The first 4 weeks of life represent one of the greatest periods of seizure hazard during childhood. The occurrence of seizures within this neonatal period is associated with significant morbidity and mortality. These seizures are often difficult to recognize clinically and to treat effectively and can represent significant diagnostic and management challenges. In addition, despite their clinical importance, there are a number of issues concerning aspects of pathophysiology, mechanisms of comorbidity, and therapeutic strategies that can make the care of affected infants complex.

The reported incidence rates of neonatal seizures range from 1.5 to 5.5 per 1,000 neonates (1–8). The onset of seizures for most neonates starts within the first week of life with a slow accumulation of incidence over the ensuing 3 weeks (5). Seizure occurrence may vary with risk factors such as degree of underlying illness, etiology, birth weight, conceptional age, and genetic contributors (8). Scher and colleagues (9,10) reported that seizures occurred in 3.9% of neonates of less than 30 weeks’ conceptional age and 1.5% in neonates older than 30 weeks. Similarly, Kohelet and colleagues (11) found an overall incidence of seizures in a cohort of very low-birth-weight infants to be 5.6/1,000, higher than most reported incidence in full-term infants.

In the past, the International League Against Epilepsy (ILAE) (12) had used the terms acute reactive or symptomatic to classify most neonatal seizures, implying an immediate cause of these events, and also designated some so-called unprovoked neonatal seizures as the basis of epileptic syndromes. The epileptic syndromes included two benign syndromes (benign neonatal convulsions and benign familial neonatal convulsions) and two so-called catastrophic syndromes (early myoclonic encephalopathy and early infantile epileptic encephalopathy).

These designations and the concepts underlying these seizures have recently been revised by the ILAE Commision on Classification and Terminology (13). A major conceptual shift proposed by the commission has been the elimination of neonatal seizures as a separate entity. Although controversial, the basis of the recommendation is to unify concepts of seizure disorders and epilepsies across age groups. In considering underlying causes of seizures (including neonatal seizures), instead of the terms idiopathic, symptomatic, and crytogenic, the following terms are recommended to categorize causes of seizures: genetic, structural/metabolic, and unknown causes.

In considering electroclinical syndromes, the commission designated three of them: benign familial neonatal epilepsy (BFNE) (discussed in Chapter 15), early myoclonic encephalopathy (EME), and Ohtahara syndrome (early infantile epileptic encephalopathy). Both EME and Ohtahara syndrome are discussed in detail in Chapter 29. The syndrome of benign neonatal convulsions was eliminated.

CLINICAL FEATURES

The ILAE Commission also recommended that neonatal seizure semiology be considered within the context of a single unifying classification scheme, which categorizes clinical seizures as generalized, focal, or unknown (13). While there are a number of subtypes of seizures designated as generalized in this proposed classification, there are no subtypes listed for focal seizures. This limits the applicability of this scheme for the neonate since almost all neonatal seizures are focal. This is currently under review by ILAE in order to recognize the special features of neonatal seizures.

Neonatal seizures have clinical features that are unique compared to those of infants and children. Neonatal seizures may be fragmented, may be disorganized, may exhibit unusual patterns of spread, and may appear in various limbs simultaneously but asynchronously. These features are, for the most part, based on mechanisms of epileptogenesis in the immature brain. Other differences are based on the relative importance of nonepileptic mechanisms of “seizure” generation in this age group.

Neonatal seizures are classified by various methods: clinical features, the relationship between clinical seizures and electrical seizure activity on the electroencephalogram (EEG), seizure pathophysiology, and epileptic syndromes. Each classification can be clinically useful. There have been a number of classification systems proposed over the years (14–20). Early classification schemes focused on the differences between neonatal seizures and those of older children; neonatal seizures were reported to be clonic or tonic, not tonic-clonic, and when the seizures were focal, they were characterized as unifocal or multifocal (14). Later classifications included myoclonus (15).

Early investigators also identified clinical events that had less of a traditional organization of motor activity (14,21,22). Such seizures were initially characterized as “anarchic” (14) and then later as “subtle” (16) or “minimal” (18). These descriptions included oral-buccal-lingual movements such as sucking and chewing; movements of progression, such as bicycling of the legs and swimming movements of the arms; and random eye movements. While these events were initially considered to be epileptic in origin, others later suggested that they were exaggerated reflex behaviors and referred to them as “brainstem release phenomena” or “motor automatisms” (20).

