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Neonatal Seizures and Neonatal Epilepsy
Introduction
Seizures are common in neonates, particularly in the first month of life. Neonatal seizures can be either provoked or unprovoked. Provoked seizures, also known as acute symptomatic seizures, may result from hypoxic-ischemic injury, cerebral infarction, brain bleeds, metabolic derangements, or infections. Unprovoked seizures are often due to underlying structural brain abnormalities or genetic conditions.
Neonatal epilepsy syndromes are a group of electroclinical syndromes that are considered a medical urgency as they may indicate underlying structural or neuro-metabolic derangements. Although some of these disorders improve over time, others can lead to severe neurodevelopmental consequences, resulting in significant morbidity and mortality.[1][2] Most neonatal seizures that occur in the first month of life are acute symptomatic. Neonatal epilepsy syndromes account for a smaller portion of neonatal seizures.[3] Timely and accurate diagnosis is crucial for initiating appropriate therapy.[4]
Etiology
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Etiology
Underlying causes of neonatal epilepsy syndromes include genetic mutations, structural brain malformations, and inborn errors of metabolism.
Genetic Abnormalities
Genetic abnormalities are common causes of neonatal epilepsy. Several types of genetic mutations associated with neonatal epilepsy are discussed below.
Self-limited neonatal epilepsy: The onset of seizures typically occurs on the second or third day of life. Seizures may be tonic, clonic, or autonomic (including apnea and changes in skin color), and typically last up to 30 seconds. Interictal electroencephalography (EEG) recordings are usually normal but may occasionally show epileptiform discharges. Amplitude-integrated EEG often reveals a distinctive pattern during seizures, characterized by a sudden rise in the upper and lower margins followed by amplitude suppression.[5]
The neurological examination is usually unremarkable. Seizures typically resolve between 6 weeks (65%) and 6 months (94%).[6] In some cases, a family history of neonatal seizures is present, with an autosomal dominant inheritance pattern. Genetic mutations associated with self-limited neonatal epilepsy include KCNQ2, KCNQ3, and SCN2A. Most children with KCNQ2- or KCNQ3-related epilepsy respond well to carbamazepine and other sodium channel blockers.[5]
Early infantile epileptic encephalopathy (Ohtahara syndrome): Seizure onset may occur in utero or within the first few days postnatally. This syndrome is often secondary to an underlying structural abnormality. Tonic seizures are commonly observed, along with focal motor and hemiconvulsive seizure types. EEG shows a burst-suppression pattern during both sleep and wakefulness. Seizures are often refractory to treatment, and the syndrome is associated with a poor prognosis. Treatment options, including steroids, valproate, zonisamide, or vitamin B, have been attempted but with limited success.[7]
Early myoclonic epileptic encephalopathy: This syndrome can present within the first few hours to any time during the first month of life and is often attributed to underlying genetic or metabolic causes, with nonketotic hyperglycinemia being the most common. Myoclonic seizures (even generalized myoclonus) are the most common seizure type, although occasional focal seizures may occur. EEG typically shows a burst-suppression pattern, more pronounced during sleep.[8] This syndrome is associated with a high seizure burden, medically refractory epilepsy, and severe neurodevelopmental morbidity. While myoclonic seizures may resolve within 3 to 4 months, they may progress to tonic seizures. A trial of vitamins may be considered.
KCNQ2 encephalopathy: Seizure onset typically occurs within the first week of life. Neonates present with tonic seizures and exhibit encephalopathy, characterized by hypotonia and visual inattention. EEG reveals abundant multifocal negative sharp waves, which may occasionally meet the criteria for a burst-suppression pattern. Although seizures often resolve by age 3, they are associated with severe global neurodevelopmental delays, regardless of seizure control. Sodium channel blockers are usually effective in treatment.[9]
Developmental delay, epilepsy, and neonatal diabetes syndrome: This condition, also known as DEND syndrome, typically presents within the first year of life, often in the neonatal period, where infants with neonatal diabetes experience severe epilepsy. Managing hyperglycemia, usually with oral sulfonylureas, can help control seizures; however, neurodevelopmental delays are commonly observed.
Epilepsy of infancy with migrating focal seizures: This condition can present between the third day of life and late infancy in neonates. The primary seizure type is focal, although tonic seizures, epileptic spasms, and autonomic seizures may also occur. EEG may reveal epileptiform discharges, seizure activity with interhemispheric migration, hypsarrhythmia, or burst-suppression patterns. The prognosis is poor, with high mortality rates within the first few years of life and severe neurodevelopmental delays in survivors.
