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INTRODUCTION — Identifying the etiology of seizures is a primary clinical objective in the management

of neonatal seizures. Accurate determination of the cause can lead to etiology-specific therapy and may
limit central nervous system (CNS) dysfunction that would otherwise occur if the underlying condition is
left untreated. Etiology-specific therapy may also be necessary to control the seizures themselves.
While there has been much discussion of the potential adverse effect of seizures on the immature brain,
the most likely overriding factors that affect long-term outcome are the etiology of the seizures and the
degree and distribution of brain injury caused by the underlying disturbance.
This topic review will discuss neonatal seizures in terms of their etiologies and will focus on acute reactive
seizures. The much less common neonatal epileptic syndromes are discussed separately. (See "Neonatal
epileptic syndromes".)
The characterization of various types of neonatal seizures, with an emphasis upon clinical features and
electrodiagnosis, is discussed elsewhere. (See "Clinical features and electrodiagnosis of neonatal
seizures".) Treatment is also discussed separately. (See "Treatment of neonatal seizures".)
CLASSIFICATION — Almost all neonatal seizures may be categorized as "symptomatic" seizures,
occurring as a consequence of a specific identifiable etiology (table 1) [1]. The seizures are considered
acute and reactive, with prognosis varying according to specific etiology. (See 'Acute reactive
seizures' below.)
However, despite a complete evaluation for etiology, there will be some seizures that occur in the
absence of any identifiable cause. When associated with other clinical signs that suggest CNS injury,
their etiology may be considered "cryptogenic." When such seizures occur in otherwise normal infants,
the seizures may be considered "idiopathic."
Although the majority of neonatal seizures occur as acute reactive events in response to identifiable
etiologic factors, additional rare but distinct neonatal epileptic syndromes are well recognized. These
include:



Benign neonatal convulsions
Benign neonatal familial convulsions
Early myoclonic encephalopathy
Early infantile epileptic encephalopathy.

The International League Against Epilepsy (ILAE) has classified these epileptic syndromes with the
purposes of standardizing terminology and developing a more uniform understanding of the clinical
features and consequences of these disorders [2-5]. In the ILAE scheme, the syndromes are
characterized by a cluster of clinical signs, symptoms, and laboratory findings that include seizure type,
age of onset, etiology, precipitating factors, severity, ictal and interictal EEG findings, duration of the
disorder, associated clinical features, chronicity, response to antiepileptic drug (AED) therapy, and
prognosis. In the most recent 2005-2009 ILAE commission proposal, benign neonatal convulsions has
been eliminated because of its diminished occurrence [5].
Seizures associated with these ILAE designated syndromes are relatively rare. However, their
identification can be important in the management of affected infants, as one has a benign prognosis and
two have a poor prognosis. (See "Neonatal epileptic syndromes".)

An orderly approach to the determination of the etiology of acute reactive neonatal seizures can be instituted in parallel with treatment (table 3) [8]. acidosis. diagnosis.7]. at times.) . and because established criteria may be too restrictive or may not be predictive of the occurrence of long-term neurologic sequelae [10-13]. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features. multisystem organ dysfunction. recognition of clinical aspects of encephalopathy. whether seizures are considered to be epileptic or nonepileptic. In an EEG monitoring study. many neonatal seizures are not recognized clinically. The diagnosis of neonatal encephalopathy and hypoxic-ischemic encephalopathy (HIE) may. with entities divided according to relative acuity [8]. (See"Treatment of neonatal seizures". and intubation in the delivery room were found to have a positive predictive value of 80 percent for clinical seizures [14]. need for resuscitation in the delivery room.0. However. While such distinctions may have therapeutic and prognostic implications. (See "Treatment of neonatal seizures". Seizures in this setting usually occur within the first one to two days of birth and often remit after a few days [9]. altered state of alertness. A more comprehensive list is provided in another Table (table 2). and hypoglycemia. and Table 1 lists the major etiologies in order of their relative occurrence (table 1). and seizures.) Thus. be difficult to make because criteria vary among institutions. (See "Metabolic emergencies at birth" and "Neonatal hypocalcemia" and "Neonatal hypoglycemia". Neonatal encephalopathy is discussed in detail separately. and treatment of neonatal encephalopathy". only the 5-minute Apgar was found to be associated with the risk of electroencephalographic seizures [15]. hypomagnesemia. The combined presence of an Apgar score <5 at five minutes. Neonatal encephalopathy — Neonatal encephalopathy occurring as the result of hypoxia-ischemia is the most common cause of neonatal seizures [9]. the occurrence of any seizure indicates the presence of CNS dysfunction and warrants thorough evaluation. particularly the metabolic and infectious causes. This has led to a sequence of empirical therapies in infants with medically refractory neonatal seizures. since both types can be the result of significant CNS disorders. since they are the most likely to be amenable to treatment. Most etiologies can be broadly categorized as:     Neonatal encephalopathy and hypoxic-ischemic encephalopathy Metabolic disturbances CNS or systemic infections Structural brain lesions Initial evaluations are typically directed toward these etiologies. most currently applied criteria include considerations such as Apgar scores. One of the main distinctions that is made early in seizure management is whether the seizures are epileptic or nonepileptic in origin.) Potentially treatable causes of medically refractory neonatal seizures have been reported to include pyridoxine deficiency (which is exceedingly rare) and biotinidase deficiency (also a rare disorder). they should not deter the clinician from a thorough evaluation of cause. However.ACUTE REACTIVE SEIZURES — Symptomatic neonatal seizures may result from a wide range of possible etiologies [6. pH <7.) Metabolic disturbances — Potentially treatable metabolic etiologies include hypocalcemia.