Tables 34.1 and 34.2 list the clinical characteristics of neonatal seizures according to a current classification scheme (23). This scheme can be applied through clinical observation of the neonate. The basic classification includes seizures characterized as focal clonic, focal tonic, myoclonic, spasms, generalized tonic, spasms, and motor automatisms (also referred to as “subtle seizures”). Paroxysmal changes in autonomic nervous system measurements have also been reported to be manifestations of seizures, such as alterations in heart rate, respiration, and blood pressure, as well as flushing, salivation, and pupillary dilation (19,24,25). However, any of these findings occurring as isolated epileptic events are rare, and when they do occur, they do so most consistently in association with other clinical manifestations of seizures (20).

Other classification systems are based upon the temporal relation of clinical events to the occurrence of electrical seizure activity on EEG. An “electroclinical” seizure occurs when the clinical event overlaps in time with electrographic seizure activity. A seizure is referred to as “clinical only” when it occurs in the absence of any EEG seizure activity. A seizure is referred to as electrographic “only” if the electrical seizure occurs without any coincident clinical seizure activity (26).

Seizures may also be classified according to their pathophysiology: epileptic or nonepileptic in character (20). Some seizures may be confidently classified as “epileptic” in nature just by their clinical appearance: focal clonic, focal tonic, some types of myoclonic seizures, and spasms (Table 34.1). These seizure types can be recognized and characterized at the bedside by the visible features of the spontaneous event. In addition, during the event, the clinician can attempt to suppress the motor behavior by holding the affected limb; a continuation of rhythmic muscle contractions indicates the epileptic basis of the event. When EEG is available, these events occur in close association with EEG seizure activity, and the clinical event cannot be provoked by stimulation nor suppressed by restraint of the infant. When EEG is utilized, seizures characterized as electrical-only seizures are also considered, by definition, epileptic in origin.

Other behaviors may best be considered as nonepileptic in origin (4,20), including some types of myoclonic events, generalized tonic posturing, and motor automatisms such as oral-buccal-lingual movements, movements of progression, and some ocular signs (Table 34.1). These events occur in the absence of electrical seizure activity, but more importantly have clinical characteristics similar to reflex behaviors. These clinical events can be provoked by stimulation of the infant. Both the provoked and spontaneous events can be suppressed by restraint or by repositioning the infant during the event. In addition, the clinical events may increase in intensity with an increase in the repetition rate of stimulation (temporal summation) or the number of sites of simultaneous stimulation (spatial summation). The response can spread to regions of the body distant from the site of stimulation.

Clinical Neurophysiology

Electroencephalography

The application of the EEG in the evalution of a newborn suspected of seizures differs from its application to older children and adults in terms of the significance of interictal focal abnormalities and the interpretation of the background activity (27).

Interictal EEG Findings. Although focal sharp waves may be present interictally in the neonatal EEG, they are not considered epileptiform. Some focal sharp waves are normal features of the neonatal EEG, such as frontal sharp transients and some temporal sharp waves (those that occur randomly, are low or moderate in voltage, and present in transitional or light sleep) (27). Other focal sharp waves are abnormal. They are persistent, excessively numerous, and high in amplitude; they are present in wakefulness and sleep; and they have complex morphology. Persistent focal sharp waves may suggest focal injury. When multifocal, such sharp waves may suggest diffuse dysfunction. There may also be focal spikes. These may suggest focal injury, such as localized stroke, or may have uncertain diagnostic significance (28). Despite the interpretation of some interictal focal sharp waves or spikes as abnormal, in the neonate, they are not usually considered direct evidence or confirmation that an individual has had or will have electrographic seizures.

TABLE 34.1

Source: From Ref. (23). Mizrahi EM, Kellaway P. Diagnosis and Management of Neonatal Seizures. Vol. 181. Philadelphia, PA: Lippincott-Raven Publishers; 1998.

The background EEG activity can provide information concerning degree of associated central nervous system (CNS) dysfunction, potential risk for seizures, and prognosis. The degree of abnormality of the interictal background activity may suggest the extent and type of CNS dysfunction associated with seizures. The nature of the interictal background activity may also indicate the potential risk the individual infants have in experiencing a seizure (29). Infants with initial normal background activity are less likely to eventually experience electrographic seizures than those with persistent diffuse background abnormalities. In addition, the extent, degree, evolution, and rate of resolution (if any) of background EEG abnormalities can suggest prognosis. An EEG with normal background activity recording within the first 24 hours of life may suggest a good outcome (30), while EEG background activity with abnormal features that persist or resolve slowly suggest a poorer outcome (28).