Genetic mutations in KCNT1 and SCN2A are associated with this epilepsy syndrome. Treatment options include levetiracetam, benzodiazepines, stiripentol, and phenytoin. Children with SCN2A mutations presenting before 3 months of age often respond well to sodium channel blockers such as oxcarbazepine and lacosamide,[10] whereas those with KCNT1 mutations respond to quinidine.[11]
Pyridoxine-dependent epilepsy: Pyridoxine-dependent epilepsy is a rare autosomal recessive epilepsy and epileptic encephalopathy caused by antiquitin deficiency due to an underlying ALDH7A1 mutation. This can be considered a type of early myoclonic epileptic encephalopathy. Seizures typically present in the neonatal period and are refractory to seizure medications. The clinical presentation may also include perinatal asphyxia.
Imaging abnormalities associated with pyridoxine-dependent epilepsy may include corpus callosum hypoplasia, intracranial hemorrhages, cerebellar hypoplasia, and white matter abnormalities. Seizures typically respond to pyridoxine, pyridoxal-5-phosphate, or folinic acid.[12] EEG often reveals diffuse high-amplitude rhythmic delta waves with spikes and associated myoclonic seizures.[13]
Structural Brain Malformations
Structural brain malformations are a common cause of neonatal epilepsy. These anomalies may include schizencephaly, porencephaly, hemimegalencephaly, subcortical band heterotopia, lissencephaly, and polymicrogyria.
Inborn Errors of Metabolism
Several inborn errors of metabolism with genetic etiologies can cause neonatal seizures. Examples include nonketotic hyperglycinemia, congenital disorders of glycosylation, Zellweger syndrome, isolated sulfite oxidase deficiency, and organic acidurias.
In certain cases, severe brain injury during the neonatal period can sometimes lead to acute symptomatic seizures that continue unremittingly and progress into epilepsy.
Epidemiology
Neonatal seizures are often challenging to recognize clinically, resulting in poor inter-rater reliability. While EEG remains the gold standard for diagnosis, its ability to capture events during short-term monitoring can be limited. This contributes to challenges in accurately estimating the true incidence of neonatal seizures. However, population studies suggest that neonatal seizures occur in 1 to 3 per 1000 live births for full-term infants.[14]
Neonatal seizures occur in 10 to 30 per 1000 live births for preterm and low-birth-weight infants.[15] Neonatal epilepsy syndromes are diagnosed in 15% of neonates with seizures. Of these, 41% are attributed to underlying structural anomalies, 42% to genetic causes, and 9% involve an overlap of both factors.[16]
Pathophysiology
Neonates are highly susceptible to seizures due to several factors influencing neuronal excitability. Structurally, the density of the synapses and dendritic spines peaks between birth and the first 1 to 2 months of life. Functionally, overexpression of glutamate receptors, prolonged current decay time of NMDA (N-methyl-D-aspartate) receptors, and increased excitability of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors contribute to greater seizure susceptibility. Additionally, inhibitory GABA (gamma-aminobutyric acid) receptor binding and expression are lower during the neonatal period. Furthermore, the overexpression of the alpha-4 subunit results in decreased sensitivity to benzodiazepines. The reversal of the chloride gradient in the neonatal brain causes depolarization instead of hyperpolarization with GABA receptor activation, resulting in resistance to GABAa receptor agonists.[17]
Secondary epileptogenesis following acute brain injury involves molecular and cellular mechanisms, including the loss of GABAergic interneurons, increased intracellular chloride, astrogliosis, and alterations in various signaling pathways that promote neuronal excitability.[18]
History and Physical
Clinical history and physical examination are essential in forming a differential diagnosis for abnormal movements in neonates. Gathering information regarding factors that may predispose the baby to seizures is crucial. Physicians should begin by evaluating prenatal risk factors, including a history of infections (such as sexually transmitted infections and TORCH infections), gestational diabetes, pregnancy-related trauma, use of prescription or illicit drugs, and consanguinity.
In addition, physicians should inquire about the perinatal period, including fetal heart tones during labor, type of delivery, use of delivery instruments, medications administered during delivery, initial APGAR scores, cord blood gas results, the neonatal exam post-delivery, and any postnatal support needed. The circumstances surrounding the seizures should be explored in detail, including the timing of onset, seizure semiology, duration, and response to initial treatment. A family history of seizures or epilepsy may be particularly relevant, especially in cases of self-limited neonatal epilepsy.
