Seizure classification, etiology, and management

Handbook of Clinical Neurology, Vol. 162 (3rd series) Neonatal Neurology L.S. de Vries and H.C. Glass, Editors https://doi.org/10.1016/B978-0-444-64029-1.00017-5 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 17

Seizure classification, etiology, and management  A. SHELLHAAS* RENEE Department of Pediatrics, Division of Pediatric Neurology, University of Michigan, Ann Arbor, MI, United States

Abstract The first weeks of life are a time of heightened risk for seizures due to age-dependent physiologic features of the developing brain that lead to increased neuronal excitation and decreased inhibition. Usually, seizures in neonates are a symptom of an acute brain injury; seizures are only rarely due to neonatal-onset epilepsy syndromes. Neonatal seizures are harmful to the developing brain; early and accurate diagnosis is critical. For suspected seizures, EEG monitoring should be initiated as soon as is feasible, in order to evaluate for events of concern, screen for subclinical seizures, and assess the EEG background. Amplitude-integrated EEG can provide excellent complementary data, particularly with regard to evolution of background patterns, but has limited sensitivity to detect individual neonatal seizures. An urgent and systematic approach to precise etiologic diagnosis is key for optimal management and estimates of prognosis. Evaluation of the seizure etiology must occur in parallel with initiation of appropriate treatment. It is critical that neonatologists and neurologists develop hospital-specific, consensus-based practice pathways for neonatal seizure evaluation and treatment. Such practice pathways can streamline medical decision making, facilitate rapid medication administration, and potentially decrease seizure burden and optimize outcomes. Herein, the pathophysiology, epidemiology, treatment, and long-term management considerations for neonatal seizures are presented.

INTRODUCTION Seizures are one of the most common neurologic emergencies in neonates. Most seizures that occur in the first days of life are symptomatic of an underlying acute central nervous system insult, such as hypoxic–ischemic encephalopathy, intracranial hemorrhage, stroke, infection, or electrolyte disturbances. Therefore, seizure diagnosis, management, and investigation of the underlying etiology must all occur simultaneously. In this chapter, we review the underlying pathophysiology that predisposes neonates to seizures, seizure classification, the most common neonatal seizure etiologies, and the approach to management.

PATHOPHYSIOLOGY The lifetime risk of seizures is highest during the neonatal period (Annegers et al., 1995). Particular susceptibility of the neonatal brain to seizures is related to age-dependent

physiologic features of the brain that lead to increased excitation (via the glutamatergic system) and decreased inhibition (through gamma-amino-butyric acid, GABA) (Jensen, 2009; Nardou et al., 2013). In the mature brain, GABA is the primary inhibitory neurotransmitter; GABAA receptor activation results in chloride influx, which leads to hyperpolarization of the neuronal cell membrane and inhibits action potential firing. In contrast, GABAA receptor activation in immature neurons results in a net efflux of chloride, with resultant membrane depolarization and increased action potential firing. This change in GABAA effect is mediated by a developmental shift in the neuronal chloride gradient via ion transporters (NKCC1 and KCC2) (Dzhala and Staley, 2003; Khazipov et al., 2004; Dzhala et al., 2005). One might surmise that GABAergic medications (barbiturates and benzodiazepines) would

*Correspondence to: Renee Shellhaas, M.D., M.S., Pediatric Neurology, C.S. Mott Children’s Hospital, Room 12-733; 1540 E. Hospital Dr, Ann Arbor, MI, 48109-4279, United States. Tel: +1-734–936-4179, Fax: +1-734-763-7551, E-mail: [email protected]

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therefore cause worsening of seizures in newborns. However, approximately half of neonates respond to initial doses of phenobarbital (Painter et al., 1999; Glass et al., 2016). This suggests that GABAergic agents are inhibitory (and therefore have antiseizure effects) for some population of neurons in the newborn. Glutamate receptors also have developmental changes that favor excitability in the newborn brain. Not only are N-methyl-D-aspartate (NMDA) receptors abundant in the developing brain, but they have increased NR2B, NR2D, and NR3A subunits, compared to mature neurons. This combination of subunits results in increased NMDAreceptor-mediated calcium influx and is thought to be necessary for synaptogenesis in the developing brain but also to heighten susceptibility to seizures. The configuration of AMPA receptors in newborn infants (increased GluR1 and decreased GluR2 subunits compared to mature brains) also favors calcium influx and longer current durations (Rakhade and Jensen, 2009).

SEIZURE CLASSIFICATION Etiology classification Acute symptomatic seizures: Most seizures in newborns can be accurately classified as acute symptomatic seizures (epidemiology and specific symptomatic etiologies are discussed later in this chapter). These seizures are usually consequences of a specific identifiable brain injury, such as hypoxic–ischemic encephalopathy, stroke, and intracranial hemorrhage (see Table 17.4 for more details). As such, neonatal seizures are usually correctly conceptualized as distinct from the epilepsies. The most appropriate treatment and prognostic indicators depend on the underlying etiology, as discussed elsewhere in this chapter.

Neonatal-onset epilepsies: About one in eight newborns with seizures has neonatal-onset epilepsy (Shellhaas et al., 2017b). These individual syndromes are rare, but together they form a sizeable fraction of neonatal seizures. The most common neonatal-onset epilepsies are outlined in the following list. (a) Benign familial neonatal epilepsy is typically caused by variants in voltage-gated potassium channel genes (KCNQ2 or KCNQ3). This epilepsy is inherited in an autosomal dominant manner. Neonates have focal seizures (often of tonic semiology) but are otherwise healthy and their interictal EEG is normal. They usually have a family history of neonatal seizures. The seizures typically resolve in early infancy, but children remain at risk for other epilepsy syndromes later in life (Grinton et al., 2015). (b) Benign idiopathic neonatal seizures (BINS, previously known as fifth-day fits) is a syndrome characterized by short-lived seizures that present during the 4th through 6th days of life in otherwise healthy-appearing neonates who do not have a family history of similar seizures. These seizures resolve within weeks and the long-term prognosis is excellent. Recently, an association between BINS and rotavirus infection has been reported (summarized in (Yeom and Park, 2016)). (c) Epilepsy related to brain malformations (focal cortical dysplasia, lissencephaly, hemimegalencephaly, etc.) can range from syndromes with relatively infrequent seizures to severe epileptic encephalopathy with infantile spasms. Classically, the latter is referred to as Ohtahara syndrome or early infantile epileptic encephalopathy (Table 17.1) and is associated with a burst suppression EEG pattern during both