Ictal EEG Findings. Although not clearly defined, it appears that electrical seizure activity in neonates is rare before 34 to 35 weeks. When recorded, the manifestations of electrical seizures have wide-ranging features (27,31). Frequency, voltage, and morphology of the seizure discharges may change within an individual seizure, between seizures in an individual infant, or among infants. The minimum duration has been designated to be 10 seconds (32), but the duration discharges can vary widely. Electrical events are typically focal and well circumscribed. They frequently arise from the central or centro-temporal region of one hemisphere and less commonly in the occipital, frontal, or midline central regions. Although seizures may arise focally and remain confined to that region, they may also spread to other regions. This spread may appear as a gradual widening of the focal area, by an abrupt change from a small regional focus to involvement of the entire hemisphere (as in a hemiconvulsive seizure), or by migration of the electrical seizure from one area of a hemisphere to another or from one hemisphere to another (27).

TABLE 34.2

There are some relatively unique ictal neonatal patterns that are typically associated with severe encephalopathies and accompanying abnormal background EEG. Seizure discharges of the depressed brain are typically low in voltage, long in duration, and highly localized (4). They may be unifocal or multifocal and show little tendency to spread or modulate; typically they are not associated with clinical seizures and occur when the EEG background is depressed and undifferentiated. Their presence suggests a poor prognosis. Alpha seizure activity is characterized by a sudden appearance of paroxysmal, rhythmic activity of the alpha frequency (8–12 Hz), typically in the temporal or central region, and may evolve from the more typical seizure discharges or may appear de novo (33–35). Like seizure discharges of the depressed brain, alpha seizure discharges usually are not accompanied by clinical events and usually indicate the presence of a severe encephalopathy and poor prognosis.

Video-EEG Monitoring, Continuous EEG Bedside Monitoring, and aEEG. Video-EEG monitoring has proved to be a powerful tool in the diagnosis and management of neonatal seizures as well as in clinical research (20,36–38). The correlation of EEG with video can be very helpful in seizure characterization and classification, although attended EEG can also provide important clinical information when performed by a well-trained electroneurodiagnostic technologist who can carefully observe an infant’s behavior and characterize the events.

Continuous bedside EEG monitoring may be performed with or without simultaneously recorded video, although it is preferable that both are recorded (39). At some centers, full channeled EEG is not available and aEEG is utilized for prolonged periods of seizure surveillance. However, EEG is considered a more complete study and its use is becoming more widespread with the appreciation of the occurrence of subclinical seizures in critically ill neonates (40–44). The American Clinical Neurophysiology Society recently issued guidelines for the application of continuous EEG monitoring in neonates (45).

Amplitude-integrated EEG (aEEG) or cerebral function monitors (CFM) have become increasingly used in the neonatal intensive care unit for ongoing bedside evaluation of cerebral activity (46–49). Typically two or four electrodes are used to acquire data, which are then processed, compressed, and displayed. Both background activity and seizure surveillance are assessed. In considering background activity, there appears to be a good agreement between conventional EEG and aEEG when tracings are normal or markedly abnormal, but less so when tracings are moderately abnormal (50,51). Neonatal seizures may be detected by aEEG and this technique may be used for long-term seizure surveillance. When neonatal seizure detection by aEEG is compared to detection by conventional EEG, aEEG is less accurate for some types of discharges, which are brief and low in amplitude (52). In contrast, advocates suggest that the ability to monitor specific brain regions with aEEG for long periods may balance the restricted localization and other limitations (53).

ETIOLOGY

Neonatal seizures are typically a correlate of CNS disease. In clinical practice, these seizures prompt a detailed evaluation for etiology. If the etiology is identified, etiologic-specific therapy is initiated. There are a wide range of potential causes of neonatal seizures, and this, in association with the susceptibility of the immature brain to injury, may account for the high incidence of acute neonatal seizures. The list of potential etiologies is extensive (23,26); however, most can be broadly categorized as hypoxia-ischemia, metabolic disturbances, CNS or systemic infections, and structural brain lesions with an increasing list of genetic causes. Tables 34.3 and 34.4 list the most frequently identified acute and chronic etiologies of neonatal seizures.

