Clinical manifestations

Presentation and course

Neonatal seizures differ clinically from those of older children and adults as the neonatal brain is not fully myelinated. Neonatal seizures may be difficult to diagnose accurately because movements in sick babies can be misinterpreted and treated as seizures. Additionally, clinical recognition of seizures may be difficult because neonatal seizures are often subtle and imitate reactions and behaviors that are normally seen in neonates (40). There are unique clinical features that distinguish neonatal seizures from seizures in a more mature brain. For example, focal clonic seizures are often asynchronous if they occur bilaterally and do not spread in a typical Jacksonian sequence (09).

Neonatal seizures do not have features of generalized seizures seen in other age groups. With the use of EEG monitoring, neonatal seizures are broadly categorized as 1) epileptic events, when associated with consistent electrographic patterns; 2) nonepileptic events, when there is no electrographic correlate; and 3) electrographic seizures, when EEG seizure discharges are not associated with obvious clinical manifestations (46).

The International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures was established in 2014 and developed a neonatal seizure framework that can be integrated into the ILAE classification of the epilepsies (55). The framework uses the same categories and terminology of the current ILAE seizure classification but is adapted to neonates and emphasizes the role of the EEG in the diagnosis (11). All seizures classified have an EEG correlate. The clinical motor seizures were described as either clonic, tonic, myoclonic, automatisms, epileptic spasms, or sequential (55). A sequential seizure was used when there was no predominant seizure type and the clinical features occurred in a sequence. It can be both a motor or nonmotor seizure. A nonmotor seizure includes autonomic seizures and behavioral arrest. Once the seizure is appropriately classified, the seizure semiology can be used to identify the presumed etiology (48). Early identification of the seizure semiology can help guide workup and treatment.

Prognosis and complications

The prognosis of the seizures varies according to the underlying etiology. A proven brain injury or certain genetic variants associated with the developmental epileptic encephalopathies generally portend a more serious prognosis. The background activity in the EEG can serve as a prognostic marker; a normal background favors a better prognosis (41). Severely abnormal EEG background at 36 and 48 hours after birth is shown to be associated with severe injury on MRI brain and abnormal neurodevelopmental outcome (77). EEG abnormalities and ictal seizure activity in the EEG are associated with worse prognosis compared to normal EEG findings (35). This is especially true for preterm neonates (60). Typically, the earlier the seizures occur, the worse the prognosis. Seizures occurring within the first 3 days of life were associated with increased risk of intraventricular hemorrhage, white matter injury, and death (74). However, it is the etiology of the seizures that truly determine the outcome. For instance, self-limited neonatal seizures are brief and frequent with a high seizure burden, but the seizures usually remit within one year of age, and it is not associated with poor outcome.

The risk of developing epilepsy after neonatal seizures varies in different studies, from 2% to 56%, and largely depends on etiology. Also, depending on the study, the adverse outcome is reported anywhere from 30% to 90% (19). Seizures persisting despite antiseizure treatment in children receiving two or more antiseizure drugs were highly prognostic for poor outcome. Treatment failure with three or four antiseizure drugs, as opposed to two antiseizure drugs, increased the risk of poor outcome (38; 73; 59). The mortality rate is 15% in developed countries and up to 40% in developing countries (50).

Clinical vignette

The patient is a product of a twin gestation (twin B) born at 38 weeks via vaginal delivery, with Apgar scores of 0, 2, and 4. At delivery, she was described as depressed, floppy, and pale. She met criteria for brain cooling, and the head cooling protocol was initiated. An hour after birth, she was noted to have abnormal twitching of her mouth; therefore, she was loaded with phenobarbital 20 mg/kg. An EEG was obtained, and she was noted to have an electroclinical seizure arising in the right frontal region. Clinically, she was having irregular tonic leg movements associated with the discharge. Phenobarbital was pushed to a level of 40 mcg/ml. During the rewarming, she continued to have electrographic seizure patterns. She was then loaded with fosphenytoin, and the 24-hour EEG did not reveal any electrographic or electroclinical seizures. She was tapered off the fosphenytoin while she was in the NICU and was given a phenobarbital taper schedule on discharge.

