Neonatal Seizures

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Template:Neonatal Seizures Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor-In-Chief: Joseph Nasr, M.D.[2]

Introduction and Definition

Neonatal seizures represent a critical neurological emergency in the newborn period, defined as seizures occurring within 4 weeks after birth in full-term infants or within 44 weeks of postmenstrual age in preterm infants. The International League Against Epilepsy (ILAE) has developed a comprehensive diagnostic framework to classify neonatal seizures,[1] which facilitates the use of common terminology and assists clinicians in making treatment decisions. This classification system has become essential for standardizing clinical practice and research in neonatal neurology.

Most neonatal seizures are transient and result from acute metabolic disturbances, infectious processes, or acute focal cerebral lesions, and are therefore considered to be provoked seizures. Provoked seizures are not classified as epilepsy, which is defined as two or more unprovoked seizures,[2] and typically do not require long-term treatment with antiseizure medication. In contrast, neonatal epilepsy syndromes, though uncommon, frequently have genetic causes and may require long-term treatment.[3]

Epidemiology and Incidence

The epidemiology of neonatal seizures reveals significant variation based on gestational age and clinical setting. The estimated incidence of neonatal seizures is 2.29 cases per 1000 live births.[4] However, this incidence varies substantially between preterm and full-term populations, with higher rates reported among preterm neonates compared to full-term neonates (14.28 cases per 1000 vs. 1.10 per 1000).[4] This differential incidence reflects the increased vulnerability of preterm infants to neurological complications and the distinct pathophysiological mechanisms underlying seizures in different gestational age groups.

The incidence data underscore the public health significance of neonatal seizures and highlight the need for specialized neonatal neurology expertise in intensive care settings, particularly those caring for preterm infants.

Etiology and Causes

The etiology of neonatal seizures varies significantly based on gestational age at birth. In full-term neonates, the most common cause of provoked seizures is hypoxic-ischemic encephalopathy (HIE), followed in frequency by stroke and infection. In contrast, in preterm neonates, the most common cause is intraventricular hemorrhage. Identifying the provoking event is essential for determining appropriate management strategies.

Hypoxic-Ischemic Encephalopathy

HIE represents the leading cause of neonatal seizures in term infants and is associated with significant morbidity and mortality. The pathophysiology involves a complex cascade of cellular injury following perinatal asphyxia. Studies have demonstrated that seizure-associated brain injury occurs in term newborns with perinatal asphyxia,[5] and prolonged seizures can exacerbate perinatal hypoxic-ischemic brain damage.[6] Risk factors for EEG seizures in neonates treated with therapeutic hypothermia for HIE have been well-characterized,[7] helping clinicians identify high-risk infants who may benefit from enhanced neuromonitoring.

Stroke and Vascular Injuries

Perinatal stroke represents an important cause of neonatal seizures, with both arterial ischemic stroke and hemorrhagic stroke contributing to the overall burden. These vascular events can result from diverse mechanisms including embolic phenomena, prothrombotic states, and vascular malformations.

Infectious Etiologies

Infectious causes of neonatal seizures include bacterial meningitis, viral encephalitis, and congenital infections. The inflammatory cascade triggered by central nervous system infections can lower seizure threshold and cause direct neuronal injury.

Genetic Epilepsies

Neonatal epilepsy syndromes, while less common than acute symptomatic seizures, represent an important category requiring distinct management. Benign familial neonatal epilepsy (BFNE) is characterized by seizures beginning in the first week of life in otherwise healthy neonates.[8] Genetic studies have identified mutations in KCNQ2 and KCNQ3 genes as causative in BFNE.[9] However, KCNQ2 mutations can also cause a severe neonatal epileptic encephalopathy with emerging phenotypic characteristics.[10] Self-limited familial neonatal epilepsy (previously called benign familial neonatal seizures) and self-limited neonatal epilepsy (previously called benign neonatal seizures or fifth-day fits) represent other genetic epilepsy syndromes with generally favorable outcomes.[11]

Early infantile epileptic encephalopathy represents the severe end of the spectrum of genetic epilepsies, with multiple genetic etiologies identified.[12] The genetic heterogeneity of neonatal epilepsies necessitates comprehensive genetic testing in appropriate clinical contexts.

Metabolic Disorders

Inborn errors of metabolism can present with neonatal seizures and require prompt recognition and specific treatment. Pyridoxine-dependent epilepsy and disorders of glycine metabolism represent examples of treatable metabolic epilepsies that must be considered in the differential diagnosis.

Pathophysiology

The pathophysiology of neonatal seizures reflects the unique developmental characteristics of the neonatal brain. The immature brain exhibits increased susceptibility to seizures due to several factors, including an imbalance between excitatory and inhibitory neurotransmission, developmental expression patterns of receptors and ion channels, and the energetic demands of the rapidly developing nervous system.

Rodent models have provided important insights into the mechanisms underlying neonatal seizures and their consequences.[13] These experimental studies have demonstrated that the developing brain responds differently to seizures compared to the mature brain, with implications for both acute injury mechanisms and long-term neurodevelopmental outcomes.