Table 17.1 Early myoclonic epilepsy (EME) vs. Early infantile epileptic encephalopathy (EIEE) EME Etiology

Inborn errors of metabolism Genetic Unknown Seizure onset Neonatal Neurologic status at Abnormal from birth or increasingly abnormal presentation after seizure onset Hallmark seizure semiology Erratic myoclonus Interictal neonatal EEG Burst suppression, especially during sleep Natural history Progressive neurologic impairment High risk of infantile spasms High risk of death in infancy

EIEE Cerebral dysgenesis Genetic Unknown Within 3 weeks of life Abnormal prior to seizure onset Tonic spasms Burst suppression, during wakefulness and sleep Static neurologic impairment High risk of infantile spasms and, later, Lennox–Gastaut syndrome High risk of death in infancy or childhood

SEIZURE CLASSIFICATION, ETIOLOGY, AND MANAGEMENT wakefulness and sleep. Recent reports suggest that these infants may be more susceptible than those with other neonatal-onset epilepsies to have comorbid systemic illnesses (e.g., sepsis, hypoxic–ischemic encephalopathy) that may exacerbate their seizures (Shellhaas et al., 2017b). (d) Epilepsy related to inborn errors of metabolism often presents with erratic myoclonus, encephalopathy, and an EEG with burst suppression during sleep. This constellation of clinical features is the hallmark of early myoclonic epilepsy (Table 17.1). A variety of inborn errors of metabolism are associated with early myoclonic epilepsy. Prompt diagnosis is critical, in order to reverse the metabolic derangement and minimize permanent brain injury. Nonketotic hyperglycinemia, propionic acidemia, molybdenum cofactor deficiency, sulfite oxidase deficiency, Menkes disease, Zellweger syndrome, and pyridoxine dependency are all included on the differential diagnosis list. (e) Neonatal epileptic encephalopathies without severe neuroimaging abnormalities are increasingly recognized. These are usually due to variants in known epilepsy genes. The most common is KCNQ2 encephalopathy, which manifests as severe neonatal-onset epilepsy with presentation in the first week of life. Neonates have encephalopathy, hypotonia, and treatment-resistant

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seizures with tonic semiology, along with a markedly abnormal EEG (Numis et al., 2014; Vilan et al., 2017).

Semiology classification Most neonatal seizures are clinically silent, since nonverbal infants cannot express sensory phenomena associated with seizures. Unless the ictal discharge affects the motor cortex, no stereotyped movements will occur. Thus, the majority of neonatal seizures are defined simply by their electroencephalographic (EEG) signatures. Seizures without overt clinical signs are termed EEG-only, or subclinical, seizures. Paroxysmal events that do not have EEG correlate (when EEG is being recorded) are very common in neonates. Although such events may be signs of neurologic dysfunction, they cannot be considered seizures (Clancy, 2006). The primary principles of the International League Against Epilepsy (ILAE) classification of seizure semiologies can be applied to neonates (Fisher et al., 2017); however, seizures in the newborn are recognized as distinct from those manifest in older children and adult. Separate ILAE committees are working to provide standardized classifications for neonatal seizures. A typical electroclinical neonatal seizure manifests as a pattern of movements or behaviors that evolve over time during the seizure. The most reliable clinical semiologies are focal clonic and focal tonic seizures (Table 17.2).

Table 17.2 Clinical manifestations of neonatal seizuresa Semiology

Features

Etiology

Comments

Focal clonic

Repetitive, rhythmic contractions of limb, face, or truncal muscles

May be unifocal, hemiclonic, migratory, or multifocal

Focal tonic

Sustained asymmetric limb posture

Myoclonic

Brief, sudden, rapid contractions of limb, trunk, or facial muscles (generalized, focal, or fragmentary) Sustained symmetric tonic stiffening of the limbs and trunk, which may be followed by jerking movements Flexor, extensor, or mixed spasms typically occur in clusters Tonic eye deviation, apnea, sucking, chewing, swimming, bicycling movements, complex purposeless movements

Most common clinical seizure semiology; seen in acute symptomatic seizures and in neonatal-onset epilepsies Often seen in neonatal-onset epilepsies May be seizures or nonseizure events

Generalized tonic or tonic–clonic

Infantile spasms Other signs

a

Usually not seizures in neonates

Rare semiologic feature of neonatal-onset epilepsies In isolation, without other associated motor manifestations, these are rarely seizures

Note: most neonatal seizures are subclinical (e.g., they have no external clinical manifestation).

Can also involve the trunk Myoclonic seizures are associated with inborn errors of metabolism and with some neonatal-onset epilepsies