intraventricular). (See "Infants of mothers with substance abuse" and "Neonatal abstinence syndrome". (See "Inborn errors of metabolism: Epidemiology. are refractory to conventional treatment. electrographic neonatal seizures (none clinically visible) were noted in 21 (11 percent) infants [19]. some infants present with isolated seizures.) Neonatal seizures may also occur after infant heart surgery. neonatal seizures are associated with the in-born errors of metabolism. and congenital anomalies of the brain. (See "Clinical manifestations and diagnosis of intraventricular hemorrhage in the newborn" and "Management and complications of intraventricular hemorrhage in the newborn" and"Stroke in the newborn". (See "Neonatal epileptic syndromes". prenatal infections are potential risk factors for seizures. urea cycle defects. The clinical features and management of these syndromes are discussed in detail separately. infarctions. In one series of 183 infants monitored with video EEG for 48 hours postoperatively.17].) CNS infections — Bacterial and viral infections of the CNS are important causes of seizures as well as their adverse sequelae [18]. or organic acidurias. These disorders should be suspected when seizures begin prepartum (although this is a rare and difficult-to-determine finding). Brain abnormalities. benzodiazepines. While the typical presentation usually includes poor feeding. and is associated with a relatively good prognosis: benign familial neonatal convulsions [21-25]. and/or barbiturates in utero may suffer a withdrawal syndrome in the first days of life that can include seizures.) Structural brain lesions — Structural brain lesions associated with neonatal seizures include hemorrhage (intracerebral.Rarely. section on 'Clinical features of TORCH infections'. as its name implies. another study utilizing specific anesthetic and surgical protocols reported a much lower seizure occurrence. pathogenesis. are associated with progressive clinical and electroencephalographic worsening. alcohol. and there are imaging findings of prominent brain atrophy or hypoxic-ischemic injury without a history of insult [16. were found in 15 of 16 who had MRI. The associated clinical features typical of inborn errors of metabolism are discussed separately. In addition. Drug withdrawal or intoxication — Neonates exposed to chronic opioids. and respiratory distress after an initial symptom-free period of a few to several days. subarachnoid.) . early (neonatal) myoclonic encephalopathy (EME) and early infantile epileptic encephalopathy (EIEE) are often categorized as severe neonatal epilepsy syndromes because of their poor prognosis (table 4). such as aminoacidurias. These syndromes are discussed separately. In contrast. Congenital anomalies of the brain have become more widely recognized as associated findings of neonatal seizures with increased resolution and application of MRI. Hemorrhage and infarction may occur in isolation or may be the consequence of other etiologies such as CNS infection. and clinical features" and "Inborn errors of metabolism: Metabolic emergencies". lethargy. In contrast. including diffuse periventricular leukomalacia or global hypoxic-ischemic injury.) NEONATAL EPILEPTIC SYNDROMES — One of the three neonatal seizure syndromes recognized by the ILAE is considered benign. 1 of 68 infants following cardiac surgery and cardiopulmonary bypass [20]. (See "Bacterial meningitis in the neonate: Neurologic complications" and "Bacterial meningitis in children: Neurologic complications"and "Overview of TORCH infections".

