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Neonatal Seizures
Neonatal Seizures EM Mizrahi, Baylor College of Medicine, Houston, TX, USA r 2014 Elsevier Inc. All rights reserved.
Introduction A neonatal seizure is a sudden paroxysmal event characterized by stereotypic and repetitive abnormal movements. Such seizures are most often generated by an epileptic process in the brain (abnormal and hypersynchronous neuronal discharges), although other pathophysiological mechanisms may also be involved. Seizures that occur in newborn infants are often considered a group of distinct entities because, when compared to those of older children and adults, their clinical manifestations are unusual, their treatment may differ, and they may have distinct impact on later life. Although some neonatal seizures may be considered of epileptic origin, they usually are not considered epilepsy per se because the seizures are typically self-limited, thought to be primarily reactive to acute brain injury, and typically do not extend beyond that period. Some seizures do persist and evolve into epilepsy, with either similar semiology or with characteristics that differ from initial presentation. The neonatal period is defined as the first 28 days of life when the infant is born at term (40 weeks of gestation). The number of days following birth is referred to as the chronological age. The gestational age (GA) is defined in weeks as the duration of pregnancy before birth based on historical data, fetal ultrasound, or neonatal examination. In clinical settings, the conceptional age (CA) of the infant is most often calculated as the sum of the GA and the chronological age calculated to the greatest completed week. Thus, for any infant, regardless of GA, the neonatal period will end at 44 weeks of CA. Estimates of CA relate directly to a variety of issues concerning neonatal seizures because the CA indicates the stage of brain development. This in turn will influence the clinical manifestations of seizures, important etiological and risk factors, therapeutic strategies, and long-term outcome following seizures. Seizures occur more often in the neonatal period than at any other time of life. Most neonatal seizures occur within the first week of life and the majority of these occur within the first few days of life. Seizure occurrence ranges from 1.8 to 3.5 per 1000 live births. Occurrence rates vary according to several risk factors, most notably the related factors of birth weight, CA, associated age-dependent etiologies, and maternal health. Thus, a greater frequency of seizures has been reported in premature or low birth-weight infants compared with fullterm and normal-weight infants. Seizures that occur in the newborn period represent unique and difficult challenges with regard to seizure recognition, accurate classification, and determination of pathophysiology. In addition, there is a diversity of etiological and risk factors associated with these seizures, limited therapeutic options, and uncertain determinants of prognosis. Traditionally, it has been suggested that the immature brain is more resistant to seizure-induced injury than the mature brain. However, recent
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animal investigations suggest a less benign effect of seizures, with a suggestion of enhanced vulnerability to further brain injury later in life. In addition, clinical studies indicate relatively high incidence of death following neonatal seizure and, in survivors, a high incidence of neurological impairment, developmental delay, and postneonatal epilepsy.
Clinical and Electroencephalographic Features Neonatal seizures are characterized as unifocal and multifocal clonic, bilateral but asynchronous clonic, focal tonic, myoclonic seizures, generalized tonic, spasms, and a group of movements referred to as ‘automatisms’ or ‘subtle seizures’ such as oral–buccal–lingual movements, limb movements of progression (bicycling, pedaling, and stepping), and ocular signs. A current description of seizure types is given in Table 1 and a working classification system is given in Table 2. Clinical and electroencephalographic (EEG) studies of neonatal seizures initiated in the mid-1950s, most notably by a group of pioneering French investigators, emphasized features that are relatively unique to neonates: multifocality, asynchrony of clonic activity on the two sides of the body, non-jacksonian patterns of migration, and the lack of generalized tonic–clonic seizures. They also developed the concept of so-called anarchic seizures in neonates, referring to clinical events not previously classified in older children or adults (oral–buccal–lingual movements, limb movements of progression, and ocular signs). These are the events that were eventually referred to as ‘subtle’ seizures, and this description, in association with the consolidation of the understanding of clinical features of neonatal seizures, evolved to a more widespread appreciation of and general interest in neonatal seizures as events with unique clinical qualities. Nonmotor phenomena manifestations have also been described, such as vasomotor changes, apnea, pallor, changes in respiration, changes in heart rate, excessive salivation, and elevation in blood pressure. With increased surveillance of autonomic nervous system, signs in neonates cared for intensive care settings, paroxysmal changes in heart rate, respirations, and blood pressure have been a greater clinical concern; however, it has been suggested that these phenomena do not occur in isolation as the sole manifestation of a seizure but rather occur most often in association with motor phenomena – thus, other physiological reasons for these changes need to be considered. Seizures may be classified in the broadest terms according to clinical and electrical–temporal relationships: electroclinical (clinical seizures overlap temporally with EEG seizure activity), electrical only (no clinical events overlapping with EEG seizure activity), or clinical only (clinical events with no overlapping electrical events) (Table 2). Clinical seizures may also be
Encyclopedia of the Neurological Sciences, Volume 3
doi:10.1016/B978-0-12-385157-4.00300-6
Neonatal Seizures
Table 1
317
Clinical characteristics, classification, and presumed pathophysiology of neonatal seizures
Classification
Characterization
Presumed pathophysiology
Focal clonic
Repetitive, rhythmic contracts of muscle groups of the limbs, face, or trunk May be unifocal or multifocal May occur synchronously or asynchronously in muscle groups on one side of the body May occur simultaneously but asynchronously on both sides Cannot be suppressed by restraint Sustained posturing of single limbs Sustained asymmetrical posturing of the trunk Sustained eye deviation Cannot be provoked by stimulation or suppressed by restraint Sustained symmetrical posturing of limbs, trunk, and neck May be flexor, extensor, or mixed extensor/flexor May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Random, single, and rapid contractions of muscle groups of the limbs, face, or trunk Typically not repetitive or may recur at a slow rate May be generalized, focal, or fragmentary May be provoked by stimulation May be flexor, extensor, or mixed extensor/flexor May occur in clusters Cannot be provoked by stimulation or suppressed by restraint
Epileptic
Focal tonic
Generalized tonic
Myoclonic
Spasms
Motor automatisms Ocular signs Oral–buccal–lingual movements Progression movements
Random and roving eye movements or nystagmus (distinct from tonic eye deviation) May be provoked or intensified by tactile stimulation Sucking, chewing, and tongue protrusions May be provoked or intensified by stimulation Rowing or swimming movements Pedaling or bicycling movements of the legs May be provoked or intensified by stimulation May be suppressed by restraint or repositioning
described in relation to accompanying electrical seizure activity recorded on EEG: When closely associated, the events are designated electroclinical in nature. Seizures may also be classified according to predominant clinical type or according to the sequence of clinical components. In most clinical settings, classification according to the predominant clinical type is appropriate. In addition, neonatal seizures may be classified according to the pathophysiology, either epileptic or nonepileptic in origin. Finally, they may also be classified as specific epileptic syndromes. These include benign neonatal familial convulsions (a syndrome with a relatively good long-term outcomes), early myoclonic encephalopathy (EME), and early infantile epileptic encephalopathy (EIEE) (both associated with a poor outcome). The definition of an EEG seizure is relatively arbitrary: paroxysmal rhythmic activity of at least 10 s in duration, with seizure discharges tending to be longer with increasing CA. Electroencephalographic seizures are also characterized by the region of onset and focality, waveform morphology, and, if present, migration. They appear most frequently in the central or temporal regions, although other regions may generate seizures. The discharges are most often unifocal, but may be multifocal. When multifocal, the seizures may occur simultaneously in different brain regions, but they often occur asynchronously. Waveform frequency, voltage, and morphology may vary considerably. The seizures may differ from one to the next within the same infant or be very consistent in
Epileptic
Nonepileptic
Epileptic or nonepileptic
Epileptic
Nonepileptic Nonepileptic Nonepileptic
appearance. The appearance of the seizure may change within a single seizure or it may remain relatively monomorphic. A single discharge may be confined to one well-circumscribed brain region or it may spread to other brain regions by a gradual widening of the field of the focus, an abrupt change from region to region, or a migration of the electrical seizure from one area to another. Most EEG seizures occur in association with clinical events, although some seizures are characterized only by electrical seizure activity. Seizure discharges of the depressed brain are low in amplitude, long in duration, and highly localized. They are associated with background EEG activity that is depressed and undifferentiated. An alpha seizure discharge is characterized by the sudden appearance of sustained rhythmic 8–12-Hz activity in the temporal or central region. Neither of these types of electrical events is associated with clinical seizures; both occur in infants with diffuse encephalopathy, and the occurrence of either type of discharge suggests a poor prognosis. Use of medications may also result in circumstances in which EEG seizures occur in the absence of clinical events. The most obvious situation is when a neonate is pharmacologically paralyzed for respiratory care. A less obvious circumstance is when neonates with EEG and clinical seizures are treated with antiepileptic drugs (AEDs). The initial response may be the control of the clinical events while the electrical events continue; this is referred to as ‘decoupling’ of the clinical from electrical events.