Structural and Metabolic Causes

Hypoxic-ischemic encephalopathy (HIE) is often cited as the most frequent cause of neonatal seizures. The diagnosis may be difficult to establish, because diagnostic criteria have not been uniformly accepted. In addition, some proposed criteria have been so restrictive that infants with encephalopathy may not meet all of them but still carry the diagnosis of “suspected HIE.” At other centers, clinical practice is directed toward the identification of measures of asphyxia that have predictive value in the occurrence of long-term sequelae (54). This strategy has resulted in less restrictive criteria for HIE. Both approaches, however, include the tabulation of delivery room Apgar scores, blood gases, requirement for resuscitation, recognition of clinical aspects of encephalopathy including seizures, and confirmation of multisystem involvement. At some centers, aEEG is used as an aid in the staging of the severity of HIE (53,55). Therapeutic hypothermia for infants with encephalopathy of hypoxic-ischemic origin has become relatively routine in high-acuity nurseries. Electroclinical and, more often, electrical-only seizures may occur (56–60). The risk for seizure onset may be early i n the cooling process or during rewarming with those events characterized as “rebound seizures” (61,62). The occurrence of seizures during hypothermia is unpredictable and EEG or aEEG monitoring is typically conducted from the onset of cooling through rewarming (63).

TABLE 34.3

Source: From Ref. (26). Chapman K, Mizrahi EM, Clancy RR. Neonatal seizures. In: Wyllie E, ed. The Treatment of Epilepsy: Principles & Practice. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:431–453.

TABLE 34.4

Source: From Ref. (26). Chapman K, Mizrahi EM, Clancy RR. Neonatal seizures. In: Wyllie E, ed. The Treatment of Epilepsy: Principles & Practice. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:431–453.

Associated metabolic disturbances range from electrolyte imbalances to inborn errors of metabolism. This category is important because of its potentially treatable disorders such as hypocalcemia, hypomagnesemia, and hypoglycemia. Inborn errors of metabolism are much less frequent and include aminoacidurias, urea cycle defects, or organic acidurias. Other rare causes of medically refractory neonatal seizures that are potentially treatable include pyridoxine dependency, pyridoxal phosphate dependency, folinic acid responsive seizures, serine deficiency, glucose transporter 1 deficiency, biotinidase deficiency, creatine deficiency, and untreated phenylketonuria (64).

Bacterial and viral agents are associated with seizures to such an extent that almost all neonates with new-onset seizures are investigated for such infection. Some viral infections, such as herpes simplex encephalitis, may be treated empirically at clinical presentation prior to confirmation of the diagnosis. In addition, prenatal toxoplasmosis, rubella, cytomegalovirus, herpes simplex, or other (so-called TORCH) infections can be risk factors for neonatal seizures.

Associated structural brain lesions include both acquired and congenital conditions, such as stroke or hemorrhage and developmental anomalies of the brain. Congenital brain malformations may range from highly localized focal dysplasias to catastrophic defects such as holoprosencephaly and lissencephaly.

Genetic Causes

There is an increasing list of genes that have been associated with neonatal seizures, most notably KCNQ2 and KCNQ3 associated with benign familial neonatal epilepsy (BFNE). Recently, Grinton et al. (65) screened families with BFNE criteria: of 33 families, 27 had KCNQ2 mutations, one had a KCNQ3 mutuation, and two had SCN2A mutations (a mutation previously associated with a mixed picture of neonatal and infantile onset seizures). However, there are also a group of genes associated with neonates who experience seizures, encephalopathy, and severe outcomes. These include mutations in aristaless-related homeobox gene (ARX), 22Q11 microdeletion, mutations or deletions of STXBP1/MUNC18 to 1 (66), and mutations of SCN8A (67). This list is not comprehensive. There are others (68) and undoubtedly other mutations will be identified with further investigations.

There has been recent interest in a newly described neonatal epileptic encephalopathy associated with a mutation of KCNQ2 (even though this gene is also associated with BFNE) (69–72). There is no distinctive seizure type although they are typically refractory to antiepileptic drugs. The neurologic examination of the affected infants is variable and the EEG is characterized most often by a persistent suppression-burst pattern (although there may be a wide range of of EEG findings). There may be an evolution to infantile spasms and hypsarrhythmia on EEG. During the follow-up, the infants demonstrate a variable range of developmental delay, autistic features, and motor impairment. Notably, the gene mutation is associated with a potassium channelopathy, leading to limited channel opening (73). New disease modifying treatment, which promotes KCNQ2 channel opening, is being investigated in attempts to both control seizures and improve the encephalopathy (74).