35-37]. and postneonatal epilepsy among survivors [27. However. easily controlled seizures or self-limited seizures are often the result of transient etiologic-specific treated or benign CNS disorders of neonates.TREATMENT — Treatment of acute reactive neonatal seizures is directed toward correcting the underlying etiology when this is possible (table 1). and also in infants with perinatal . seizures may be either partial or generalized [40]. developmental delay. Mechanisms of brain injury — It is difficult to assess the relative contribution of various factors that may determine long-term outcome of those who have experienced neonatal seizures: the direct effect of seizures on the developing brain. One study found that a greater amount of electrographic seizure activity correlated with subsequent relative increased mortality and morbidity in at-risk infants in general. and rates as high as 56 percent have been reported among populations with relatively high risk factors for CNS dysfunction.) PROGNOSIS — The consequences of acute reactive seizures in neonates are determined mainly by the etiology of the seizures [26. particularly phenobarbital.32] Cerebral palsy in 25 to 43 percent. since infants who experience brief and infrequent seizures can have relatively good long-term outcomes. but this has yet to be fully defined [28]. and benzodiazepines. respectively [31. direct or indirect effects of AEDs. the following ranges of outcomes have been reported:       Abnormalities on neurologic examination in 42 to 59 percent Developmental delay in 55 percent [30] Mental retardation in 20 to 40 percent [31. while those with prolonged seizures may not do as well. These include impairment of visual-spatial memory and reduced seizure threshold that. Seizure duration and use of AEDs may also have some impact.) Mortality and neurologic impairment — There is a high incidence of early death (24 to 30 percent) associated with neonatal seizures. the indirect effect of seizures. while medically refractory neonatal seizures may be the result of more sustained. When seizures do occur in the postneonatal period. in part. Immature animals are more resistant to some types of seizure-induced brain injury than are older animals [42]. (See "Neonatal epileptic syndromes".35]. phenytoin. However. For infants with neonatal seizures who were followed until 17 months to 10 years of age [29-33]. there eventually may be functional abnormalities in older animals that have had seizures during the neonatal period. These issues are discussed separately.27]. they most often do so within the first six to nine months of life [32.44]. are related to altered synaptogenesis and reduction in neurogenesis [43. (See "Treatment of neonatal seizures".29-34]. less treatable. In clinical practice it may appear that seizure duration influences outcome.39]. such as more frequent seizures or status epilepticus [38. are used in select cases. and a high incidence of neurologic impairment. or the effect of the underlying cause of seizures [41]. or more severe brain disorders [45]. Antiepileptic drugs (AEDs). The same is true of neonates who have a clearly defined epileptic syndrome.32] Learning disabilities in 27 percent [32] No neurologic abnormalities in 22 to 35 percent [29] Postneonatal epilepsy — Postneonatal epilepsy has been reported to occur in between 20 to 30 percent of survivors of neonatal seizures [29-33.

all these variables ultimately are related to the degree of brain injury at the time of seizure occurrence. Neonatal encephalopathy occurring as the result of hypoxia-ischemia is the most common of these etiologies. A number of clinical variables in addition to etiology and character of the seizures may be predictors of outcome.55-59]:          features of the interictal EEG from one or serial recordings features of the ictal EEG seizure burden. However. compared with those associated with hypoglycemia and hypocalcemia [6. or degree of brain involvement of the epileptic seizures themselves. duration. Generalized tonic posturing. the seizures may be considered "idiopathic.27. In addition. In clinical studies.) .32. SUMMARY   Almost all neonatal seizures may be categorized as "symptomatic" (acute and reactive) seizures. the seizure etiology. or hemorrhage. These results suggest that brain injury is not limited to structural damage detected by MRI [47]. (See 'Acute reactive seizures' above." When such seizures occur in otherwise normal infants.32. including the number of sites of seizure onset and seizure duration status epilepticus the neurologic examination at the time of seizures [3] number of drugs required to treat seizures findings on neuroimaging conceptional age (term versus preterm) birth weight Multiple rather than single factors appear to be most accurate in predicting outcome. other investigators utilizing proton magnetic resonance spectroscopy (H-MRS) in neonates found both an association of seizure severity with impaired cerebral metabolism measured by lactate/choline.asphyxia [46]. motor automatisms. Predictive variables — The dominant factor that predicts outcome appears to be the underlying cause of the seizures rather than the presence. normal developmental outcomes are less frequent in association with HIE. The presence of focal-clonic and focal-tonic seizures suggests a relatively good outcome primarily because these are typically associated with brain injury confined to one region and spared CNS function in the remaining brain regions. occurring as a consequence of a specific identifiable etiology (table 1). When associated with other clinical signs that suggest CNS injury. Seizure type may also predict outcome.27.56]. and. since they are associated with diffuse CNS dysfunction. these include [26." (See 'Classification' above. and compromised neuronal integrity measured byN-acetylaspartate/choline [47].) Some neonatal seizures occur in the absence of any identifiable cause. severe infection. due in part to the degree of CNS dysfunction typically associated with various categories of seizures [31. their etiology may be considered "cryptogenic.48-55]. and myoclonus suggest a poor outcome. in turn.

and postneonatal epilepsy (20 to 30 percent) among survivors. (See 'Predictive variables' above.   Four rare but distinct neonatal epileptic syndromes are well recognized: benign neonatal convulsions. (See 'Prognosis' above. and early infantile epileptic encephalopathy. developmental delay (up to 55 percent).) The most likely overriding factors that affect long-term outcome are the etiology of the seizures and the degree and distribution of brain injury caused by the underlying disturbance. as well as a high incidence of neurologic impairments (20 to 60 percent). benign neonatal familial convulsions.) There is a high incidence of early death (24 to 30 percent) associated with neonatal seizures. . (See "Neonatal epileptic syndromes". early myoclonic encephalopathy.