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Table 2 findings
Neonatal Seizures
Classification of neonatal seizures based on electroclinical
Clinical seizures with a consistent electrocortical signature (pathophysiology: epileptic) Focal clonic Unifocal Multifocal Hemiconvulsive Axial Focal tonic Asymmetrical truncal posturing Limb posturing Sustained eye deviation Myoclonic Generalized Focal Spasms Flexor Extensor Mixed extensor/flexor Clinical seizures without a consistent electrocortical signature (pathophysiology: presumed nonepileptic) Myoclonic Generalized Focal Fragmentary Generalized tonic Flexor Extensor Mixed extensor/flexor Motor automatisms Oral–buccal–lingual movements Ocular signs Progression movements Electrical seizures without clinical seizure activity
occur in all seizures in the newborn, but experimental data suggest that in some this process may lead to seizure-induced sequelae. Initially, all neonatal seizures were thought to be of epileptic origin, but it was eventually recognized that some types of clinical seizures may be generated by a nonepileptic mechanism. Focal clonic, focal tonic, spasms, and some types of myoclonic events are generated by an epileptic mechanism (i.e., initiated and maintained by abnormal, paroxysmal, and hypersynchronous electrical discharges of cortical neurons) and occur in close association with EEG seizure activity. Generalized tonic seizures and so-called subtle seizures (also referred to as motor automatisms) are generated by a nonepileptic mechanism. When they occur spontaneously, these clinical events have the appearance and responsive features of reflex behaviors. They can also be provoked by tactile stimulation of the infant. Increased levels of stimulation of the infant (spatial and temporal) result in increased intensity of the response, and both provoked and spontaneous events can be suppressed by restraint of the infant. Although these clinical events may occur in the absence of EEG seizure activity, their designation as nonepileptic in origin is based on their clinical similarities to reflex behaviors and not to the absence of EEG seizure activity associated with clinical seizure activity. Because tonic posturing and motor automatisms occur in infants with forebrain depression due to diffuse brain injury and they manifest characteristics of movements generated or mediated at the brainstem level, these types of clinical events have been referred to as brainstem release phenomena and are considered nonepileptic neonatal seizures.
Etiology Pathophysiology As in older children and adults, seizures in the neonate are related to an imbalance of factors, which influence excitation and inhibition. In the neonate, the neurotransmitter g-aminobutyric acid (GABA) is initially excitatory and eventually, with age, acquires its mature inhibitory characteristics. In the neonate, early excitation is not only critical for synaptogenesis and brain development but also represents enhanced vulnerability to epileptogenesis. This paradoxical excitatory action is due to the regulation of intracellular concentration of chloride ions in immature neurons, which is mediated by (1) the Na þ K þ Cl cotransporter NKCC1 facilitating the accumulation of chloride ions in neurons and (2) a delayed expression of K þ Cl cotransporter KCC2 that extrudes intracellular chloride ions. In addition to this enhanced excitation, limited cortical networks and immature circuitry contribute to the clinical manifestations of neonatal seizures. The time course of epileptogenesis in the neonate may also differ from older children and adults. The initial epileptogenic insult may involve neuronal death and inflammation, followed by a latent period. During that time, molecular and cellular events may alter excitability and there may be morphological changes including circuit reorganization, gliosis, neurogenesis, and epigenic changes. This process may not
For each infant with new-onset seizures, regardless of seizure type, a thorough evaluation is conducted to determine seizure etiology, prompting the initiation of available etiologicspecific therapies. In addition to treating the underlying etiology and limiting further brain injury due to the cause of the seizures, etiologic-specific therapy may be needed to control the seizures themselves. Tables 3 and 4 list frequently identified etiologies and categorize them as either acute or chronic factors. From a clinical perspective, the major categories of etiological factors initially considered are hypoxia–ischemia, metabolic disturbances (e.g., hypoglycemia, hypomagnesium, and hypocalcemia), infection (central nervous system (CNS), systemic, or intrauterine), structural brain lesions (e.g., hemorrhage, infarction, and malformations), familial disorders, and inborn errors of metabolisms (e.g., amino acidurias, urea cycle defects, organic acidurias, mitochondrial disorders, paroxysmal disorders, and metabolic substrate deficiencies). Typically, the assessment for etiology is individualized and based on specific clinical, historical, and laboratory data obtained from each affected infant. This is done with the understanding that in clinical practice there may be more than one factor contributing to seizure onset in an infant. Although there has been a recent focus on newly identified genetic factors – particularly for intractable neonatal seizures – the diagnostic approach is typically stepwise, with the consideration of the
Neonatal Seizures
Table 3
Acute etiologies of neonatal seizuresa
• Acute neonatal encephalopathy • • • • • • • • • • • • •
Includes classic hypoxic–ischemic encephalopathy, both antenatal and intrapartum Arterial ischemic stroke Sinovenous thrombosis Extracorporeal membrane oxygenation Congential heart disease Vein of Galen malformation Giant arteriovenous malformation Hypertensive encephalopathy Intracranial hemorrhage Subdural, subarachoid, and intraventricular, intraparenchymal Trauma Intrapartum and nonaccidental Infections Sepsis, meningitis, and encephalitis Metabolic disorders Transient and simple Hypoglycemia, hypocalcemia, and hypomagnesemia Inborn errors of metabolism Including amino acidurias Including disorders of pyridoxine, folinic acid, and biotin Drug intoxication or withdrawal
a
Reproduced from Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia: Lippincott Williams and Wilkins.
