table 12.2).

Simple febrile seizures are relatively brief (<10-15 minutes) generalized tonicclonic seizures that do not recur during the same febrile illness. Complex febrile seizures are characterized by one of the following features: prolonged duration (>10-15 minutes), focal onset or focal neurologic symptoms, or multiple recurrences within 24 hours. A careful history will reveal complex features in approximately one-third of all febrile seizures presenting to the emergency department. The baseline EEG is unremarkable in most patients. The EEG in the immediate postictal period may have slowing of the background rhythm.

In a neurologically abnormal child, seizures in the context of a febrile illness are still considered simple or complex according to the above criteria. Although children who have preexisting neurologic abnormalities are more likely to present with complex febrile seizures and to develop subsequent epilepsy, they can also have simple febrile seizures. Children with abnormal neurologic exams may also have focal or generalized interictal discharges or slowing on EEG.

Multiple studies have demonstrated that chronic antiseizure medications are not effective for preventing febrile convulsions and may have adverse cognitive and developmental effects. However, acute benzodiazepines at the time of fever may be helpful in patients with a history of febrile convulsions who develop a febrile illness. Most patients with febrile convulsions do not develop lifelong recurrent seizures
after childhood, though a history of febrile convulsions is more common in adult patients presenting with focal seizure disorders like temporal lobe epilepsy (TLE) than in the general population.

TABLE 12.2 Simple and complex febrile seizures

Simple Febrile Seizures	Complex Febrile Seizures
Generalized tonic-clonic Duration <15 min No recurrence within 24 h	Focal Duration more than 15 min Two or more seizures within 24 h

CHILDHOOD SYNDROMES WITH ADVERSE PROGNOSIS

Early Myoclonic Encephalopathy

The onset of symptoms is typically before 3 months of age. Usually there are several different types of seizures, such as fragmentary myoclonic and focal seizures. The EEG typically shows suppression bursts evolving to a hypsarrhythmia pattern (see Fig. 9.11). Nonketotic hyperglycinemia is a typical cause of this syndrome (see Fig. 12.3). The pregnant mother may report excessive fetal hiccupping or even intrauterine seizures. The baby remains sleepy or lethargic most of the time. As noted above, mutations in the enzymes responsible for glycine cleavage lead to severe hyperglycinemia in the CSF, resulting in excessive neuronal excitation via NMDA receptors. Treatments include dextromethorphan or ketamine to block NMDA receptors or sodium benzoate to reduce glycine levels. For other causes of early myoclonic encephalopathy (EME), seizures may be resistant to treatment, and mortality is up to 50% before age 1 year.

FIGURE 12.3. Early myoclonic encephalopathy. The EEG from a patient with nonketotic hyperglycinemia shows a suppression-burst pattern with multifocal sharp waves, primarily left temporal in this example.

Infantile Spasms

Infantile spasms (IS) consist of a jackknife flexion movement at the waist or hips and associated myoclonus involving the arms or head. The spasms begin suddenly, often at the onset of sleep, upon awakening or feeding, and frequently present in clusters that can last 10-20 minutes. Since similar seizures occur in patients older than infancy, the term “epileptic spasms” is now preferred by the International League Against Epilepsy (ILAE). Several other conditions cause behavioral “spasms” that can easily be confused with IS, including colic, acid reflux, and focal seizures of infancy, though a video brought in by a parent may be diagnostic even prior to video-EEG recording.

IS can be classified according to the etiology. Symptomatic IS are those in which a preexisting cause or condition is readily identified such as hemorrhage at birth, HIE, or cerebral dysgenesis. Idiopathic or cryptogenic IS refers to patients who had a normal neurologic exam and development before onset of seizures.

IS seizures are one of the three diagnostic criteria of West syndrome. The other two are arrest of cognitive developmental and a hypsarrhythmia EEG pattern. West syndrome typically begins between 3 months and 3 years of age, with peak age of onset at 6 months.¹⁴^,¹⁵^,¹⁶ The degree of intellectual disability varies according to the age of onset and etiology of the spasms. West syndrome is not a single disorder but a pattern of symptoms associated with a variety of other neurodevelopmental conditions including trauma, brain malformations such as hemimegalencephaly or cortical dysplasia, infections, Down syndrome, tuberous sclerosis complex (TSC), Sturge-Weber syndrome, incontinentia pigmenti, pyridoxine deficiency, nonketotic hyperglycemia, maple syrup urine disorder, phenylketonuria, mitochondrial encephalopathies and biotinidase deficiency, Ohtahara syndrome, and X-linked disorders including gene mutations in ARX, a homeobox transcription factor, or CDKL5, a protein kinase.¹⁷ Aicardi syndrome is another X-linked neurodevelopmental disorder present from birth, which can present with infantile spasms, though alternating hemiconvulsions may also be seen. The clinical features of Aicardi syndrome include coloboma, chorioretinal lacunae, agenesis of the corpus callosum, vertebral anomalies, and seizures.¹⁸ A specific cause for West syndrome can be identified in ˜70%-75% of those affected.¹⁷

The interictal EEG in West syndrome consists of a hypsarrhythmia pattern with bursts of asynchronous slow waves, spikes, and sharp waves alternating with a suppressed EEG.¹⁹ The spasms are typically associated with bursts of generalized paroxysmal fast activity (GPFA, a low-amplitude rhythmic beta at about 18-25 Hz) followed by a sudden drop in voltage known as an “electrodecremental event” that
can last several seconds (Fig. 12.4). Sometimes only the voltage drop and loss of interictal activity are seen.

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