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Focal clonic seizures: The most commonly recognized seizure semiology consists of rhythmic, repeated contractions of limb, face, or trunk muscles. The clonic jerks are typically slower than the movements associated with clonus or tremors in a neonate. Additionally, nonseizure movements like clonus or tremor are usually suppressible with gentle restraint, while clonic jerks from seizures continue even when gentle restraint is applied. Often, each clonic jerk corresponds to a time-locked EEG sharp wave; as such, the electroencephalographer must carefully evaluate whether the EEG feature is an artifact related to rhythmic movement or is an electrographic seizure. Clonic seizures may have various patterns of evolution. Unifocal seizures affect only one limb or motor group. Migratory seizures begin in one body area and later move to involve a different muscle group or alternate between sides of the body. Migration of the clonic pattern can be Jacksonian (spread along the cortical homunculus resulting in an evolution from the limb to the face and trunk, or vice versa) or can be less regular. Multifocal seizures involve more than one area simultaneously, but the jerking rhythm is asynchronous. Multifocal clonic seizures may be misinterpreted as generalized seizures, but true generalized-onset seizures are extremely rare in neonates (Korff and Nordli, 2005). Focal tonic seizures: Focal tonic seizures are somewhat less common than focal clonic neonatal seizures. They are a feature of several neonatal epilepsy syndromes, so prominent focal tonic semiology should raise concern for epilepsy rather than an acute symptomatic cause of the seizures. Focal tonic seizures are manifest as sustained asymmetrical stiffening of the limb or trunk, sometimes with associated tonic eye deviation, with an accompanying focal EEG signature. Myoclonic seizures: Neonatal myoclonic seizures are manifest as brief contractions of muscle groups in the limbs, trunk, or face. These may occur synchronously or erratically and may be focal, generalized, or fragmentary. Generalized myoclonic seizures tend to be symmetric jerks of all extremities and the trunk. Fragmentary myoclonus is typically characterized by asynchronous, rapid twitching of distal muscle groups and is often nonseizure in etiology. The most common etiology of myoclonic movements in neonates is benign neonatal sleep myoclonus; this can be diagnosed in the context of an otherwise healthy newborn whose myoclonus resolves when the infant is awake. In contrast, myoclonus can be associated with inborn errors of metabolism and with early myoclonic epilepsy of infancy (Yamamoto et al., 2011). In those instances, the myoclonus is not always epileptic (e.g., does not have an associated EEG seizure discharge). Yet, the myoclonus is typically associated with other clear seizure types.

Epileptic spasms: Epileptic spasms are not associated with acute symptomatic neonatal seizures, but with rare forms of neonatal-onset epilepsy. Spasms typically involve the muscles of the trunk and extremities and can be flexor, extensor, or mixed. They usually occur in clusters as an infant falls asleep or awakens. The corresponding EEG pattern generally consists of a high amplitude, diffuse sharp wave or spike, followed by a brief period of profound attenuation (an electrodecrement). Autonomic semiologies: Paroxysmal changes in heart rate, respiration, and blood pressure, flushing, salivation, and pupillary dilatation have been reported as elements of neonatal seizure semiology. However, these features are virtually never true electroclinical seizures if they occur in isolation. When they are associated with seizures, autonomic features typically have concomitant motor manifestations (e.g., apnea with associated tonic eye deviation) (Dang and Shellhaas, 2016). Electroclinical dissociation: It is common for neonates who have electroclinical seizures (EEG seizure with clearly associated clinical signs) to lose the clinical semiology after treatment is initiated. In this scenario, EEG seizures may continue for some time despite resolution of the clinical seizures. This is called electroclinical dissociation (Boylan et al., 2002; Scher et al., 2003). Status epilepticus: The definition of status epilepticus is different for newborns than for older infants and children. The classical definition of a continuous seizure lasting longer than 30 min remains valid, but individual neonatal seizures are almost never this prolonged (Shellhaas and Clancy, 2007). Additionally, for older patients status epilepticus can be characterized as a series of seizures without return to baseline mental status between the clinical events. A return to baseline mental status is very difficult to discern in a sick newborn infant. Thus, a different definition is widely adopted: neonatal status epilepticus is defined as
50% of a 1-h EEG epoch comprised of seizures (Tsuchida et al., 2013). Thus, a newborn with three 10-min seizures in 1 h has status epilepticus, and so does a neonate with 60 30-s seizures in 1 h. Identification of status epilepticus in the neonates is important, as it has implications for treatment and for prognosis (Uria-Avellanal et al., 2013).

EPIDEMIOLOGY Incidence of neonatal seizures The true incidence of seizures in neonates is challenging to discern. Most population-based studies are based on clinical diagnosis of neonatal seizures, without EEG confirmation. The overall incidence is reported as 1–4 per 1000 live births, with much higher risk among preterm and low birth-weight neonates (Table 17.3).

Table 17.3 Summary of neonatal seizure incidence data Overall incidencea

NBW/term

<36 week

<2500 g

VLBW

National Collaborative Perinatal Project Database Discharge records

5.0

—

29.5

31

—

2.84

2.4

—

9.4

—

Birth certificates Hospital records Trained NICU clinicians Birth and death certificates Birth certificates Hospital records

3.5

3.6

—

18.6

57.5

2.6

2.0

11.1

13.5

—

1.8

1.4

4.85

5.6

19

0.95

—

—

—

—

Reference

Birth years

Study design

Study location

Data source

Holden et al. (1982)

1959–1966

Lanska and Lanska (1996) Lanska et al. (1995)

1980–1991

Prospective enrollment of mothers, retrospective infant chart review Retrospective

1985–1989

Retrospective

USA National Collaborative Perinatal Project National Hospital Discharge Survey Fayette County Kentucky

Ronen et al. (1999)

1990–1994

Prospective

Newfoundland Canada

Saliba et al. (1999)

1992–1994

Harris County Texas

Glass et al. (2009b)

1998–2002

Retrospective and Prospective Retrospective

a

Per 1000 live births. NBW, normal birth weight; VLBW, very low birth weight.

California

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Boys are more often affected than girls and AfricanAmerican neonates have consistently been reported to have higher risk than infants of other races (Saliba et al., 2001; Glass et al., 2009b). Clinical seizures are usually diagnosed during the first 2 days of life, with >70% of seizures reported in large epidemiologic studies beginning within the first week after birth (Ronen et al., 1999; Saliba et al., 2001; Glass et al., 2009b). Most neonatal seizures are brief (60% lasted less than 90 s in one EEG-based study) (Shellhaas and Clancy, 2007). Status epilepticus is a clinically important problem, as it affects up to 16% of neonates with seizures who are systematically monitored with EEG (Glass et al., 2016) and is a risk factor for adverse outcomes (Uria-Avellanal et al., 2013).