Table 4
Chronic etiologies of neonatal seizuresa
• Cerebral dysgenesis
Focal dysplasias, lissencephaly, and hemimegalencephaly
• Cerebral dysgenesis associated with inborn errors of metabolism • Chronic infections TORCH syndrome
• Neurocutaneous syndrome
• •
Incontinenita pigmenti Hypomelanosis of Ito syndrome Sturge–Weber syndrome Tuberous sclerosis Linear sebaceous (epidermal nevus) Genetic conditions 22q11 microdeletion Aristaless-related homeobox Specific early epilepsy syndromes Benign neonatal convulsions Benign familial neonatal convulsions Early myoclonic encephalopathy Early infantile epileptic encephalopathy Migrating partial seizures of infancy
a
Reproduced from Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia, PA: Lippincott Williams and Wilkins.
major factors first, with an emphasis on potentially treatable causes. For some categories of etiology, there are specific diagnostic criteria that are universally accepted, but for others there continues to be debate, particularly regarding the diagnosis of hypoxic–ischemic encephalopathy. The definition of this disorder may vary among practitioners, investigators, or clinical centers. In general, the diagnosis is based on a number of
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factors, including perinatal history, serial Apgar scores, umbilical blood gas determinations, acid–base balance, the presence of multisystem impairment, and the neurological examination. Even utilizing strict criteria, it is not clear whether they accurately predict outcome, including the eventual development of cerebral palsy. There are also risk factors that may have an indirect impact on seizure occurrence, such as relatively young GA, low birthweight, extremes of maternal age or the presence of maternal fever, and some circumstances of labor and delivery. Any of these may coexist with other specific etiological factors.
Neonatal Epileptic Syndromes Three epileptic syndromes have been designated by the International League Against Epilepsy as occurring in the neonatal period. The syndrome of benign familial neonatal seizures is characterized by focal clonic or focal tonic seizures, a family history of neonatal seizures, and normal neurological examination at seizure onset. The seizures are typically brief and remit spontaneously, although they may persist into the second or third month of life. The interictal EEG is normal although a generalized pattern referred to as ‘theta pointu alternant’ (a pattern of intermittent fluctuation of amplitude) may occur in some infants. The outcome is generally good, although there is a reported higher incidence in postneonatal epilepsy. There is an autosomal dominant pattern of inheritance with incomplete penetrance. Potassium channel genes have been associated with the disorder: KCNQ2 at chromosomal locus 20q13.3 and KCNQ3, located on 8q24, both coding to an aberrant a-subunit of a voltage-gated potassium channel. EME has onset in the first month of life. The infants are abnormal neurologically at birth or at seizure onset. The predominant seizure type is erratic or fragmentary distal myoclonus. Additional seizure types may eventually include generalized myoclonus, focal clonic seizures, and spasms. The EEG is characterized by a suppression-burst pattern. Inborn errors of metabolism are frequently associated etiologies. There is progressive neurological impairment with a high death rate in infancy. Survivors experience sustained static encephalopathy and, for some, onset of infantile spasms. EIEE is most often associated with Ohtahara’s syndrome. Onset may be in the neonatal period, although may extend through the first 3 months of life. The infants may be neurologically abnormal before seizure onset. The characteristic seizure type is generalized tonic spasm – an important differentiation from EME. Additional seizure types may include focal clonic and hemiconvulsive clonic. The EEG is also characterized by suppression-burst pattern. Traditionally, the most frequently associated etiology has been cerebral dysgenesis, although most recently genetic mutations have been identified in affected infants. There is also a high death rate, although later in life when compared with EME. Survivors have significant developmental delay and seizure types may evolve to West’s syndrome and then Lennox–Gastaut syndrome. These syndromes have both similarities and important differences. However, some investigators believe that EME and
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Neonatal Seizures
EIEE represent different aspects of a spectrum of a single disorder.
Treatment A rational therapeutic plan begins with accurate seizure diagnosis, precise characterization and classification of seizure type, appropriate interpretation of the EEG findings, identification of etiology, and determination of the pathophysiology of seizures and the severity of the epileptic neonatal seizures. The duration of epileptic seizures, their rate of recurrence, and the potential for spontaneous resolve may determine whether AEDs are given because some epileptic seizures may be too brief, infrequent, or self-limiting to justify such therapy. Initial supportive measures are based on the principles of general medical management, cardiovascular stabilization, and respiratory support. Although all neonates with seizures may not require these measures, others do, particularly when seizures occur in critically ill neonates, when seizures are frequent or prolonged, or when seizures are associated with clinically significant changes in respiration, heart rate, or blood pressure as a consequence of the seizures themselves or vigorous AED therapy. In neonates with symptomatic seizures, etiology-specific therapy is directed to limit further brain injury and to contribute to the control of seizures. In some cases, etiologyspecific therapy may be the only treatment needed, such as in the correction of some metabolic disturbances, whereas in other circumstances in which brain injury has already occurred, both etiology-specific and AED therapy may be needed to control seizures. In other circumstances, some seizures may not be responsive to AED therapy unless the underlying causes are successfully treated. For neonates with AED-resistant seizures, agents are typically administered empirically to treat presumptive metabolic disturbances. These include pyridoxine, folinic acid, and biotin. The most frequently utilized AEDs in the acute treatment of neonatal seizures are phenobarbital, phenytoin (or fosphenytoin), and a benzodiazepine (lorazepam or midazolam) given intravenously. Phenobarbital is almost universally accepted as the first-line AED. Phenytoin (fosphenytoin) and, more recently, midazolam are most often accepted as second-line AEDs. Closer attention has also been paid to the use of lidocaine; some clinical trials have suggested both efficacy and, with cardiac monitoring, safety. The newer AEDs such as levetiracetam and topiramate have also received attention, although clinical trials have not defined their efficacy in neonates. Clinical trials are also underway for the diuretic bumetanide because of its properties to regulate intracellular chloride in the immature neuron.
End Point of Acute Therapy The determination of the appropriate end point of acute therapy may not be straightforward. In untreated infants with electroclinical seizures, clinical epileptic seizures occur in a time-locked relationship to EEG seizure activity. An initial response to acute AED administration is the cessation of
clinical seizures, although EEG seizure activity may persist (socalled decoupling). The response of the electrical seizures to either increasing dosages of an AED or the addition of other AEDs is variable. Even as AED dosage and number increase, these electrical discharges may be difficult to eliminate. Attempts to further control the electrical seizure activity may result in high-dosage AED therapy and/or polypharmacy and may produce CNS depression, systemic hypotension, and respiratory depression. Thus, the potential risks of aggressive AED treatment must be weighed against any potential benefits of therapy.