The relationship between seizures and brain injury in the neonatal period is complex and bidirectional. While acute brain injuries cause seizures, the seizures themselves may contribute to additional injury. [5][6] This has important implications for treatment decisions and the urgency of seizure control.

Clinical Presentation and Semiology

Neonatal seizures start focally but can spread to involve the entire body.[1] Seizures that begin in a generalized fashion are rare. Clinical seizures in neonates can be difficult to recognize because convulsive movements in babies are often complex, irregular, or subtle. This diagnostic challenge is compounded by the fact that some seizures have only an electroencephalographic (EEG) component without clinical manifestations.[14] The ILAE has emphasized the importance of EEG as essential for the identification of neonatal seizures.

Clinical Seizure Types

The semiology of neonatal seizures differs from that observed in older children and adults. Clinical manifestations may include:

  • Focal clonic seizures: Rhythmic focal jerking movements
  • Focal tonic seizures: Prolonged extension or posturing of the limbs
  • Automatisms: Repetitive, stereotyped movements such as oral-buccal movements, pedaling, or swimming motions
  • Autonomic features: Changes in heart rate, blood pressure, or oxygen saturation

Electroclinical Dissociation

A critical concept in neonatal seizure management is electroclinical dissociation—the phenomenon where electrical seizure activity on EEG occurs without corresponding clinical manifestations, or where clinical events occur without EEG correlates.[15] This dissociation has important implications for diagnosis and treatment monitoring.

Diagnosis and Diagnostic Methods

Diagnostic Certainty Framework

To address the limited availability of EEG in some settings, the Brighton Collaboration, a nonprofit global vaccine safety research network, has proposed a scheme with five levels of diagnostic certainty that can guide treatment decisions if EEG is not available.[16]

  • Level 1 (Highest certainty): A clinical event that occurs simultaneously with a seizure pattern on continuous EEG recording provides the highest level of certainty that the event is truly a seizure and requires treatment.
  • Level 2: When a suspected event has a focal clonic feature (rhythmic focal jerking) or tonic feature (prolonged extension of the limbs), with or without EEG corroboration, treatment is also considered to be justified.
  • Level 3: If there has been an event that could be a seizure but is not focal, clonic, or tonic and EEG is not available, treatment may be considered, but there is no clear guidance.[16]
  • Levels 4 and 5: Represent suspected seizures and events that are not seizures, respectively, where treatment is not required.

The same approach can be applied to single or multiple seizures.

Electroencephalographic Monitoring

Continuous EEG monitoring has become the gold standard for seizure detection in high-risk neonates. Studies have demonstrated that seizure control differs between neonates undergoing screening versus confirmatory EEG monitoring,[17] highlighting the importance of comprehensive neuromonitoring strategies.

The prognostic value of neonatal conventional-EEG monitoring in hypoxic-ischemic encephalopathy during therapeutic hypothermia has been well-established.[18] Early EEG findings in hypoxic-ischemic encephalopathy can predict outcomes at 2 years,[19] providing valuable information for counseling families and guiding clinical decision-making.

Amplitude-integrated EEG (aEEG) represents a simplified form of cerebral function monitoring that can be interpreted at the bedside.[20] While aEEG has limitations in seizure detection compared to conventional EEG,[21][22][23] it provides valuable information about background cerebral activity and can detect some seizures.

The exact ictal and interictal duration of electroencephalographic neonatal seizures has been characterized,[24] providing important information for understanding seizure burden and treatment response.

Neuroimaging

Neuroimaging plays a crucial role in identifying the underlying etiology of neonatal seizures. Magnetic resonance imaging (MRI) provides superior anatomical detail and is the preferred modality for characterizing brain injury patterns. Cranial ultrasonography offers the advantage of bedside availability and can detect hemorrhage and major structural abnormalities. Computed tomography may be used in acute settings when MRI is not immediately available.

Laboratory Investigations

Comprehensive laboratory evaluation is essential for identifying treatable causes of neonatal seizures. This includes assessment of glucose, electrolytes (particularly sodium, calcium, and magnesium), blood gas analysis, complete blood count, and markers of infection. In appropriate clinical contexts, metabolic screening, cerebrospinal fluid analysis, and genetic testing should be pursued.

Differential Diagnosis

Distinguishing true seizures from non-epileptic paroxysmal events in neonates presents a significant clinical challenge. Several benign phenomena can mimic seizures:

  • Jitteriness: Characterized by tremulous movements that are stimulus-sensitive and can be suppressed by passive flexion or gentle restraint
  • Benign neonatal sleep myoclonus: Myoclonic jerks occurring during sleep that cease when the infant awakens
  • Normal startles: Exaggerated startle responses to stimuli
  • Apnea: While apnea can be a manifestation of seizures, isolated apnea without other features is rarely ictal

The distinction between epileptic and non-epileptic events often requires EEG correlation, particularly when clinical features are ambiguous.