Etiologies of acute symptomatic neonatal seizures Most neonatal seizures are a reflection of acute brain injury. Precise diagnosis of the seizure etiology is key to optimal management and estimates of prognosis. The advent of EEG monitoring, advanced neuroimaging, and metabolic and genetic testing has improved precision of etiologic diagnoses. Yet, even with the most sophisticated testing up to 9% of neonates may have uncertain etiologies (Glass et al., 2016). A summary of the reported profiles of neonatal seizure semiologies from seven large studies is presented in Table 17.4. Hypoxic–ischemic encephalopathy (HIE) is the most common neonatal seizure etiology. HIE causes about

40% of all neonatal seizures (Tekgul et al., 2006; Weeke et al., 2015; Glass et al., 2016). Therapeutic hypothermia is now the standard of care as a neuroprotective strategy for neonates >36 weeks with HIE (Jacobs et al., 2013). Although cooling is reported to decrease seizure burden, in a multicenter study of neonates monitored with continuous neonatal EEG, about half of all cooled neonates with HIE were found to have seizures (Glass et al., 2014). Therefore it is recommended that all neonates with HIE receive continuous conventional EEG monitoring during therapeutic hypothermia and rewarming (Shellhaas et al., 2011). In instances where conventional EEG is not feasible, amplitude-integrated EEG monitoring is suggested. Stroke is the next most common neonatal seizure etiology and accounted for 18% of all seizures in a large prospective cohort (Glass et al., 2016). Arterial ischemic stroke occurs in about 1 in 2300–5000 live births (Raju et al., 2007) and seizures are the most common presenting sign (Kirton et al., 2011). About two-thirds of arterial ischemic perinatal strokes involve the left middle cerebral artery territory, and most are caused by embolism from the placenta, the umbilical cord, or the heart. Congenital heart disease, systemic infections, thrombophilia, placental abnormalities, and male sex are the most common neonatal risk factors for arterial ischemic stroke. Maternal risk factors include chorioamnionitis, premature rupture of membranes, oligohydramnios, preeclampsia, diabetes, and smoking (Kirton et al., 2011; Darmency-Stamboul et al., 2012; Harteman et al., 2012; Martinez-Biarge et al., 2016). Arterial ischemic

Table 17.4 Profile of neonatal seizure etiologies

HIE Stroke Intracranial hemorrhage Metabolic or electrolyte disturbances Infections Congenital CNS malformations Inborn errors of metabolism Genetic epilepsy syndromes Unknown

Glass et al. (2016) 2013–2015 N ¼ 426

Weeke et al. (2015) 2009–2013 N ¼ 378

Loman et al. (2014) 2002–2009 N ¼ 221

Pisani et al. (2007) 1999–2004 N ¼ 106

Tekgul et al. (2006) 1997–2000 N ¼ 89

Mastrangelo et al. (2005) 1990–1998 N ¼ 94

Ronen et al. (1999) 1990–1994 N ¼ 89

38% 18% 12% 4%

46% 10.6% 12.2% 4.7%

57.5% 7.7% 9.0% 10.9%

43.4% — 23.6% 6.6%

40% 18% 17% 3%

44.7% 7.4% 4.3% 3.2%

40% 7% 11% 19%

4% 4%

7.1% 2.9%

6.3% 3.2%

7.5% 5.7%

3% 5%

10.6% 9.6%

20% 10%

3%

4.2%

2.3%

6.6%

1%

7.4%

—

9%

2.1%

2.3%

—

—

5.3%

6%

9%

6.3%

0.5%

6.6%

12%

1.1%

14%

CNS, central nervous system; HIE, hypoxic–ischemic encephalopathy.

SEIZURE CLASSIFICATION, ETIOLOGY, AND MANAGEMENT stroke should be considered when a neonate presents with unifocal seizures, especially if the EEG pattern over the contralateral hemisphere is relatively normal. Intracranial hemorrhage is a common seizure etiology in preterm neonates, given their risk for intraventricular hemorrhage (Sheth et al., 1999; Glass et al., 2017). Intracranial hemorrhages in term newborns can be caused by vascular malformations, coagulopathy, or trauma. Term neonates with intraventricular hemorrhages should be evaluated for coexisting venous sinus thrombosis. Brain MRI (with MR angiogram and venogram) and head ultrasound, are the preferred imaging modalities. Prompt neurosurgical consultation is indicated when an intraparenchymal hemorrhage is detected, or if there is concern for posthemorrhagic hydrocephalus. Notably, many healthy neonates will have small subarachnoid or subdural hemorrhages related to labor and delivery, without any associated clinical signs. Such small hemorrhages should not be assumed to be the primary reason for seizures and additional evaluation should be completed. Cerebral venous sinus thrombosis is relatively rare (1–2.7 per 100,000 neonates) and usually involves the superior sagittal or transverse sinuses in full-term neonates and the medullary veins in premature newborns (Berfelo et al., 2010). Risk factors for cerebral venous sinus thrombosis are similar to those for arterial ischemic strokes, in addition to dehydration and sepsis. Many affected neonates will have a combination of risk factors (Jordan et al., 2010). The associated seizures often arise from the midline vertex region (near the sagittal sinus); hence, if seizures consistently originate in the vertex EEG electrodes, it is reasonable to consider the possibility of sagittal sinus thrombosis. Diagnosis is by MR-venogram. Treatment is supportive, with hydration, antibiotics (if indicated), and antiseizure medications. For many neonates, anticoagulation is appropriate treatment (Berfelo et al., 2010). Caution should be exercised for neonates with sinus thrombosis and comorbid diffuse brain injury, as anticoagulation may precipitate clinically important intracranial hemorrhage (especially subdural hematomas) (Dang et al., 2014). Systemic or central nervous system infections are the third most common neonatal seizure etiologies. These infections include congenital viral infections, such as herpes simplex virus (HSV), cytomegalovirus (CMV), parechovirus, lymphocytic choriomeningitis virus (LCMV), disseminated enterovirus, rotavirus, and parvovirus. Affected children typically have multisystem disease. Notably, some viral infections can result in congenital brain malformations, as highlighted recently by the epidemic of congenital Zika virus infections in Brazil (Baud et al., 2017). Bacterial infections