Biological basis

Localization

Motor seizures of clonic type consist of focal, rhythmic, slow (approximately one to three jerks per second) repetitive movements of the face, arm, or legs. They can be multifocal or unilateral and may spread. These types are most easily identified as a seizure by clinical observation (40).

Myoclonic seizures consist of irregular, erratic rapid twitching or contractions of muscle groups involving the face, limbs, or trunk. They can occur focally or involve all limbs.

Tonic seizures consist of prolonged contraction/posturing in any skeletal muscle group and can be purely focal or multifocal.

Motor automatisms are frequent paroxysmal changes in behavior or autonomic functions with minimal motor manifestations. These consist of various irregular and disconjugate ocular movements, eye-opening, chewing, oral-buccal movements, and peculiar extremity movements such as pedaling, stepping, boxing, or swimming movements. Mizrahi and Kellaway found these behaviors to be inconsistently associated with EEG seizure and classify them as nonepileptic. Therefore, it is important to capture these events on EEG before determining if they are epileptic or not.

Epileptic spasms are characterized by sudden flexion or extension of limbs, or both, often occurring in clusters. On EEG, they are associated with a generalized attenuation of the background or a high-voltage slow wave. Spasms are not included in Volpe’s classification scheme.

A systematic review has determined that specific etiologies can be associated with a specific clinical seizure type (48). Focal clonic seizures are usually associated with focal brain lesions, such as cerebral infarctions, but can also occur with more diffuse neuropathologic processes (48). Sequential seizures followed by tonic seizures were more commonly seen with the genetic etiologies. Additionally, tonic seizures were often seen in sequential seizures regardless of etiology. Tonic seizures were also described in metabolic, vascular, hypoxic ischemic encephalopathy (HIE), and cortical malformations, and seizures of unknown etiology. Sequential seizures followed by myoclonic seizures were often seen in metabolic etiologies.

When EEG monitoring capabilities are limited, the likelihood of a movement being a seizure can be determined based on the clinical semiology (51). A definite seizure (level 1) is confirmed by continuous EEG monitoring (gold standard). A probable seizure (level 2) is defined by a seizure confirmed by aEEG (2a) or a clinically assessed focal clonic or focal tonic seizure witnessed by experienced medical personnel (2b). A possible seizure (level 3) is a seizure suggestive of a neonatal seizure other than focal clonic or focal tonic.

Etiology and pathogenesis

In the neonatal period, most seizures are acute provoked events due to severe insults or acute metabolic changes. The etiology of these insults range from vascular, infection, hypoxic ischemic encephalopathy, acute metabolic disturbances, trauma, and neonatal abstinence. Many of these seizures resolve once the underlying etiology is corrected or the acute neurologic disruption of the causal event subsides. The seizures that persist beyond the neonatal period often result from cerebral pathology, such as developmental brain anomalies, or are part of an epilepsy syndrome with or without genetic abnormalities. The ILAE provided a position statement on the classification and definition of neonatal epilepsy syndromes (80). They incorporate previously recognized syndromes and can be divided into two broad categories: self-limited epilepsies and developmental and epileptic encephalopathies (DEE). Please see below for the specific syndrome descriptions.

Pathophysiology

Seizures occur more frequently in the neonatal period than at any other time in life (27; 36). In neonates, there is increased neuronal excitability due to an increased receptor expression of glutamate receptors (AMPA, NMDA) with age-specific subunit composition. In the immature brain, potassium tends to accumulate in the extracellular space, secondary to decreased Na+, K-ATPase activity, and immature enzyme systems. This leads to the development of a hyperexcitable state and decreased seizure threshold (71). There is also a delayed development of efficient inhibitory mechanisms (47). It is worth noting that the effects of GABA on chloride conductance change with age. In an immature neuron, there is decreased expression of the chloride pump KCC2. As a result, chloride accumulates in the cell and application of GABA leads to outward chloride movement, which results in depolarization. In the mature cells, GABA application results in hyperpolarization because KCC2 is active. The presence of depolarizing GABA-mediated currents may, on certain occasions, lead to excitatory discharges (07). In animal models, the substantia nigra pars reticularis, which is involved in the control of seizures in adults, has been shown to amplify seizures in immature animals (13).