On physical examination, the mental status of neonates is a key feature, as it can aid in identifying epileptic encephalopathies. Dysmorphic features may also be present, suggesting underlying genetic etiologies. Measuring head size is crucial, as congenital or in-utero insults may lead to microcephaly, in addition to underlying genetic etiologies. Macrocephaly may indicate hydrocephalus or certain inborn errors of metabolism. A bulging fontanelle can suggest hydrocephalus, potentially caused by intraventricular hemorrhage, pointing to acute provoked seizures.
Specific skin findings can often indicate neurocutaneous disorders, such as ash leaf macules associated with tuberous sclerosis, port wine stains in the V1 and V2 distributions linked to Sturge-Weber syndrome, and dermatomal blisters in incontinentia pigmenti.[19] Tone is a crucial component of neonatal neurological assessment, as it can help identify the timing of the insult (hypotonia in the acute phase and hypertonicity in the chronic phase) and may also suggest an underlying genetic or structural cause for the seizures.
Evaluation
The diagnosis of seizures in the neonatal age group can be challenging, requiring evaluation alongside treatment. The initial evaluation begins with a detailed history and physical examination, including a thorough neurological assessment. Initial laboratory tests should include blood gas analysis, serum glucose, electrolyte profile, calcium and magnesium levels, liver function tests, ammonia, pyruvate, lactate, serum amino acids, urine organic acids, and acylcarnitine profile.
Ruling out infection is crucial for any infant presenting with seizures. A full sepsis evaluation should include a complete blood count, blood culture, and cerebrospinal fluid studies, including herpes simplex virus analysis, particularly for infants experiencing seizures in the neonatal period. Identifying an acute provoked cause is also essential, as these are the most common causes of seizures in neonates.
Seizures in neonates may present with or without clinical signs. Continuous EEG monitoring should be initiated for high-risk neonates. Video EEG is considered the gold standard,[20] and is recommended for 24 hours by the American Clinical Neurophysiology Society. A standard 60-minute EEG is considered insufficient, as it takes a median of 7 hours to detect electrographic seizures.[21] If seizures are not recorded after 24 hours, monitoring may be discontinued, except in patients with hypoxic-ischemic encephalopathy who are undergoing therapeutic hypothermia. However, if seizures are detected, EEG should continue until the infant remains seizure-free for 24 to 48 hours. Prolonged EEG monitoring helps characterize the interictal background and classify the seizures. Amplitude-integrated EEG is considered only when video EEG or continuous EEG is unavailable, as its sensitivity and specificity are lower, and artifacts in these recordings can result in a high false-positive rate.[22]
Magnetic resonance imaging (MRI) is the preferred imaging modality for all neonates with seizures. Additional sequencing imaging, such as magnetic resonance angiography or magnetic resonance venography, is performed if arterial ischemic stroke or venous thrombosis is suspected. Magnetic resonance spectroscopy may be useful if an underlying metabolic disorder is suspected. In clinically unstable infants, a head ultrasound can be performed to assess for intraventricular hemorrhage or hydrocephalus. Ultrasounds can be performed at the bedside, making them a quicker and noninvasive assessment method. The use of computed tomography (CT) scans is restricted in neonates due to concerns about radiation exposure.
Initial genetic evaluation includes chromosomal microarray, karyotype, and epilepsy genetic panel testing. If a clear cause is not identified, whole exome sequencing or whole genome sequencing is recommended for neonates without apparent dysmorphic features. Genetic testing is essential in almost all neonates with epilepsy to guide management and prognosis discussions with the family.[16] Some of the most commonly identified genetic characteristics associated with specific epileptic diagnoses are listed in the Table below.[23]
Table. Genetic Characteristics Associated With Neonatal Epilepsy Syndromes
|
Epilepsy Syndromes |
Genetic Testing |
|
Self-limited neonatal epilepsy |
An autosomal dominant pattern with incomplete penetrance associated with pathogenic variants KCNQ2 and KCNQ3. |
|
Early infantile epileptic encephalopathy |
Causative pathogenic genes are identified in more than 50% of the cases. Commonly associated variants include SCN2A, SCN8A, STXBP1, KCNQ2, CDKL5, UBA5, and KCNT1. |
|
Early myoclonic epileptic encephalopathy |
A family history of epilepsy or febrile seizures is reported in <10% of cases. No causal gene has been identified. |
|
Epilepsy of infancy with migrating focal seizures |
Rare familial inheritance. De novo gene abnormalities are implicated, with KCNT1 identified in 50% of patients. Other associated genes include SCN1A, SCN2A, SLC12A5, and TBC1D24. |