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are classically due to Group B streptococcus and Escherichia coli. Since meningoencephalitis is such a common cause of neonatal seizures, a lumbar puncture is recommended for all newborns with seizures and suspected infection. If the neonate is not stable enough for a lumbar puncture, empiric treatment with antibiotics and antiviral medications are necessary. Reversible metabolic disturbances cause a minority of neonatal seizures, but should not be missed since they are potentially completely treatable. Usually, normalization of glucose, calcium, or sodium levels will result in resolution of the acute seizures, while antiseizure medications are likely to fail to control seizures in this context. Neonates with severe, persistent hypoglycemia (<45 mg/dL in term neonates, <30 mg/dL in preterms) may have associated brain injury. When this occurs, the injury is usually maximal in the posterior brain quadrants and is not completely reversible (Boardman et al., 2013). Such infants often require both glucose management and antiseizure medications. Risk factors for neonatal hypoglycemia include maternal diabetes and small for gestational age status, especially when the newborn also has systemic illness or feeding difficulties. Hypocalcemia (based on free ionized calcium level) can occur in the first days of life for neonates whose mothers had diabetes, and those with low birth weight, hypoxic–ischemic encephalopathy, or endocrinopathies. Hypocalcemia after the first week of life is seen in DiGeorge syndrome, maternal vitamin D deficiency or maternal hyperparathyroidism. Hyponatremia or hypernatremia can occur if a neonate’s formula is mixed incorrectly, the infant is severely dehydrated or was extremely premature, or has severe intracranial injury. Severe hyponatremia may result in cerebral venous sinus thrombosis. Incompletely reversible metabolic disorders (e.g., pyridoxine dependency, nonketotic hyperglycinemia, and many others) are also important causes of neonatal seizures (see Neonatal-Onset Epilepsies, previously).

EVALUATION OF A NEONATE WITH SUSPECTED OR CONFIRMED SEIZURES Neonatal seizures are a medical emergency, since they are usually a reflection of a severe underlying neurologic condition. The evaluation and treatment of a newborn with suspected seizures must occur simultaneously. Initial assessment for vital signs must be followed by immediate measurement of glucose and electrolytes. EEG monitoring should be initiated as soon as is feasible, in order to evaluate for events of concern, screen for subclinical seizures, and assess the EEG background. The American Clinical Neurophysiology Society has

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published guidelines on neonatal conventional EEG monitoring. It is recommended that neonates with known or suspected acute brain injury, combined with encephalopathy, be monitored with 24 h of video EEG to evaluate for seizures. Other indications for EEG monitoring include characterization of abnormal paroxysmal events and screening in high-risk clinical scenarios (Shellhaas et al., 2011). Whenever available, conventional, multichannel EEG monitoring is the preferred modality. Amplitude-integrated EEG can provide excellent complementary data, particularly with regard to evolution of background patterns, but has limited sensitivity to detect individual neonatal seizures (Glass et al., 2013). If infection is suspected, blood, urine, and cerebrospinal fluid cultures should be sent and antibiotics and antiviral medications initiated in order to treat for presumed bacterial meningitis or herpes simplex virus encephalitis. General and neurologic examination findings may provide clues as to the etiology of a neonate’s seizures (Table 17.5). Particular attention to the head size, skin, and any dysmorphic features is important. The pregnancy history must be reviewed for risk factors for HIE, stroke, intracranial hemorrhage, infection, or drug withdrawal. Maternal nutritional deficiencies or gestational diabetes may influence the developing brain and should be assessed. A family history of benign familial neonatal epilepsy could reveal the cause of seizures in an otherwise healthy-appearing infant (caution, however, that all neonates should be evaluated for infectious or reversible etiologies regardless of the family history). If seizures persist after initial therapeutic interventions, it is prudent to reassess the infant. A series of advanced evaluations may be necessary. The most appropriate testing should be determined on a case-by-case basis, according to the clinical scenario (Table 17.6; Fig. 17.1).

MANAGEMENT OF NEONATAL SEIZURES Treatment for acute symptomatic neonatal seizures For high risk neonates, treatment with antiseizure medication should be initiated immediately when seizures are suspected (for example, focal clonic limb movements in a newborn with HIE). If the diagnosis is uncertain (no clear clinical risk factors and paroxysmal events that are not felt by the clinician to be definite seizures), treatment may be held until EEG seizures are confirmed. In that instance, additional evaluation and treatment for seizure risk factors should begin even before EEG can be initiated (labs, head ultrasound, hydration, antibiotics).

Once seizures are recorded on EEG, prompt treatment is indicated. Antiseizure medication should be administered in loading bolus doses that are titrated to eliminate EEG seizures as rapidly as possible. Many neonates will have electroclinical dissociation (the clinical seizures vanish, but EEG seizures persist); EEG seizures should be treated just as aggressively as electroclinical seizures. A sample treatment algorithm is presented in Fig. 17.2). Phenobarbital remains the first-line treatment for neonatal seizures. International surveys have consistently reflected a preference for this medication (Bartha et al., 2007; Glass et al., 2012). More recently, in a large prospective registry of more than 600 consecutive neonates with seizures treated at seven American tertiary care children’s hospitals, 89% of neonates received loading doses of phenobarbital (Shellhaas et al., 2017a). Seizures are controlled for about half of neonates after a phenobarbital loading dose of 20 mg/kg (Painter et al., 1999; Glass et al., 2016). Fosphenytoin is preferred over phenytoin due to improved safety with intravenous administration. In a randomized controlled trial, phenytoin was shown to have similar efficacy compared to phenobarbital; with a loading dose of 20 mg/kg of either drug, about half of neonates experienced resolution of seizures (Painter et al., 1999). Phenytoin is not preferred for long-term treatment, due to its less predictable absorption and pharmacokinetics compared with phenobarbital. Levetiracetam is increasingly prescribed for neonatal seizure treatment, despite a lack of safety and efficacy data (Ahmad et al., 2017). Studies of pharmacokinetics suggest a levetiracetam loading dose >40 mg/kg and a maintenance dose of >10 mg/kg/dose administered every 8 h is appropriate (Merhar et al., 2011; Sharpe et al., 2012). A single center study of levetiracetam as an add-on treatment for 32 neonates with HIE whose seizures persisted despite phenobarbital reported that a loading dose of 60mg/kg and maintenance 60 mg/kg/day was efficacious without obvious side effects (Venkatesan et al., 2017). Data from a current clinical trial of phenobarbital vs. levetiracetam as a first-line treatment for EEG confirmed neonatal seizures is ongoing and will inform future practice (NCT01720667). If seizures persist after standard medications are maximized, or if the neonate has status epilepticus, infusions may be indicated. Options include midazolam or lidocaine. Midazolam may be initiated with a bolus dose and then titrated to effect. This medication can be continued for several days and is gradually tapered once the neonate has been seizure-free for 24 h (Castro Conde et al., 2005). Lidocaine can also be effective in cases of status epilepticus. Importantly, lidocaine is contraindicated for neonates who had previously received phenytoin/fosphenytoin or who have congenital heart disease