In the presence of an acute or underlying injury, repeated seizures may lead to a cascade of events such as hypoventilation or apnea, increased blood pressure, and decreased ATP. Hypoventilation may lead to cardiovascular collapse and decreased cerebral blood flow, causing brain damage. Increased blood pressure may lead to increased cerebral blood flow and hemorrhage, also contributing to brain damage. Decreased energy metabolism leads to decreased brain glucose and increased lactate, which harms the brain and is reminiscent of hypoxic-ischemic brain insult. Thus, several factors cooperate in this cascade of events leading to brain injury (75). It is worth noting that the repeated seizures that are the hallmark of the genetic disorder, benign familial neonatal seizures, do not produce brain damage, implying that the underlying cause may contribute to its appearance.

Indeed, the severity of seizures in neonates with perinatal asphyxia has been shown to be independently associated with brain injury and adverse outcome (14; 59). In response to hypoxemia-ischemia, the preterm brain is most vulnerable in the white matter, whereas a term neonate has gray matter susceptibility (02). MRI and ultrasound studies of preterm neonates with gestational age below 34 weeks identified periventricular hemorrhagic infarct more often in neonates with seizures. Seizure severity was higher and treatment response was lower in term infants with complicated intracranial hemorrhage (29). Infants with seizures more often showed signs of white matter injury (18). In premature neonates, electrographic seizures tend to occur in relatively sicker and younger infants (60). The presence of neonatal status epilepticus was independently associated with epilepsy later on in life (20). All of the children with epilepsy had injury on neonatal MRI; the majority had injury in the basal ganglia and thalamus, predominantly.

Obvious causes of neonatal seizures are numerous, the most common being hypoxia-ischemia, stroke, trauma, and infections. Other causes include metabolic disorders, malformation of cortical development, drug withdrawal, and toxic exposure. Neonatal seizures may also occur in the setting of benign familial or nonfamilial neonatal epilepsy syndromes from channelopathies, or in more malignant epilepsy syndromes of diverse etiologies.

Epidemiology

The prevalence of neonatal seizures is approximately 1.5%, and the overall incidence is approximately 0.5 to 3 per 1000 live births. The incidence in pre-term infants is higher, ranging from 1% to 13% (04). The majority of neonatal seizures occur in the first 1 to 2 days to the first week of life. Most of these epidemiological studies include only clinical seizures, so the exact incidence of electrographic seizures is unknown. A study that looked at preterm seizures found that most seizures in this population are subclinical, have small regions of onset, and do not frequently propagate (34).

Differential diagnosis

Confusing conditions

Many neonatal seizures result from an external trigger. Causes may include infection, hemorrhage, direct drug effects, metabolic disturbances, or vitamin deficiency or dependency.

The differential diagnosis of neonatal seizures depends on the time of onset of the seizures. If the seizures begin in the first 24 hours of life, the most common causes of seizure are hypoxic-ischemic encephalopathy, hypoglycemia, bacterial meningitis and sepsis, intrauterine infection, direct drug effect, intraventricular hemorrhage at term, subarachnoid hemorrhage, or pyridoxine dependency. With hypoxic-ischemic encephalopathy, the typical onset without cooling is 6 to 8 hours after the hypoxic insult but within the first 24 hours of life. In a group of patients with hypoxic ischemic encephalopathy, the maximum seizure burden was reached within the first 23 hours of life, and the last electrographic seizure was recorded at 55.5 hours of life (37). Over the next 24 to 72 hours, the causes include bacterial meningitis and sepsis, cerebral dysgenesis, cerebral infarction, drug withdrawal, glycine encephalopathy, urea cycle disturbances, hypoparathyroidism, pyridoxine dependency, cerebral contusion and subdural hemorrhage, idiopathic cerebral venous thrombosis, intracerebral hemorrhage, intraventricular hemorrhage in premature newborns, or subarachnoid hemorrhage. Over the next 72 hours to a week, the causes include familial neonatal seizures, cerebral dysgenesis, cerebral infarction, hypoparathyroidism, idiopathic cerebral venous thrombosis, intracerebral hemorrhage, kernicterus, or metabolic disorders. In the next 1 to 4 weeks, that differential includes cerebral dysgenesis, herpes simplex, and metabolic disorders (75; 10). In rare instances, neonatal epilepsy can be the presenting feature of tuberous sclerosis or Sturge-Weber syndrome, though in most cases, onset of seizures is later in infancy (70; 44; 32).