Chronic Antiepileptic Drug Therapy and its Eventual Discontinuation When a therapeutic effect is obtained acutely, infants are typically placed on maintenance doses of the successful AED. However, the chronic levels of these AEDs may be difficult to stabilize over time for the following reasons: Drug metabolism may be conceptionally age-dependent or altered by underlying systemic disease, phenobarbital elimination may be slowed in asphyxiated infants who may have concomitant hepatic or renal dysfunction, and maintenance dosing requirements may be relatively lower early in the course of therapy, but increase later. Thus, careful monitoring of AEDs early in the course of chronic therapy is necessary to prevent adverse effects associated with drug buildup and, perhaps, seizure breakthrough as AED metabolism increases and levels decline. There are no well-defined practice guidelines for the discontinuation of chronic therapy, although reports of maintenance schedules range from 1 week to 12 months after the last seizure. At many centers, short-term AED therapy is advocated, with AED withdrawal within 2 weeks following the infant’s last clinical seizure and in the absence of electrical seizure activity on EEG.
Relative Risks and Benefits of Acute and Chronic Therapy There is emerging experimental evidence to suggest that there may be sequelae associated with the occurrence of epileptic seizures in the developing brain. It has been suggested that although the immature brain may be more susceptible to the generation of epileptic seizures in response to injury compared with the brains of older children and adults, the neonatal brain may also be more resistant to seizure-induced injury compared with the mature brain. There are a number of imputed mechanisms of seizure-induced injury. Most involve initial injury, with a latent period, followed by the manifestation of sequelae such as impaired memory, behavioral changes, or postneonatal epilepsy. Such mechanisms include aberrant growth of axons with reorganization of excitatory synapses, disruption of patterns of neuron organization, enhanced susceptibility to remote brain injury, amplification of concurrent brain injury, and reprograming of brain organization through epigenetic changes in gene expression. Much of the data suggest that animals that experience seizures in the neonatal period may have impaired memory and learning,
Neonatal Seizures
emotional lability, or increased occurrence of postneonatal epilepsy compared to animals without neonatal seizures; recent clinical studies in humans have shown conflicting data. The relative risks of AEDs have also not been well determined. Experimental data suggest some alterations in cell growth and energy substrate utilization with AEDs, apoptotic neuronal degeneration with selective AEDs, and impairment of neuroprotective mechanisms, although the applicability of these findings to human neonates has not been defined. The relative risks of AEDs in this age group are considered small compared with the overall potential gain. There are few clinical studies of the adverse systemic effects of acute AED therapy, although acute and aggressive treatment may result in CNS depression, hypotension, bradycardia, cardiac arrhythmia, and respiratory depression.
Prognosis Outcome of neonatal seizures is measured in terms of survival, neurological disability, developmental delay, and the presence of postneonatal epilepsy. Most clinical studies describe an increased occurrence of these measures in subjects who experience seizures as newborns. Longitudinal studies have shown that death occurs in approximately 25% of neonates with seizures. In survivors, between approximately 30% and 50% have some type of neurological or developmental impairment. In addition, approximately 20% experience postneonatal epilepsy. There is a loose relationship with these disabilities, with some comorbidity in affected infants. The objectives of rapid diagnosis, accurate identification of etiology, and successful AED treatment of neonatal seizures are to prevent such adverse sequelae and to improve long-term outcomes of affected neonates, although few investigations have conclusively linked cessation of seizures and prognosis. Overall, it appears that the primary factor that predicts outcome is the underlying cause of the seizures rather than specific characteristics of the epileptic events.
See also: Electroencephalogram (EEG). Encephalopathy, Anoxic–Ischemic. Epilepsy, Diagnosis of. Epilepsy; Genetics. Epileptic Syndromes and Diseases. GABAA Receptor Channels; Properties and Regulation. Malformations of Central Nervous System
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Further Reading Aicardi J and Ohtahara S (2005) Severe neonatal epilepsies with suppression-burst. In: Roger J, Bureau M, Ch Dravet, et al. (eds.) Epileptic Syndromes in Infancy, pp. 39–50. France: John Libby Eurotext. Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia: Lippincott Williams and Wilkins. Garkinfle J and Shevell MI (2011) Cerebral palsy, developmental delay, and epilepsy after neonatal seizures. Pediatric Neurology 44: 88–96. Glass HC, Glidden D, Jeremy RJ, et al. (2009) Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic–ischemic brain injury. Journal of Pediatrics 155b: 318–323. Holmes GL (2009) The long-term effects of neonatal seizures. Clinics in Perinatology 36: 901–914. Kwon JM, Guillet R, Shankaran S, et al. (2011) Clinical seizures in neonatal hypoxic–ischemic encephalopathy have no independent outcome: Secondary analysis of data from the Neonatal Research Network Hypothermia Trial. Journal of Child Neurology 26: 322–328. Lanska MJ, Lanska DJ, Baumann RJ, et al. (1995) A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 45: 724–732. Mizrahi EM, Hrachovy RA, and Kellaway P (2004) Atlas of Neonatal Electroencephalography, 3rd edn., p. 250. Philadelphia: Lippincott Williams and Wilkins. Mizrahi EM and Kellaway P (1987) Characterization and classification of neonatal seizures. Neurology 37: 1837–1844. Mizrahi EM and Milh M (2012) Early severe neonatal and infantile epilepies. In: Bureau M, Genton P, Delgado-Escueta DV, et al. (eds.) Epileptic Syndromes in Infancy, Childhood and Adolescence, 5th edn. Montrouge, France: John Libbey Eurotext. Painter MJ, Scher MS, Stein AD, et al. (1999) Phenobarbital compared with phenytoin for the treatment of neonatal seizures. New England Journal of Medicine 341: 485–489. Pearl PL (2009) New treatment paradigms in neonatal metabolic epilepsies. Journal of Inherited Metabolic Disease 32: 204–213. Pisani F, Piccolo B, Cantalupo G, et al. (2012) Neonatal seizures and postneonatal epilepsy: 7-Year follow-up study. Pediatric Research 72: 186–193. Rakhade SN and Jensen FE (2009) Epileptogenesis in the immature brain: Emerging mechanisms. Nature Reviews Neurology. doi:10.1038/ nrneurol.2009.80. Sayin U, Sutula TP, and Stafstrom CE (2004) Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 45: 1539–1548. Silverstein FS, Jensen FE, Inder T, et al. (2008) Improving the treatment of neonatal seizures: National Institute of Neurological Disorders and Stroke workshop report. Journal of Pediatrics 153: 12–15. Tekgul H, Gauvreau K, Soul J, et al. (2006) The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 117: 1270–1280. Volpe JJ (2008) Neurology of the Newborn, 5th edn. Philadelphia: Elsevier.