SEIZURE CLASSIFICATION, ETIOLOGY, AND MANAGEMENT Table 17.5 Key general physical examination findings for newborns with suspected seizures Physical examination finding

Diagnostic considerations

Head circumference

● Microcephaly

●

Skin examination

●

● ● ● ● ●

Ophthalmologic examination

● ● ● ● ●

Facial (or other) dysmorphism

● ●

Mental status

●

●

– congenital CNS infections (especially TORCH infections or Zika virus) – cerebral dysgenesis – serine deficiency Macrocephaly – hydrocephalus – hemimegalencephaly – megalencephaly-capillary malformation (MCAP) Vesicular lesions – diffuse pattern—consider HSV infection – dermatomal pattern—Incontinentia pigmenti Port wine stain of the forehead/eyelid – Sturge–Weber syndrome (and evaluate for glaucoma) Nevus or discoloration in a dermatomal or whorled pattern – cerebral dysgenesis “Blueberry muffin” skin appearance – congenital rubella infection (or other TORCH infections) Ash leaf macule – tuberous sclerosis Cutis aplasia (lack of hair and skin in a localized area) – cerebral dysgenesis – genetic disorders Hypoplastic optic nerves – septo-optic dysplasia or other cerebral dysgenesis Chorioretinitis – congenital CNS infections Abnormal retinal pigmentation – neuronal ceroid lipofuscinosis Coloboma – agenesis of the corpus callosum (Aicardi syndrome) Congenital cataract – congenital CNS infections (especially TORCH infections) – metabolic (storage) diseases – COL4A1 and COL4A2 mutation Midface abnormalities (hypotelorism, cleft lip/palate) – holoprosencephaly Multiple congenital anomalies – Chromosomal abnormalities (trisomy syndromes, microdeletions/ duplications) Irritable, jittery – neonatal encephalopathy (e.g., due to HIE, neonatal abstinence syndrome) Lethargy, decreased responsiveness – neonatal encephalopathy (e.g., due to HIE); – severe systemic illness – infection (e.g., meningoencephalitis)

CNS, central nervous system; HIE, hypoxic–ischemic encephalopathy; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus.

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Table 17.6 Diagnostic evaluation for neonates with suspected seizures Immediate evaluation

Advanced evaluationa

EEG to record events of concern or to screen for subclinical seizures Clinical Complete history, general Family history of epilepsy physical and Dilated ophthalmology exam neurologic examinations Pyridoxine/PLP trial Blood Electrolytes Acylcarnitine, carnitine, ammonia Glucose Carbohydrate deficient transferrin Calcium Biotinidase enzyme activity (if not on newborn screen) Liver function tests Epilepsy gene panel Arterial blood gas for pH, lactate Newborn screen TORCH titers (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, other infections) Blood culture Urine Urine culture Sulfites, reducing substances, organic acids, creatine, alpha-AASA, guanidinoacetate Cerebrospinal fluid Cell counts and differential Lactate Glucose and total protein Amino acids HSV, EV, and PeV PCR Neurotransmitter profile Gram stain and culture Neuroimaging Head ultrasound MRI (with MRA and MRV) MRI spectroscopy a

Proceed with advanced evaluation if (1) the initial evaluation does not reveal the etiology of the seizures, and (2) the seizures persist. The advanced evaluation should proceed stepwise, with priority tests ordered based on the clinical scenario.

due to the risk of cardiac arrhythmia. Additionally, to avoid toxicity, lidocaine infusions should only be continued for <30 h (Weeke et al., 2016). Initial observational data suggest that lidocaine might have superior efficacy when compared to midazolam, but no randomized trial has been conducted (Shany et al., 2007; Weeke et al., 2017). Lidocaine dosing should be adjusted based on birth weight and exposure to therapeutic hypothermia (Table 17.7). It is also crucial that the etiology of the seizures be reevaluated if seizures do not respond as expected to

usual therapies. If seizures are treatment-resistant, a trial of pyridoxine should be strongly considered so that pyridoxine-dependent epilepsy is not missed. Additional advanced diagnostic considerations (e.g., for neonatalonset epilepsy or inborn errors of metabolism) should also be pursued, on a case-by-case basis (Table 17.6 and Fig. 17.2). There are no available data to suggest that any of the antiseizure medications are more efficacious than the others. Thus multiple potential treatment algorithms may be reasonable. It is critical that neonatologists and neurologists develop hospital-specific, consensus-based practice pathways for neonatal seizure evaluation and treatment. Such practice pathways can streamline medical decision making, facilitate rapid medication administration, and potentially decrease seizure burden.