Seizures early in life differ clinically from those of older children and adults because the immature brain is not fully myelinated. The EEG is important to provide clarification of the infant’s movements, as the motor manifestations of seizures in neonates can be subtle and easily misdiagnosed (06; 40; 15). There are several nonepileptic motor phenomena that may be difficult to differentiate from seizures. Tremor, jitteriness, and myoclonus may be benign signs in an otherwise healthy infant, but may also signal a pathological condition. Examples include metabolic disturbance, infection, stroke, drug withdrawal, etc. (31). Benign neonatal sleep myoclonus, mainly during quiet sleep, has normal EEG findings (25). Neonatal hyperekplexia (startle disease) is characterized by muscle rigidity, increased startle reaction, and nocturnal myoclonus and is usually a familial condition that does not have EEG changes (54). Many of the subtle seizures, generalized tonic posturing, and some myoclonic seizures show clinical similarities to reflex behaviors of the neonate; however, the reflexes are not associated with ictal EEG changes.

Associated and underlying disorders

Neonatal epileptic syndromes are less common than acute provoked seizures but occur in the neonatal period. The International League Against Epilepsy (ILAE) have described the following neonatal epilepsy syndromes (80):

Self-limited epilepsy syndromes.

Self-limited. Self-limited neonatal epilepsy (SeLNE) and self-limited familial neonatal-infantile epilepsy (SeLFNIE) have been described (80). Being self-limited syndromes, they are typically drug responsive and are associated with normal cognition or minor cognitive impairment. The syndromes are due to genetic variants that can occur de novo or are inherited. Both the familial and nonfamilial cases produce similar clinical features.

SeLNE and SeLFNE have the same overall clinical features. The seizures typically present between days 2 and 7 of life and remit by six months. The seizure semiology is often focal tonic, focal clonic, or sequential (55). The history, neurologic examination, imaging, and EEG background are otherwise normal. When it occurs within families, it is inherited in an autosomal dominant pattern. There is a pathogenic variant in KCNQ2 and KCNQ3 (80). A family history is required for SeLFNE. Antiseizure medications may not always be required. A sodium channel blocking agent (carbamazepine or phenytoin) is recommended if due to KCNQ2 and KCNQ3 (55).

Self-limited familial neonatal-infantile epilepsy (SeLFNIE) is an autosomal dominant syndrome with high penetrance and onset in both the neonatal and infantile period (80). These families most commonly have the SCN2A gene mutation (28). This syndrome can only be distinguished from the SeLNE or self-limited infantile epilepsy (SeLIE) by the presence of a family history of epilepsy in the neonatal or infantile period. SELFNIE presents between day 1 and 23 months of age and remits between 12 to 24 months. The seizure semiology is often focal tonic that evolves into other tonic or clonic features. It occurs equally between the sexes. The history, neurologic examination, imaging, and EEG background are otherwise normal.

Developmental and epileptic encephalopathies.

Early infantile developmental and epileptic encephalopathy (EIDEE) was previously known as Ohtahara syndrome and early myoclonic encephalopathy. Early infantile developmental and epileptic encephalopathy is an epileptic encephalopathy that initially presents within the first three months of life with drug resistant seizures (80). Unlike the self-limited epilepsies, the neurologic examination and EEG background are abnormal. The seizure semiology is focal tonic, myoclonic, focal clonic, and epileptic spasms as well as sequential seizures. The EEG background is either burst suppression or multifocal epileptiform discharges with diffuse slowing. Neuroimaging, genetics, and metabolic studies may be abnormal in 80% of cases (30; 72). The seizures are drug resistant, and the neurologic examination and development is severely abnormal with profound developmental impairment. None of the conventional antiseizure medications including adrenocorticotropic hormone, corticosteroids, or pyridoxine are thought to be particularly effective. If appropriate, the treatment can be targeted at an underlying metabolic disorder or structural lesion.