Introduction A neonatal seizure is a sudden paroxysmal event characterized by stereotypic and repetitive abnormal movements. Such seizures are most often generated by an epileptic process in the brain (abnormal and hypersynchronous neuronal discharges), although other pathophysiological mechanisms may also be involved. Seizures that occur in newborn infants are often considered a group of distinct entities because, when compared to those of older children and adults, their clinical manifestations are unusual, their treatment may differ, and they may have distinct impact on later life. Although some neonatal seizures may be considered of epileptic origin, they usually are not considered epilepsy per se because the seizures are typically self-limited, thought to be primarily reactive to acute brain injury, and typically do not extend beyond that period. Some seizures do persist and evolve into epilepsy, with either similar semiology or with characteristics that differ from initial presentation. The neonatal period is defined as the first 28 days of life when the infant is born at term (40 weeks of gestation). The number of days following birth is referred to as the chronological age. The gestational age (GA) is defined in weeks as the duration of pregnancy before birth based on historical data, fetal ultrasound, or neonatal examination. In clinical settings, the conceptional age (CA) of the infant is most often calculated as the sum of the GA and the chronological age calculated to the greatest completed week. Thus, for any infant, regardless of GA, the neonatal period will end at 44 weeks of CA. Estimates of CA relate directly to a variety of issues concerning neonatal seizures because the CA indicates the stage of brain development. This in turn will influence the clinical manifestations of seizures, important etiological and risk factors, therapeutic strategies, and long-term outcome following seizures. Seizures occur more often in the neonatal period than at any other time of life. Most neonatal seizures occur within the first week of life and the majority of these occur within the first few days of life. Seizure occurrence ranges from 1.8 to 3.5 per 1000 live births. Occurrence rates vary according to several risk factors, most notably the related factors of birth weight, CA, associated age-dependent etiologies, and maternal health. Thus, a greater frequency of seizures has been reported in premature or low birth-weight infants compared with fullterm and normal-weight infants. Seizures that occur in the newborn period represent unique and difficult challenges with regard to seizure recognition, accurate classification, and determination of pathophysiology. In addition, there is a diversity of etiological and risk factors associated with these seizures, limited therapeutic options, and uncertain determinants of prognosis. Traditionally, it has been suggested that the immature brain is more resistant to seizure-induced injury than the mature brain. However, recent
316
animal investigations suggest a less benign effect of seizures, with a suggestion of enhanced vulnerability to further brain injury later in life. In addition, clinical studies indicate relatively high incidence of death following neonatal seizure and, in survivors, a high incidence of neurological impairment, developmental delay, and postneonatal epilepsy.
Clinical and Electroencephalographic Features Neonatal seizures are characterized as unifocal and multifocal clonic, bilateral but asynchronous clonic, focal tonic, myoclonic seizures, generalized tonic, spasms, and a group of movements referred to as ‘automatisms’ or ‘subtle seizures’ such as oral–buccal–lingual movements, limb movements of progression (bicycling, pedaling, and stepping), and ocular signs. A current description of seizure types is given in Table 1 and a working classification system is given in Table 2. Clinical and electroencephalographic (EEG) studies of neonatal seizures initiated in the mid-1950s, most notably by a group of pioneering French investigators, emphasized features that are relatively unique to neonates: multifocality, asynchrony of clonic activity on the two sides of the body, non-jacksonian patterns of migration, and the lack of generalized tonic–clonic seizures. They also developed the concept of so-called anarchic seizures in neonates, referring to clinical events not previously classified in older children or adults (oral–buccal–lingual movements, limb movements of progression, and ocular signs). These are the events that were eventually referred to as ‘subtle’ seizures, and this description, in association with the consolidation of the understanding of clinical features of neonatal seizures, evolved to a more widespread appreciation of and general interest in neonatal seizures as events with unique clinical qualities. Nonmotor phenomena manifestations have also been described, such as vasomotor changes, apnea, pallor, changes in respiration, changes in heart rate, excessive salivation, and elevation in blood pressure. With increased surveillance of autonomic nervous system, signs in neonates cared for intensive care settings, paroxysmal changes in heart rate, respirations, and blood pressure have been a greater clinical concern; however, it has been suggested that these phenomena do not occur in isolation as the sole manifestation of a seizure but rather occur most often in association with motor phenomena – thus, other physiological reasons for these changes need to be considered. Seizures may be classified in the broadest terms according to clinical and electrical–temporal relationships: electroclinical (clinical seizures overlap temporally with EEG seizure activity), electrical only (no clinical events overlapping with EEG seizure activity), or clinical only (clinical events with no overlapping electrical events) (Table 2). Clinical seizures may also be
Encyclopedia of the Neurological Sciences, Volume 3
doi:10.1016/B978-0-12-385157-4.00300-6
Neonatal Seizures
Table 1
317
Clinical characteristics, classification, and presumed pathophysiology of neonatal seizures
Classification
Characterization
Presumed pathophysiology
Focal clonic
Repetitive, rhythmic contracts of muscle groups of the limbs, face, or trunk May be unifocal or multifocal May occur synchronously or asynchronously in muscle groups on one side of the body May occur simultaneously but asynchronously on both sides Cannot be suppressed by restraint Sustained posturing of single limbs Sustained asymmetrical posturing of the trunk Sustained eye deviation Cannot be provoked by stimulation or suppressed by restraint Sustained symmetrical posturing of limbs, trunk, and neck May be flexor, extensor, or mixed extensor/flexor May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Random, single, and rapid contractions of muscle groups of the limbs, face, or trunk Typically not repetitive or may recur at a slow rate May be generalized, focal, or fragmentary May be provoked by stimulation May be flexor, extensor, or mixed extensor/flexor May occur in clusters Cannot be provoked by stimulation or suppressed by restraint
Epileptic
Focal tonic
Generalized tonic
Myoclonic
Spasms
Motor automatisms Ocular signs Oral–buccal–lingual movements Progression movements
Random and roving eye movements or nystagmus (distinct from tonic eye deviation) May be provoked or intensified by tactile stimulation Sucking, chewing, and tongue protrusions May be provoked or intensified by stimulation Rowing or swimming movements Pedaling or bicycling movements of the legs May be provoked or intensified by stimulation May be suppressed by restraint or repositioning
described in relation to accompanying electrical seizure activity recorded on EEG: When closely associated, the events are designated electroclinical in nature. Seizures may also be classified according to predominant clinical type or according to the sequence of clinical components. In most clinical settings, classification according to the predominant clinical type is appropriate. In addition, neonatal seizures may be classified according to the pathophysiology, either epileptic or nonepileptic in origin. Finally, they may also be classified as specific epileptic syndromes. These include benign neonatal familial convulsions (a syndrome with a relatively good long-term outcomes), early myoclonic encephalopathy (EME), and early infantile epileptic encephalopathy (EIEE) (both associated with a poor outcome). The definition of an EEG seizure is relatively arbitrary: paroxysmal rhythmic activity of at least 10 s in duration, with seizure discharges tending to be longer with increasing CA. Electroencephalographic seizures are also characterized by the region of onset and focality, waveform morphology, and, if present, migration. They appear most frequently in the central or temporal regions, although other regions may generate seizures. The discharges are most often unifocal, but may be multifocal. When multifocal, the seizures may occur simultaneously in different brain regions, but they often occur asynchronously. Waveform frequency, voltage, and morphology may vary considerably. The seizures may differ from one to the next within the same infant or be very consistent in
Epileptic
Nonepileptic
Epileptic or nonepileptic
Epileptic
Nonepileptic Nonepileptic Nonepileptic
appearance. The appearance of the seizure may change within a single seizure or it may remain relatively monomorphic. A single discharge may be confined to one well-circumscribed brain region or it may spread to other brain regions by a gradual widening of the field of the focus, an abrupt change from region to region, or a migration of the electrical seizure from one area to another. Most EEG seizures occur in association with clinical events, although some seizures are characterized only by electrical seizure activity. Seizure discharges of the depressed brain are low in amplitude, long in duration, and highly localized. They are associated with background EEG activity that is depressed and undifferentiated. An alpha seizure discharge is characterized by the sudden appearance of sustained rhythmic 8–12-Hz activity in the temporal or central region. Neither of these types of electrical events is associated with clinical seizures; both occur in infants with diffuse encephalopathy, and the occurrence of either type of discharge suggests a poor prognosis. Use of medications may also result in circumstances in which EEG seizures occur in the absence of clinical events. The most obvious situation is when a neonate is pharmacologically paralyzed for respiratory care. A less obvious circumstance is when neonates with EEG and clinical seizures are treated with antiepileptic drugs (AEDs). The initial response may be the control of the clinical events while the electrical events continue; this is referred to as ‘decoupling’ of the clinical from electrical events.