Long-term management for acute symptomatic neonatal seizures For neonates who had EEG-confirmed seizures, maintenance antiseizure medication dosing should be initiated once the seizures are controlled with bolus doses or infusions. If the clinical events are found not to have an EEG correlate, then they were not seizures and antiseizure medications should be discontinued. The ideal duration of treatment after acute symptomatic neonatal seizures is unknown and there is marked practice variability (Shellhaas et al., 2017a). There are no current data to suggest that short vs. prolonged treatment duration is preferable. For most neonates, acute symptomatic seizures persist for 48–96 h before they subside. The recurrence risk of seizures in the neonatal period is relatively low, so antiseizure medications may be discontinued quickly for some patients. Due to its long half-life, if phenobarbital has been administered for less than 1 week, there is no need to taper the dose before discontinuing the medication. In many instances, clinicians and parents prefer to continue medications for several weeks or months after the neonatal seizures have resolved. If the infant will be maintained on antiseizure medication, it is advisable to simplify the regimen as much as possible. Oral phenytoin is to be avoided due to poor absorption in infants. Infants should be followed closely after hospital discharge so that antiseizure medications may be discontinued within the first few months of life. Importantly, a history of neonatal seizures is a major risk factor for infantile spasms. Clinical surveillance for developmental regression and for emergence of postneonatal epilepsy is warranted, since the medications typically prescribed for neonatal seizures are usually not effective for postneonatal epilepsy syndromes.

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Immediate testing Glucose Electrolytes Sepsis evaluation Consider lumbar puncture Consider urgent head ultrasound Birth and family histories Check placental pathology

Brain MRI

Suspected HIE

Stroke

Suspected infection

Suspected epilepsy, or etiology unknown

Etiology-specific diagnostic considerations

Consider evaluation for secondary seizure etiology (e.g., infection), depending on clinical scenario.

Echocardiogram if any clinical suspicion for congenital heart disease. Consider anticoagulation for venous thrombosis. Consider thrombophilia evaluation in the nonacute setting.

TORCH titers CSF testing, if not already performed: Glucose/protein Cell counts HSV PCR Bacterial culture Enterovirus PCR Parechovirus PCR

Pyridoxine trial Genetic testing* PAA, UOA, lactate, pyruvate, NH3 CSF testing (AA, neurotransmitters) Check newborn screen results Ophthalmology exam

Neurology and neurodevelopmental follow-up * Genetic testing can include: karyotype, chromosomal microarray, epilepsy gene panel, or single gene testing, depending on the clinical context.

Fig. 17.1. Assessment algorithm for newborns with seizures. Immediate testing should occur simultaneously with initiation of EEG (and initiation of antiseizure medication in high-risk clinical scenarios). Most neonates with seizures should receive neuroimaging, and brain MRI is the preferred neuroimaging modality. Etiology-specific testing depends on the clinical scenario and MRI findings. All neonates with seizures are at high risk for long-term neurodevelopmental disability and epilepsy, so they require careful follow-up by appropriate clinicians. AA, amino acids; CSF, cerebrospinal fluid; HSV, herpes simplex virus; MRI, magnetic resonance imaging; PAA, plasma amino acids; PCR, polymerase chain reaction; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, UOA, urine organic acids.

Treatment of neonatal-onset epilepsies Neonatal-onset epilepsy should be suspected when no acute symptomatic cause for seizures is identified, especially if the neonate has prominent tonic seizure semiology. This distinction is critical, since the approach to treatment for neonatal epilepsy is quite different from that of acute symptomatic seizures. Rapid titration of medication to treat neonatal epilepsy is unlikely to have a long-term impact on seizure burden or outcome. Since epilepsy-related seizures may be difficult to treat, it is important that individual medications be carefully titrated to maximally tolerated doses in order to assess efficacy; if a medication does not provide benefit it should be tapered off. Failure to discontinue medications that do not provide seizure control leads to polypharmacy

and associated challenges with drug interactions, side effects, and feasibility of long-term administration of the medication regimen. Whereas some neonates with acute symptomatic seizures can safely stop medications quite quickly after seizures resolve, newborns with epilepsy will always require ongoing treatment after discharge to home. Emerging evidence suggests that neonates with epilepsy related to KCNQ2, KCNQ3, or SCN2a gene variants may respond exquisitely to treatment with low-dose carbamazepine or oxcarbazepine (Numis et al., 2014; Sands et al., 2016). It is reasonable to consider a trial of carbamazepine or oxcarbazepine for newborns with epilepsy even prior to the receipt of genetic test results. In one case series, prompt initiation with carbamazepine

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R.A. SHELLHAAS Phenobarbital loading dose 20–30 mg/kg IV

Seizures resolve? Yes

No Begin, or continue EEG monitoring Additional 10–20 mg/kg IV phenobarbital boluses to total 50–60 mg/kg.

Continue EEG monitoring until 24 h seizure free Begin maintenance phenobarbital 4–6 mg/kg/day (oral or IV)

Seizures resolve?

No

Select second line treatment*, depending on the clinical circumstances.

Frequent seizures and no cardiac abnormalities and never received phenytoin or fosphenytoin.

Lidocaine Infusion: 2 mg/kg bolus, then follow algorithm in table 17.7 (maximum infusion time is <48 h) and continue phenobarbital.

Cardiac abnormality and/or cardiovascular instability, and/or hepatic disorder.

Levetiracetam 40–60 mg/kg initial IV bolus, then 40– 60 mg/kg/day in two or three divided doses (maintenance dose may be oral or IV).

Infrequent seizures, no hepatic or cardiac abnormalities, and no or minimal cardiovascular instability.

Fosphenytoin 20 mg/kg bolus, then 5–8 mg/kg per day IV in two or three divided doses; check free and total blood levels.

Frequent seizures, airway secure, and no hypotension.

Midazolam 0.15 mg/kg IV bolus, then 1 µg/kg/min infusion, titrating upward to effect. Wean infusion gradually after 24 h of seizure freedom.

*Few data support the efficacy or best dosing strategies for the second line medications.