Etiology-specific syndromes.

Due to the increase availability of genetic testing, more genetic tests can be performed. The following genetic variants have been identified as syndromes with a specific clinical presentations.

KCNQ2 developmental and epileptic encephalopathy typically presents with seizures within the first few days of life. It is associated with a de novo missense mutation. Identification of this syndrome is important because the seizures typically respond to a sodium channel blocking agent (52). The clinical seizures are typically characterized by focal tonic seizures. However, focal clonic and myoclonic can also occur (76). Despite treatment and possible seizure remission, the developmental outcome is typically impaired (43). The interictal EEG typically demonstrates a burst suppression pattern. MRI brain imaging may reveal abnormalities in the basal ganglia or thalamus.

Pyridoxine-dependent (ALDH7A1)-developmental and epileptic encephalopathy (PD-DEE) and pyridoxal phosphate deficiency developmental and epileptic encephalopathy are important genetic diagnoses to identify because the treatment is different than the other types of neonatal epilepsies. With pharmacological doses of pyridoxine and pyridoxal-5’ phosphate, seizure control may be able to be achieved. Patients with this genetic abnormality present shortly after birth within the first hours to days of life with encephalopathy and medically intractable seizures. The seizures are frequent multifocal myoclonic movements of the face, arms, legs, and trunk. Epileptic spasms can also occur. The interictal EEG can demonstrate a burst suppression pattern. MRI is not required for diagnosis and may be normal or can demonstrate white matter edema in encephalopathic cases (45; 69). Patients with this diagnosis typically require life-long vitamin supplementation.

CDKL5-developmental and epileptic encephalopathy is a developmental and epileptic encephalopathy that results from a pathogenic variant in the cyclin-dependent kinase like 5 (CKDL5) gene. These seizures typically present in a hypotonic neonate with a sequential seizure semiology consisting of a cluster of epileptic spasms and tonic seizures. The seizures present within the first few weeks of life and are drug resistant. Essentially, all cases have profound global impairment. The interictal EEG consists of three stages (03). The first stage can have a normal EEG between the tonic seizures. Stage 2 has an abnormal interictal EEG with bilateral or generalized slowing with spikes and polyspikes. Stage 3 is characterized by diffuse, high amplitude delta slowing with pseudo-periodic bursts of spikes, polyspikes, and spike and wave discharges. Ganaxolone has been approved for patients two years and older with CDKL5 deficiency disorder.

Diagnostic workup

Family history, pre- and perinatal history, thorough physical examination, and biochemical tests (blood glucose, calcium, urine/blood, CSF cultures, etc.) are standard clinical steps in the evaluation process when neonatal seizures are suspected. In refractory cases, trials with vitamin B6 (pyridoxine), pyridoxal-5 phosphate, and folinic acid may result in seizure resolution if there is an inborn error in metabolism. Additionally, glucose transporter-1 (GLUT1) deficiency, as well as biotinidase deficiency, should be considered in any neonate with poorly controlled seizures. Genetic testing may also be done to further evaluate the etiology. The emergence of new panels has made this easier. Two studies demonstrated a high diagnostic yield in genetic investigations in newly diagnosed early-life epilepsies (05; 65).

The preferred setup for conventional EEG is a polygraphic recording where brain activity; ocular, respiratory, and muscle movements; and ECG are recorded. Continuous EEG monitoring is the gold standard for accurate neonatal seizure detection (62). About 60% to 70% of neonatal seizures are subclinical and will not be recognized without continuous EEG monitoring (06). Electrographic seizures are common and have been identified in nearly half of neonates with hypoxic-ischemic encephalopathy during hypothermia treatment (15). A study found that 51% of neonates had a seizure within the first hour of continuous EEG monitoring (39). Another study found that within the first hour of continuous EEG monitoring, a severely abnormal background resulted in a seven-fold increased risk of developing seizures, whereas an abnormal background resulted in a 2.4 times increased risk of seizure during subsequent monitoring (39). Rennie looked at hypoxic-ischemic encephalopathy patients with a high seizure burden and a median maximum hourly seizure burden of 21 min/hour (56). The study found that 19% of infants with no EEG seizures received antiseizure medication, whereas the same percentage with electrographic seizures on EEG seizures did not. Of the 35% with confirmed seizures on cEEG, seizures were generally seen within six hours, but only 11% (24/221 seizure episodes) were treated within 60 minutes.