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Table 2 findings
Neonatal Seizures
Classification of neonatal seizures based on electroclinical
Clinical seizures with a consistent electrocortical signature (pathophysiology: epileptic) Focal clonic Unifocal Multifocal Hemiconvulsive Axial Focal tonic Asymmetrical truncal posturing Limb posturing Sustained eye deviation Myoclonic Generalized Focal Spasms Flexor Extensor Mixed extensor/flexor Clinical seizures without a consistent electrocortical signature (pathophysiology: presumed nonepileptic) Myoclonic Generalized Focal Fragmentary Generalized tonic Flexor Extensor Mixed extensor/flexor Motor automatisms Oral–buccal–lingual movements Ocular signs Progression movements Electrical seizures without clinical seizure activity
occur in all seizures in the newborn, but experimental data suggest that in some this process may lead to seizure-induced sequelae. Initially, all neonatal seizures were thought to be of epileptic origin, but it was eventually recognized that some types of clinical seizures may be generated by a nonepileptic mechanism. Focal clonic, focal tonic, spasms, and some types of myoclonic events are generated by an epileptic mechanism (i.e., initiated and maintained by abnormal, paroxysmal, and hypersynchronous electrical discharges of cortical neurons) and occur in close association with EEG seizure activity. Generalized tonic seizures and so-called subtle seizures (also referred to as motor automatisms) are generated by a nonepileptic mechanism. When they occur spontaneously, these clinical events have the appearance and responsive features of reflex behaviors. They can also be provoked by tactile stimulation of the infant. Increased levels of stimulation of the infant (spatial and temporal) result in increased intensity of the response, and both provoked and spontaneous events can be suppressed by restraint of the infant. Although these clinical events may occur in the absence of EEG seizure activity, their designation as nonepileptic in origin is based on their clinical similarities to reflex behaviors and not to the absence of EEG seizure activity associated with clinical seizure activity. Because tonic posturing and motor automatisms occur in infants with forebrain depression due to diffuse brain injury and they manifest characteristics of movements generated or mediated at the brainstem level, these types of clinical events have been referred to as brainstem release phenomena and are considered nonepileptic neonatal seizures.
Etiology Pathophysiology As in older children and adults, seizures in the neonate are related to an imbalance of factors, which influence excitation and inhibition. In the neonate, the neurotransmitter g-aminobutyric acid (GABA) is initially excitatory and eventually, with age, acquires its mature inhibitory characteristics. In the neonate, early excitation is not only critical for synaptogenesis and brain development but also represents enhanced vulnerability to epileptogenesis. This paradoxical excitatory action is due to the regulation of intracellular concentration of chloride ions in immature neurons, which is mediated by (1) the Na þ K þ Cl cotransporter NKCC1 facilitating the accumulation of chloride ions in neurons and (2) a delayed expression of K þ Cl cotransporter KCC2 that extrudes intracellular chloride ions. In addition to this enhanced excitation, limited cortical networks and immature circuitry contribute to the clinical manifestations of neonatal seizures. The time course of epileptogenesis in the neonate may also differ from older children and adults. The initial epileptogenic insult may involve neuronal death and inflammation, followed by a latent period. During that time, molecular and cellular events may alter excitability and there may be morphological changes including circuit reorganization, gliosis, neurogenesis, and epigenic changes. This process may not
For each infant with new-onset seizures, regardless of seizure type, a thorough evaluation is conducted to determine seizure etiology, prompting the initiation of available etiologicspecific therapies. In addition to treating the underlying etiology and limiting further brain injury due to the cause of the seizures, etiologic-specific therapy may be needed to control the seizures themselves. Tables 3 and 4 list frequently identified etiologies and categorize them as either acute or chronic factors. From a clinical perspective, the major categories of etiological factors initially considered are hypoxia–ischemia, metabolic disturbances (e.g., hypoglycemia, hypomagnesium, and hypocalcemia), infection (central nervous system (CNS), systemic, or intrauterine), structural brain lesions (e.g., hemorrhage, infarction, and malformations), familial disorders, and inborn errors of metabolisms (e.g., amino acidurias, urea cycle defects, organic acidurias, mitochondrial disorders, paroxysmal disorders, and metabolic substrate deficiencies). Typically, the assessment for etiology is individualized and based on specific clinical, historical, and laboratory data obtained from each affected infant. This is done with the understanding that in clinical practice there may be more than one factor contributing to seizure onset in an infant. Although there has been a recent focus on newly identified genetic factors – particularly for intractable neonatal seizures – the diagnostic approach is typically stepwise, with the consideration of the
Neonatal Seizures
Table 3
Acute etiologies of neonatal seizuresa
• Acute neonatal encephalopathy • • • • • • • • • • • • •
Includes classic hypoxic–ischemic encephalopathy, both antenatal and intrapartum Arterial ischemic stroke Sinovenous thrombosis Extracorporeal membrane oxygenation Congential heart disease Vein of Galen malformation Giant arteriovenous malformation Hypertensive encephalopathy Intracranial hemorrhage Subdural, subarachoid, and intraventricular, intraparenchymal Trauma Intrapartum and nonaccidental Infections Sepsis, meningitis, and encephalitis Metabolic disorders Transient and simple Hypoglycemia, hypocalcemia, and hypomagnesemia Inborn errors of metabolism Including amino acidurias Including disorders of pyridoxine, folinic acid, and biotin Drug intoxication or withdrawal
a
Reproduced from Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia: Lippincott Williams and Wilkins.