Neonatal Epileptic Syndromes

The recent revision by the ILAE Commission on Classification and Terminology (13) designated three syndromes in the neonatal period: benign neonatal familial epilepsy (BNFE), early myoclonic encephalopathy (EME), and Ohtahara syndrome (OS) (early infantile epileptic encephalopathy). The previous classification (12) had also designated benign neonatal convulsions (BFC) as an epileptic syndrome in this age group. However, it was eliminated in the newer classification because of its rare occurrence. The diagnosis of BFC is typically one of exclusion; as etiologies have become more apparent in this disorder, this designation became outdated. These syndromes are discussed in detail in Chapters 15 (BNFE) and 29 (EME and OS). The syndrome of BFNE is associated with a relatively good prognosis (75), while the others suggest a poor outcome (68).

The syndrome of benign neonatal familial epilepsy (BNFE) is characterized by early-onset focal clonic or focal tonic seizures in a neonate with a family history of neonatal seizures and with no other neurologic findings (75–78). There is an autosomal dominant pattern of inheritance with incomplete penetrance with two known chromosomal loci: one on chromosome 20q13 (79) and the other on chromosome 8q (80–82). Genes responsible for this disorder are potassium channel genes, referred to as KCNQ2 for the chromosome 20q gene (83,84), and KCNQ3 for the chromosome 8q gene (82).

The clinical seizures are best characterized as focal clonic or focal tonic. The seizure onset occurs between the first few days and one week of life (85), although there have been reports of onset as late as the second month of life. These various ages of onset may be developmentally determined, since infants who are born prematurely with this disorder will have seizure onset at an older chronologic age than the infants born at term. The seizures may be brief but can recur up to 2 to 3 months of age, when they will remit spontaneously. The interictal EEG is typically normal, although theta point altering pattern has also been reported. This is characterized by a background that is discontinuous and nonreactive. The bursts include rhythmic theta (4–7 Hz) activity, which may be mixed with sharp waves that alternate between sides. While the outcome is generally good, there is a higher incidence of seizures in affected infants later in life; ranging from 11% to 16% (75,86). Phenobarbital therapy is often used with success, although some investigators use valproate as an alternative (75).

The syndromes of early myoclonic encephalopathy (EME)–described by Aicardi–and Ohtahara syndrome (OS) (also known as early infantile epileptic encephalopathy [EIEE]) both share some clinical and electroencephalographic features and also have some distinct characteristics (Table 34.5) (87). Both syndromes are characterized by a suppression-burst pattern on EEG that may persist beyond the neonatal period. Tonic spasms may be present in both, although more prominent and occurring earlier in the course of illness in EIEE. Affected infants with both syndromes have severe and persistent neurologic and developmental abnormalities. Traditionally, EME has been most often associated with metabolic disorders and EIEE with structural brain abnormalities. However, there is an increasing recognition of overlapping underlying etiologies and the contribution of genetic mutations to each condition (68).

TABLE 34.5

Source: Based on data from Ref. (87). Aicardi J, Ohtahara S. Severe neonatal epilepsies with suppression-burst. In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. Montrouge: John Libbey Eurotext; 2005:39–50.

In 2005, Aicardi and Ohtahara (87) commented that although the syndromes of EME and EIEE are well defined, a number of cases remain difficult to classify because of lack of precision in the clinical and EEG of many of the reported cases. They also note that some authors consider some etiologies syndrome-specific while others believe there is an overlap.

There are some important differences in the clinical presentation of neonates with each disorder. Those with EME typically present with erratic, fragmentary myoclonus as the primary seizure type (if tonic spasms occur, they do so late in the course of the illness). Those with EIEE typically present with tonic spasms. There has also been discussion concerning the characteristics of the suppression-burst pattern on EEG. The pattern in EME has been characterized with short bursts and longer periods of suppression, with suppression-burst enhanced in sleep–perhaps only being found in sleep. The pattern in EIEE demonstrates longer periods of bursts and shorter periods of suppresion and occurs in both wakefulness and sleep (87).

A unifying hypothesis for both syndromes has been proposed by Djukic and colleagues (88) based upon the timing of the presentation of tonic spasms in the course of illness. They suggest that the spasms represent a manifestation of brainstem dysfunction and that in EIEE-affected infants, this dysfunction is present at birth, but less severe in EME infants at birth–consistent with the presence and absence, respectively, of tonic spasm. Over time, the brainstem disease burden increases in both disorders. Current thought, however, still considers EME and EIEE two well-defined syndromes in their purest form. Whether they represent two aspects of a continuum of one disorder remains an open question.

TREATMENT

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