Ictal EEG patterns vary and may do so even in the same neonate and in the same EEG. The EEG shows repetitive waves with varying frequency and morphology that evolve. The most common locations are centrotemporal, midline, and temporal. The background EEG may be normal or abnormal. Disturbances of background activity in neonatal seizures mainly apply to term neonates and often consist of amplitude depression (general or focal) and/or slowing of the activity (general or focal), a hyperactive background, and spontaneous burst suppression pattern. An abnormal EEG background (particularly suppression or an attenuated EEG background) may be predictive of unfavorable developmental outcome (01; 41).

Particularly in the setting of hypoxic-ischemic encephalopathy, amplitude-integrated EEG is being increasingly adopted by neonatologists to complement conventional EEG in monitoring the status of term neonates (63). Its main utility is in rapid bedside identification of normal and abnormal background patterns that predict favorable or adverse outcomes (68). As a seizure-detection tool, it is limited by its low sensitivity (due to limited channels used and time-compressed tracings that filter out short, low-frequency seizures). However, published studies report good specificity (58; 12). A study found that low amplitudes on aEEG (less than 10uV2) during the first hour of recording were associated with a 90% risk of subsequent seizures (33).

Neuroimaging is essential in order to detect hemorrhage, infarction, abnormalities of cortical development, and other structural pathology. In preterm infants with clinical suspicion of seizures, the MRI seems better at characterizing abnormalities compared to ultrasound (17) and should be performed in all infants presenting with EEG or a-EEG confirmed seizures (78). Ultrasound, CT, and MRI are performed to evaluate maturation and detect cortical abnormalities. MR angiography and venography should be done if a vascular cause is suspected. MR spectroscopy can help diagnose an inborn error of metabolism.

Management

In order to initiate treatment, it is important to accurately recognize seizures in the newborn infant and, thus, avoid misdiagnosis (40). The next step is to search for an etiologic diagnosis and start treatment accordingly (ie, metabolic disturbance, infection, cardiovascular problem, and other found abnormalities need to be corrected and treated). The current practice is to treat all seizures.

There is limited literature as to the best treatments for neonatal seizures. The ILAE has proposed guidelines regarding the management of neonatal seizures based on systematic review, metaanalysis, and expert-based consensus by Delphi (55). They proposed evidence-based recommendations to use phenobarbital first-line. Consensus-based recommendations is that phenobarbital should be used as a first-line antiseizure medication (ASM), regardless of etiology (hypoxic ischemic encephalopathy, stroke, and hemorrhage). If a channelopathy is suspected due to family history, a sodium channel blocker should instead be used first-line. If the neonate does not respond to the first antiseizure medication, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second line antiseizure medication. If a channelopathy is suspected because of clinical history of EEG, a sodium channel blacker should be used. In a neonate with a cardiac disorder, levetiracetam should be preferred as a second line antiseizure medication due to its lower risk of cardiac arrhythmias. There is a consensus-based recommendation on when to stop an antiseizure medication in acute symptomatic seizures. The recommendation for patients with cessation of seizures (electroclinical and electrographic) is to stop the medication before discharge regardless of MRI or EEG findings (16). This does not apply to the neonatal onset epilepsies. The recommendation was based on a nine-center prospective observational study in acute symptomatic seizures that evaluated seizure etiology, gestational age, therapeutic hypothermia, EEG background, days of EEG seizures, and discharge neurologic exam. After propensity adjustment, discontinuing medication prior to discharge home did not alter the risk of functional disability at 2-years and was not associated with increased risk of post-neonatal epilepsy (16).