Table 4
Chronic etiologies of neonatal seizuresa
• Cerebral dysgenesis
Focal dysplasias, lissencephaly, and hemimegalencephaly
• Cerebral dysgenesis associated with inborn errors of metabolism • Chronic infections TORCH syndrome
• Neurocutaneous syndrome
• •
Incontinenita pigmenti Hypomelanosis of Ito syndrome Sturge–Weber syndrome Tuberous sclerosis Linear sebaceous (epidermal nevus) Genetic conditions 22q11 microdeletion Aristaless-related homeobox Specific early epilepsy syndromes Benign neonatal convulsions Benign familial neonatal convulsions Early myoclonic encephalopathy Early infantile epileptic encephalopathy Migrating partial seizures of infancy
a
Reproduced from Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia, PA: Lippincott Williams and Wilkins.
major factors first, with an emphasis on potentially treatable causes. For some categories of etiology, there are specific diagnostic criteria that are universally accepted, but for others there continues to be debate, particularly regarding the diagnosis of hypoxic–ischemic encephalopathy. The definition of this disorder may vary among practitioners, investigators, or clinical centers. In general, the diagnosis is based on a number of
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factors, including perinatal history, serial Apgar scores, umbilical blood gas determinations, acid–base balance, the presence of multisystem impairment, and the neurological examination. Even utilizing strict criteria, it is not clear whether they accurately predict outcome, including the eventual development of cerebral palsy. There are also risk factors that may have an indirect impact on seizure occurrence, such as relatively young GA, low birthweight, extremes of maternal age or the presence of maternal fever, and some circumstances of labor and delivery. Any of these may coexist with other specific etiological factors.
Neonatal Epileptic Syndromes Three epileptic syndromes have been designated by the International League Against Epilepsy as occurring in the neonatal period. The syndrome of benign familial neonatal seizures is characterized by focal clonic or focal tonic seizures, a family history of neonatal seizures, and normal neurological examination at seizure onset. The seizures are typically brief and remit spontaneously, although they may persist into the second or third month of life. The interictal EEG is normal although a generalized pattern referred to as ‘theta pointu alternant’ (a pattern of intermittent fluctuation of amplitude) may occur in some infants. The outcome is generally good, although there is a reported higher incidence in postneonatal epilepsy. There is an autosomal dominant pattern of inheritance with incomplete penetrance. Potassium channel genes have been associated with the disorder: KCNQ2 at chromosomal locus 20q13.3 and KCNQ3, located on 8q24, both coding to an aberrant a-subunit of a voltage-gated potassium channel. EME has onset in the first month of life. The infants are abnormal neurologically at birth or at seizure onset. The predominant seizure type is erratic or fragmentary distal myoclonus. Additional seizure types may eventually include generalized myoclonus, focal clonic seizures, and spasms. The EEG is characterized by a suppression-burst pattern. Inborn errors of metabolism are frequently associated etiologies. There is progressive neurological impairment with a high death rate in infancy. Survivors experience sustained static encephalopathy and, for some, onset of infantile spasms. EIEE is most often associated with Ohtahara’s syndrome. Onset may be in the neonatal period, although may extend through the first 3 months of life. The infants may be neurologically abnormal before seizure onset. The characteristic seizure type is generalized tonic spasm – an important differentiation from EME. Additional seizure types may include focal clonic and hemiconvulsive clonic. The EEG is also characterized by suppression-burst pattern. Traditionally, the most frequently associated etiology has been cerebral dysgenesis, although most recently genetic mutations have been identified in affected infants. There is also a high death rate, although later in life when compared with EME. Survivors have significant developmental delay and seizure types may evolve to West’s syndrome and then Lennox–Gastaut syndrome. These syndromes have both similarities and important differences. However, some investigators believe that EME and
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Neonatal Seizures
EIEE represent different aspects of a spectrum of a single disorder.
Treatment A rational therapeutic plan begins with accurate seizure diagnosis, precise characterization and classification of seizure type, appropriate interpretation of the EEG findings, identification of etiology, and determination of the pathophysiology of seizures and the severity of the epileptic neonatal seizures. The duration of epileptic seizures, their rate of recurrence, and the potential for spontaneous resolve may determine whether AEDs are given because some epileptic seizures may be too brief, infrequent, or self-limiting to justify such therapy. Initial supportive measures are based on the principles of general medical management, cardiovascular stabilization, and respiratory support. Although all neonates with seizures may not require these measures, others do, particularly when seizures occur in critically ill neonates, when seizures are frequent or prolonged, or when seizures are associated with clinically significant changes in respiration, heart rate, or blood pressure as a consequence of the seizures themselves or vigorous AED therapy. In neonates with symptomatic seizures, etiology-specific therapy is directed to limit further brain injury and to contribute to the control of seizures. In some cases, etiologyspecific therapy may be the only treatment needed, such as in the correction of some metabolic disturbances, whereas in other circumstances in which brain injury has already occurred, both etiology-specific and AED therapy may be needed to control seizures. In other circumstances, some seizures may not be responsive to AED therapy unless the underlying causes are successfully treated. For neonates with AED-resistant seizures, agents are typically administered empirically to treat presumptive metabolic disturbances. These include pyridoxine, folinic acid, and biotin. The most frequently utilized AEDs in the acute treatment of neonatal seizures are phenobarbital, phenytoin (or fosphenytoin), and a benzodiazepine (lorazepam or midazolam) given intravenously. Phenobarbital is almost universally accepted as the first-line AED. Phenytoin (fosphenytoin) and, more recently, midazolam are most often accepted as second-line AEDs. Closer attention has also been paid to the use of lidocaine; some clinical trials have suggested both efficacy and, with cardiac monitoring, safety. The newer AEDs such as levetiracetam and topiramate have also received attention, although clinical trials have not defined their efficacy in neonates. Clinical trials are also underway for the diuretic bumetanide because of its properties to regulate intracellular chloride in the immature neuron.
End Point of Acute Therapy The determination of the appropriate end point of acute therapy may not be straightforward. In untreated infants with electroclinical seizures, clinical epileptic seizures occur in a time-locked relationship to EEG seizure activity. An initial response to acute AED administration is the cessation of
clinical seizures, although EEG seizure activity may persist (socalled decoupling). The response of the electrical seizures to either increasing dosages of an AED or the addition of other AEDs is variable. Even as AED dosage and number increase, these electrical discharges may be difficult to eliminate. Attempts to further control the electrical seizure activity may result in high-dosage AED therapy and/or polypharmacy and may produce CNS depression, systemic hypotension, and respiratory depression. Thus, the potential risks of aggressive AED treatment must be weighed against any potential benefits of therapy.