|
DEND syndrome |
De novo variant or dominant (rarely recessive) inheritance. Activating mutations are observed in the KCNJ11 or ABCC8 genes. |
|
Pyridoxine-dependent epilepsy |
Most cases are associated with biallelic variants in ALDH7A1; a minority are associated with PLPBP mutations. |
Treatment / Management
The management of neonatal seizures focuses on identifying and addressing the underlying etiology. This is particularly critical in cases involving metabolic derangements, such as hypoglycemia or hypocalcemia, or central nervous system infections requiring treatment with antivirals, antibiotics, or antifungals. The Neonatal Task Force of the International League Against Epilepsy (ILAE) provides evidence-based recommendations for antiseizure medications (ASMs) in neonates.[24][25] Phenobarbital is the recommended first-line ASM. For neonates with channelopathies, phenytoin or carbamazepine may be more appropriate. If seizures persist despite phenobarbital, second-line ASMs include phenytoin, levetiracetam, midazolam, or lidocaine.(A1)
A trial dose of pyridoxine may be considered for neonates with seizures unresponsive to second-line ASMs. Using EEG to guide neonatal seizure treatment helps minimize unnecessary exposure to ASMs. The ILAE recommends discontinuing ASMs after 72 hours of seizure freedom in patients diagnosed with acute provoked seizures, provided there is no evidence of neonatal epilepsy, before discharge. Some evidence suggests that long-term phenobarbital use may lead to neuronal apoptosis in immature rats, although this has not been definitively proven in human neonates.[26] This is one reason why early discontinuation of phenobarbital in the acute setting is recommended.
Infants at risk for neonatal epilepsy include those with EEG-confirmed seizures lasting more than 3 days, a severely abnormal EEG background, or abnormal findings on a neurological examination. These patients require close follow-up by a pediatric neurologist. Neonates with a confirmed diagnosis of neonatal epilepsy should be discharged with prescribed ASMs to manage and control seizures effectively.
In neonatal epilepsy, it is crucial to classify the type and provide targeted treatment, as mentioned below.
- Self-limited neonatal epilepsy: Most cases have a spontaneous remission of seizures; however, approximately 30% of patients may develop epilepsy later in life. Initial treatment involves a routine ASM pathway. When the diagnosis is confirmed, carbamazepine or oxcarbazepine may be effective.[27] The administration of ASMs is typically discontinued after 6 weeks.
- Early infantile epileptic encephalopathy: Management includes a combination of ASMs, dietary therapies, and, in rare cases, epilepsy surgery for a few infants.[28]
- Early myoclonic epileptic encephalopathy: Treatment is not yet evidence-based. Seizures are managed with standard broad-spectrum ASMs.
- Epilepsy of infancy with migrating focal seizures: Seizures are often drug-resistant, and the prognosis is poor. However, 4 cases have been reported where complete seizure control was achieved using various medications, including bromide, clonazepam, stiripentol, and levetiracetam. Vagal nerve stimulation and ketogenic diet therapies have shown inconclusive results regarding their efficacy.[29][30]
- DEND syndrome: Oral sulfonylureas have demonstrated significant success in achieving euglycemia and managing epilepsy symptoms effectively.[31]
- Pyridoxine-dependent epilepsy: ASMs are typically ineffective. A trial of intravenous (IV) pyridoxine (100 mg) should be performed under EEG monitoring and close cardiopulmonary observation due to the risk of apnea. This dose may be repeated up to 4 times, with a maximum cumulative dose of 500 mg.[32] In cases where pyridoxine is ineffective, pyridoxal phosphate may be used, particularly for pyridoxamine 5'-phosphate oxidase or PNPO deficiency.[33] For long-term management, the recommended pyridoxine dosage is 15 to 30 mg/kg/d (up to 200 mg/d in neonates).[32] (B2)
Differential Diagnosis
Seizure activity is more common during the newborn period than at any other stage of life. However, normal newborn behaviors can sometimes mimic seizures, complicating diagnosis. Premature neonates experience seizures more frequently, often presenting with less organized patterns. A multicenter study by Murray et al found that many seizure-like events were either unrecognized or misinterpreted.[34] Clinical evaluation at the bedside alone is often insufficient and typically requires confirmatory EEG monitoring.[34] Inaccurate diagnosis of neonatal seizures can have serious consequences, as both undertreatment and overtreatment may adversely affect the neurological development of neonates.
Physiological movements in normal newborns that may mimic seizures include neonatal tremors, jitteriness, tremulousness, hyperekplexia, and benign neonatal sleep myoclonus.[35] Notably, benign neonatal sleep myoclonus can be differentiated from seizures because the myoclonic movements cease when the neonate awakens.