There are limited randomized, controlled antiseizure medication trials in neonates. A multicenter, randomized, blinded, controlled trial comparing phenobarbital to levetiracetam found that phenobarbital was more effective than levetiracetam in the treatment of neonatal seizures (61). In this study, 80% of patients randomly assigned to phenobarbital achieved seizure freedom for 24 hours compared to 28% of the levetiracetam group. The Painter study compared the efficacy of phenobarbital and phenytoin in 59 neonates with seizures. Painter found that 43% of children assigned to phenobarbital as the first drug showed complete seizure control (49), where 45% treated with phenytoin showed seizure suppression. When phenytoin or phenobarbital was added as a second drug, seizure control increased to 57% and 62%, respectively (49). The phenytoin precursor, fosphenytoin, may be an alternative to phenytoin due to reduced irritation at the injection site as well as lowered incidence of cardiac arrhythmias.

There are only suggested dosing recommendations based on the literature. For phenobarbital, the usual loading dose is usually 20 mg/kg intravenous, with a second loading dose of 10 to 20 mg/kg, if required. Initial maintenance is doses of 5 mg/kg/day in two divided doses. Apparent half-life after 5 to 7 days is 100 hours. Titration of the dose to achieve levels of up to 40 mcg/ml may be necessary in refractory cases. For (fos)phenytoin, a loading dose of 20 mg PE/kg intravenous is recommended, with subsequent maintenance doses of 5 mg PE/kg/day in two to three divided doses. Average therapeutic range is 10 to 20 mcg/ml. If seizures still persist after administration of optimal dosages of phenobarbital and phenytoin, second-line drugs such as benzodiazepines are usually added. A prospective cohort found that in patients with acute symptomatic seizures, 66% of patients had an incomplete response to the initial loading dose of the specific antiseizure medication that was unrelated to gestational age, sex, medication, or dose (22).

For levetiracetam, the usual loading dose is 40 mg/kg intravenously and a second loading dose of 20 mg/kg can be given if required. Maintenance is 40 to 60 mg/kg/day intravenously or orally in three divided doses.

Midazolam is a short-acting benzodiazepine suitable for titration in the neonate, with a half-life below one hour. Lidocaine is also used for therapy-resistant seizures in neonates (79). As with all drugs administered to neonates, especially premature infants, precaution should be taken to minimize adverse effects.

As a consequence of the limited efficacy of many current neonatal antiseizure medications, off-label medications are sometimes used. Topiramate has also been assessed because of its presumed neuroprotective efficacy in animal models of hypoxic-ischemic injury (42). In a small retrospective cohort study of clinical topiramate use in newborns with acute seizures that were refractory to current agents, Glass and colleagues reported reduced occurrence or complete seizure suppression in four of six infants. Carbamazepine has been found to be safe and effective in neonates with benign familial neonatal epilepsy (57) and in KCNQ2 encephalopathy (52). A pilot study randomized patients to receive either phenobarbital with either placebo or bumetanide. Although additional studies are needed, this study demonstrated an additional reduction in seizure in the patients with received bumetanide without serious adverse events (67).

Therapeutic hypothermia, in the form of whole-body cooling or head cooling, has become the standard of care for term and near-term neonates with hypoxic ischemic encephalopathy. Besides improving developmental outcomes, it has been shown to lower the seizure burden during cooling in hypoxic ischemic encephalopathy (26). When assessing EEG abnormalities and MRI findings in infants with hypoxic ischemic encephalopathy, the infants who received whole body cooling had less prevalent abnormalities on imaging and EEG than the selective head cooling infants (24). The ILAE consensus-based recommendation is that therapeutic hypothermia may reduce seizure burden in neonates with hypoxic ischemic encephalopathy (55).

Outcomes

It is important to identify the etiology in order to direct treatment of the seizures and determine prognosis. Seizures persisting despite antiseizure treatment in children receiving two or more antiseizure drugs were highly prognostic for poor outcome. Treatment failure with three or four antiseizure drugs, as opposed to two antiseizure drugs, increased the risk of poor outcome (38; 73). Electrographic seizures and mortality were greater in preterm infants compared to term infants (21). In a multicenter study, only 13% of infants with acute symptomatic seizures developed epilepsy by age 24 months (66).