Chronic Antiepileptic Drug Therapy and its Eventual Discontinuation When a therapeutic effect is obtained acutely, infants are typically placed on maintenance doses of the successful AED. However, the chronic levels of these AEDs may be difficult to stabilize over time for the following reasons: Drug metabolism may be conceptionally age-dependent or altered by underlying systemic disease, phenobarbital elimination may be slowed in asphyxiated infants who may have concomitant hepatic or renal dysfunction, and maintenance dosing requirements may be relatively lower early in the course of therapy, but increase later. Thus, careful monitoring of AEDs early in the course of chronic therapy is necessary to prevent adverse effects associated with drug buildup and, perhaps, seizure breakthrough as AED metabolism increases and levels decline. There are no well-defined practice guidelines for the discontinuation of chronic therapy, although reports of maintenance schedules range from 1 week to 12 months after the last seizure. At many centers, short-term AED therapy is advocated, with AED withdrawal within 2 weeks following the infant’s last clinical seizure and in the absence of electrical seizure activity on EEG.
Relative Risks and Benefits of Acute and Chronic Therapy There is emerging experimental evidence to suggest that there may be sequelae associated with the occurrence of epileptic seizures in the developing brain. It has been suggested that although the immature brain may be more susceptible to the generation of epileptic seizures in response to injury compared with the brains of older children and adults, the neonatal brain may also be more resistant to seizure-induced injury compared with the mature brain. There are a number of imputed mechanisms of seizure-induced injury. Most involve initial injury, with a latent period, followed by the manifestation of sequelae such as impaired memory, behavioral changes, or postneonatal epilepsy. Such mechanisms include aberrant growth of axons with reorganization of excitatory synapses, disruption of patterns of neuron organization, enhanced susceptibility to remote brain injury, amplification of concurrent brain injury, and reprograming of brain organization through epigenetic changes in gene expression. Much of the data suggest that animals that experience seizures in the neonatal period may have impaired memory and learning,
Neonatal Seizures
emotional lability, or increased occurrence of postneonatal epilepsy compared to animals without neonatal seizures; recent clinical studies in humans have shown conflicting data. The relative risks of AEDs have also not been well determined. Experimental data suggest some alterations in cell growth and energy substrate utilization with AEDs, apoptotic neuronal degeneration with selective AEDs, and impairment of neuroprotective mechanisms, although the applicability of these findings to human neonates has not been defined. The relative risks of AEDs in this age group are considered small compared with the overall potential gain. There are few clinical studies of the adverse systemic effects of acute AED therapy, although acute and aggressive treatment may result in CNS depression, hypotension, bradycardia, cardiac arrhythmia, and respiratory depression.
Prognosis Outcome of neonatal seizures is measured in terms of survival, neurological disability, developmental delay, and the presence of postneonatal epilepsy. Most clinical studies describe an increased occurrence of these measures in subjects who experience seizures as newborns. Longitudinal studies have shown that death occurs in approximately 25% of neonates with seizures. In survivors, between approximately 30% and 50% have some type of neurological or developmental impairment. In addition, approximately 20% experience postneonatal epilepsy. There is a loose relationship with these disabilities, with some comorbidity in affected infants. The objectives of rapid diagnosis, accurate identification of etiology, and successful AED treatment of neonatal seizures are to prevent such adverse sequelae and to improve long-term outcomes of affected neonates, although few investigations have conclusively linked cessation of seizures and prognosis. Overall, it appears that the primary factor that predicts outcome is the underlying cause of the seizures rather than specific characteristics of the epileptic events.
See also: Electroencephalogram (EEG). Encephalopathy, Anoxic–Ischemic. Epilepsy, Diagnosis of. Epilepsy; Genetics. Epileptic Syndromes and Diseases. GABAA Receptor Channels; Properties and Regulation. Malformations of Central Nervous System
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Further Reading Aicardi J and Ohtahara S (2005) Severe neonatal epilepsies with suppression-burst. In: Roger J, Bureau M, Ch Dravet, et al. (eds.) Epileptic Syndromes in Infancy, pp. 39–50. France: John Libby Eurotext. Chapman KE, Mizrahi EM, and Clancy RR (2011) Neonatal seizures. In: Wyllie E (ed.) The Treatment of Epilepsy: Principles and Practice, 5th edn., pp. 405–427. Philadelphia: Lippincott Williams and Wilkins. Garkinfle J and Shevell MI (2011) Cerebral palsy, developmental delay, and epilepsy after neonatal seizures. Pediatric Neurology 44: 88–96. Glass HC, Glidden D, Jeremy RJ, et al. (2009) Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic–ischemic brain injury. Journal of Pediatrics 155b: 318–323. Holmes GL (2009) The long-term effects of neonatal seizures. Clinics in Perinatology 36: 901–914. Kwon JM, Guillet R, Shankaran S, et al. (2011) Clinical seizures in neonatal hypoxic–ischemic encephalopathy have no independent outcome: Secondary analysis of data from the Neonatal Research Network Hypothermia Trial. Journal of Child Neurology 26: 322–328. Lanska MJ, Lanska DJ, Baumann RJ, et al. (1995) A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 45: 724–732. Mizrahi EM, Hrachovy RA, and Kellaway P (2004) Atlas of Neonatal Electroencephalography, 3rd edn., p. 250. Philadelphia: Lippincott Williams and Wilkins. Mizrahi EM and Kellaway P (1987) Characterization and classification of neonatal seizures. Neurology 37: 1837–1844. Mizrahi EM and Milh M (2012) Early severe neonatal and infantile epilepies. In: Bureau M, Genton P, Delgado-Escueta DV, et al. (eds.) Epileptic Syndromes in Infancy, Childhood and Adolescence, 5th edn. Montrouge, France: John Libbey Eurotext. Painter MJ, Scher MS, Stein AD, et al. (1999) Phenobarbital compared with phenytoin for the treatment of neonatal seizures. New England Journal of Medicine 341: 485–489. Pearl PL (2009) New treatment paradigms in neonatal metabolic epilepsies. Journal of Inherited Metabolic Disease 32: 204–213. Pisani F, Piccolo B, Cantalupo G, et al. (2012) Neonatal seizures and postneonatal epilepsy: 7-Year follow-up study. Pediatric Research 72: 186–193. Rakhade SN and Jensen FE (2009) Epileptogenesis in the immature brain: Emerging mechanisms. Nature Reviews Neurology. doi:10.1038/ nrneurol.2009.80. Sayin U, Sutula TP, and Stafstrom CE (2004) Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety. Epilepsia 45: 1539–1548. Silverstein FS, Jensen FE, Inder T, et al. (2008) Improving the treatment of neonatal seizures: National Institute of Neurological Disorders and Stroke workshop report. Journal of Pediatrics 153: 12–15. Tekgul H, Gauvreau K, Soul J, et al. (2006) The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 117: 1270–1280. Volpe JJ (2008) Neurology of the Newborn, 5th edn. Philadelphia: Elsevier.