Hyperekplexia typically manifests at birth, with symptoms including generalized stiffness while awake, nocturnal myoclonus, and an exaggerated startle reflex. These features are more evident during awakening or in response to stimuli atypical for seizures.[36] Most nonepileptic events can be suppressed through restraint or changes in posture, aiding in their differentiation from true seizures. A study by Scher and Painter revealed that 90% of abnormal paroxysmal movements suspected to be seizures were associated with normal EEG recordings.[37]
Isolated apnea is more common in premature neonates during sleep and is typically associated with desaturations and bradycardia, usually being nonepileptic in nature. An epileptic seizure should be suspected in term neonates when apnea is accompanied by abnormal eye movements, mouth movements, hypertension, or tachycardia.
Sandifer syndrome in neonates can also be mistaken for seizures. This syndrome typically presents with paroxysmal head and neck spasms, often sparing the limbs, along with back arching. This syndrome is associated with gastroesophageal reflux. Reassuring the parents is essential in these cases.
Other symptoms that may mimic seizures include motor automatisms such as repetitive eye opening, eye deviation, tongue movements, or tonic posturing. Patients exhibiting these symptoms should be thoroughly evaluated for underlying nervous system pathology.
Prognosis
The prognosis of neonatal seizures depends on the underlying pathology. Acute-provoked seizures may require a shorter course of treatment, while patients with epilepsy often require ongoing treatment after discharge. In cases of self-limited neonatal epilepsy, the prognosis is generally favorable, with most infants experiencing seizure remission; however, a small proportion may develop learning difficulties or mild motor impairment.[38] However, in individuals with KCNQ2 encephalopathy, seizures resolve within a few months to years in 50% of cases but affected children often develop moderate to severe global neurodevelopmental disabilities later in life.[23]
The prognosis for early myoclonic epilepsy is poor, with 50% of affected individuals dying within the first few years of life. Survivors typically experience severe developmental delays. Early infantile epileptic encephalopathy, also known as Ohtahara syndrome, is also associated with a poor prognosis. Seizures are often refractory, leading to severe developmental delays, motor disabilities, and a reduced life expectancy.[23][39] At least half of affected individuals die within the first year of life.
Pyridoxine-dependent epilepsy has a variable prognosis, ranging from mild-to-severe intellectual disability, although motor outcomes are generally better. Early diagnosis and appropriate treatment can lead to normal developmental outcomes in some cases. Epilepsy of infancy with migrating focal seizures typically has a poor prognosis, often resulting in severe neurological disability and reduced life expectancy. However, some individuals may experience a milder progression. Genetic testing is crucial in determining the prognosis for many patients with epilepsy.
Complications
Neonatal seizures can disrupt normal brain synaptogenesis, potentially leading to cognitive deficits in some infants. Other serious neurological outcomes include an increased risk of cerebral palsy, particularly in infants with extremely low birth weight.[40] Complications associated with neonatal epilepsy vary depending on the specific type diagnosed and can worsen if treatment is delayed. These complications can range from mild learning disabilities to severe neurodevelopmental delays and reduced lifespan. Additionally, some types of epilepsy may result in lifelong, medication-resistant seizures, as outlined in the Prognosis section.
Deterrence and Patient Education
Neonatal epilepsy syndromes, although rare, can significantly impact a child's neurodevelopment, lifespan, and overall quality of life, affecting both the child and the entire family. A collaborative approach involving subspecialists and the primary care team is essential to discuss the management plan and prognosis. After hospital discharge, close follow-up with a pediatric neurologist is crucial to monitor and detect any recurring seizure activity. Families are encouraged to connect with local networks of parents with children who have seizure disorders, providing mutual support. These programs, which vary by community, often include informal gatherings where families can share experiences and create a supportive environment.
Enhancing Healthcare Team Outcomes
Neonatal epilepsy syndromes are complex and necessitate care from multiple disciplines. Identifying these syndromes requires high suspicion from the neonatologist, who is often the first to evaluate these infants. When a syndrome is suspected, the neurology, neonatal neurology, and pediatric epilepsy teams are consulted for further evaluation. This includes EEG interpretation, determining the underlying cause, managing difficult seizures, predicting neurodevelopmental outcomes, and providing counseling to parents.
An interprofessional team of healthcare providers is crucial for managing complex cases both in the hospital and during outpatient follow-up. These neonates often require care from multiple specialists, and a multidisciplinary clinic helps streamline their treatment while ensuring coordination among providers. The collaboration of pediatricians, developmental specialists, pediatric neurologists or epileptologists, physical medicine and rehabilitation specialists, and therapists provides optimal support for the child and their family.
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