Fig. 17.2. Sample treatment algorithm for acute symptomatic neonatal seizures. Table 17.7 Suggested protocol for lidocaine infusiona

Birth weight

Bolus dose (given over 10 min)

Normothermia <2.5 kg 2 mg/kg
2.5 kg 2 mg/kg Therapeutic hypothermia <2.5 kg 2 mg/kg
2.5 kg 2 mg/kg

Total lidocaine dose (mg/kg)

Initial infusion

Second infusion

Third infusion

Total treatment duration (h)

6 mg/kg/h for 4 h 7 mg/kg/h for 4 h

3 mg/kg/h for 12 h 3.5 mg/kg/h for 4 h

1.5 mg/kg/h for 12 h 1.75 mg/kg/h for 12 h

28 28

80 93

6 mg/kg/h for 3.5 h 7 mg/kg/h for 3.5 h

3 mg/kg/h for 12 h 3.5 mg/kg/h for 4 h

1.5 mg/kg/h for 12 h 1.75 mg/kg/h for 12 h

27.5 27.5

77 89.5

Based on Weeke LC, Toet MC, van Rooij LG et al. (2016). Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants. Epilepsia 57: 233–242. a Intravenous lidocaine may cause cardiac arrhythmias. Neonates should receive continuous monitoring of ECG, heart rate, and blood pressure during the infusion. Lidocaine is contraindicated for congenital heart disease and for infants who are pretreated with phenytoin/fosphenytoin.

was associated with shorter hospital admission (Sands et al., 2016). This is important, since neonates with epilepsy tend to have much longer initial admissions than newborns with acute symptomatic seizures (Shellhaas et al., 2017b).

Neurologic and neurodevelopmental follow-up for survivors of neonatal seizures Newborns with seizures are at high risk for death in the neonatal period (10%–30% mortality) (Uria-Avellanal

SEIZURE CLASSIFICATION, ETIOLOGY, AND MANAGEMENT et al., 2013; Glass et al., 2016). Preterm infants with seizures are at particularly elevated risk, compared with term newborns (Glass et al., 2017). Cultural differences related to decisions about withdrawal of intensive care for newborns with poor prognosis likely underlie the broad variation in reported mortality. Even among neonates who survive their acute seizures, the risk of death remains elevated throughout childhood. Survivors of neonatal seizures are at risk for a range of neurodevelopmental disability. Up to half of children will have global developmental delays (Ronen et al., 2007; Garfinkle and Shevell, 2011; Uria-Avellanal et al., 2013). Particular subgroups are at heightened risk. Preterm infants with neonatal seizures are more likely to experience global delays than term infants. The approximately 50% of neonates with HIE who have seizures are more likely to have developmental delays than those who do not have seizures, after adjusting for the degree of neonatal encephalopathy (Wyatt et al., 2007). In one study, the average full-scale IQ score for neonates with HIE with severe clinical seizures was 2 standard deviations (30 points) lower than those who had no seizures (Glass et al., 2009a). Given this high risk for intellectual disability, it is advisable for all survivors of neonatal seizures to be monitored carefully for developmental disability so that early interventions can be implemented. Beyond intellectual disability, children who had neonatal seizures are at risk for cerebral palsy. About one-third of long-term survivors will have cerebral palsy (Ronen et al., 2007; Garfinkle and Shevell, 2011). Such children may benefit from physical and occupational therapies, and coordination of care with a specialist in physical medicine and rehabilitation. Postneonatal epilepsy is defined as recurrent unprovoked seizures that develop later in the life of a child who had transient acute symptomatic neonatal seizures. About 25% of survivors will go on to have epilepsy (Pisani et al., 2007; Ronen et al., 2007; Nunes et al., 2008; Garfinkle and Shevell, 2011; Painter et al., 2012). Children with comorbid cerebral palsy are at particularly high risk (Mert et al., 2011; Yildiz et al., 2012). Clinical risk factors for epilepsy can be identified in the neonate and include: abnormal neuroimaging, need for more than one medication to control the acute seizures, moderate or severe neonatal encephalopathy, and low birth weight. Neonatal EEG features can also be used to identify high-risk individuals: status epilepticus, persistently abnormal interictal EEG patterns, multifocal (vs. focal) onset seizures, and ictal spread to the contralateral hemisphere (Uria-Avellanal et al., 2013). Few details have been presented about the specific epilepsy syndromes experienced by long-term survivors of neonatal seizures. However, a particular risk for

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West syndrome (infantile spasms with developmental regression and hypsarhythmia on EEG) is wellrecognized (Ronen et al., 2007; Nunes et al., 2008; Garfinkle and Shevell, 2011; Gano et al., 2013). The peak age of onset of infantile spasms is at a corrected age of 6 months. Since prompt diagnosis and early, effective treatment of infantile spasms with specific medications offer the best chance to rescue neurodevelopment (Knupp et al., 2016), it is suggested that infants be monitored carefully for infantile spasms during the first year of life. Parents should be counseled about infantile spasms and other seizure semiologies, based on their infant’s risk and neonatal seizure etiology. Prompt assessment by a neurologist, with a low threshold to obtain an EEG, should be triggered by any sign of developmental regression or new clinical events concerning for seizures.

CONCLUSIONS Neuronal excitation is necessary for normal brain development, but it predisposes the neonatal brain to seizures. Seizures in the newborn are usually a sign of acute underlying brain injury, but a minority of neonates may have epilepsy as the cause of their seizures. Evaluations to determine and treat the cause of the seizures must be coincident with confirmation (by EEG) of the seizure diagnosis. There is very little evidence to guide treatment decisions. Phenobarbital is still, by far, the most commonly prescribed medication for neonatal seizures. The optimal duration of treatment remains uncertain. For survivors, there is high risk for neurodevelopmental disability and postneonatal epilepsy. Careful clinical coordination between neonatologists and neurologists is necessary in order to manage the acute phase of evaluation and treatment; ongoing coordination between the neurologist, pediatrician, and other subspecialists is required in order to monitor development, optimize therapies, and manage comorbid conditions. There is a pressing need for high-quality research to determine the best treatment approaches for neonatal seizures; hopefully such work will eventually result in improved long-term outcomes for these vulnerable patients.

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