Treatment and Management

Acute Seizure Management

The management of neonatal seizures involves both acute treatment of ongoing seizures and identification and treatment of the underlying etiology. First-line antiseizure medications typically include phenobarbital, which remains the most commonly used initial agent.[25];[26] Painter et al., 1999). Second-line options include phenytoin or fosphenytoin, levetiracetam,[27] and lidocaine.[28][29]

Treatment Controversies

The optimal approach to treating neonatal seizures remains controversial, particularly regarding the treatment of electrographic-only seizures. A randomized controlled trial examining the effect of treatment of subclinical neonatal seizures detected with aEEG found no significant difference in neurodevelopmental outcomes between treated and untreated groups.[30] Similarly, another randomized controlled trial of treating EEG seizures in hypoxic-ischemic encephalopathy showed no clear benefit.[31] These findings have raised important questions about the risks and benefits of aggressive seizure treatment in the neonatal period.

However, observational studies have suggested associations between seizure burden and adverse outcomes. High electroencephalographic seizure exposure has been associated with unfavorable outcomes in neonates with hypoxic-ischemic encephalopathy.[32] Seizure burden has been independently associated with short-term outcome in critically ill children,[33] and seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy have been correlated.[34] The distinction between neonatal status epilepticus and recurrent neonatal seizures has clinical significance, with different clinical findings and outcomes.[35]

Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use has been documented,[15] and phenobarbital treatment has been associated with this phenomenon.[36]

Medication Options and Considerations

Several antiseizure medications are used in neonatal practice, though many are used off-label.[37] The choice of medication depends on multiple factors including etiology, availability, and institutional practice patterns.

Phenobarbital: Remains the most commonly used first-line agent.[25][26]

Levetiracetam: Has emerged as an alternative first-line or second-line option. A randomized controlled trial comparing levetiracetam versus phenobarbital showed similar efficacy.[27] However, concerns about adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam have been raised.[38]

Phenytoin: Used as a second-line agent, particularly when phenobarbital is ineffective. [26]

Midazolam: Can be used for refractory seizures.[39]

Lidocaine: Has been studied for neonatal seizures with development of optimal infusion strategies.[28] Lidocaine response rates in aEEG-confirmed neonatal seizures have been characterized.[29]

Etiology-Specific Treatment

Identifying and treating the underlying cause represents a critical component of neonatal seizure management. For HIE, therapeutic hypothermia has become standard of care and has been shown to improve outcomes. For metabolic causes such as hypoglycemia, hypocalcemia, or hypomagnesemia, correction of the metabolic derangement is essential. Pyridoxine-dependent epilepsy requires treatment with pyridoxine supplementation. Infectious causes require appropriate antimicrobial therapy.

Treatment of Genetic Epilepsies

Neonatal epilepsy syndromes may require specific treatment approaches. For example, self-limited familial neonatal epilepsy may respond to specific antiseizure medications, while early infantile epileptic encephalopathy may require multiple medications and specialized treatment approaches. The underlying etiology influences the extent to which seizures and EEG abnormalities affect outcome.[40]

Duration of Treatment

For acute symptomatic seizures, antiseizure medications are typically discontinued after the acute period if seizures have resolved and the EEG has normalized. In contrast, genetic epilepsy syndromes may require prolonged or lifelong treatment depending on the specific syndrome and response to therapy.

Design of Therapeutic Trials

Recommendations for the design of therapeutic trials for neonatal seizures have been developed,[41] recognizing the need for rigorous evidence to guide clinical practice.

Prognosis and Outcomes

The prognosis of neonatal seizures depends heavily on the underlying etiology, seizure burden, and associated brain injury. Neonatal seizures associated with HIE, stroke, or central nervous system infections generally carry a higher risk of adverse neurodevelopmental outcomes compared to seizures from transient metabolic disturbances.

Prognostic Factors

Several factors influence long-term outcomes:

Etiology: The underlying cause is the strongest predictor of outcome. Genetic epilepsies have variable prognoses depending on the specific syndrome, with self-limited epilepsies having favorable outcomes while early infantile epileptic encephalopathy carries a poor prognosis.

Seizure burden: Higher seizure burden has been associated with worse outcomes,[32][34] though the causal relationship remains debated given that seizure burden may be a marker of injury severity rather than an independent contributor to poor outcome. Seizure burden is independently associated with short-term outcome in critically ill children.[33]

EEG background: The background EEG pattern provides important prognostic information. Early EEG findings can predict outcomes at 2 years,[19] and the prognostic value of EEG monitoring during therapeutic hypothermia has been demonstrated.[18]

Response to treatment: Seizures that are difficult to control may indicate more severe underlying brain injury or genetic epilepsy syndromes.

Neuroimaging findings: The pattern and extent of brain injury on MRI correlate with neurodevelopmental outcomes.

Long-term Neurodevelopmental Outcomes

Long-term follow-up of infants with neonatal seizures reveals a spectrum of outcomes ranging from normal development to significant neurodevelopmental disabilities including cerebral palsy, intellectual disability, and epilepsy[4]. The risk of developing epilepsy later in childhood varies based on etiology, with higher risks in genetic epilepsy syndromes and lower risks in transient metabolic causes.

Future Directions

Several important areas require further investigation to improve the care of neonates with seizures:

Therapeutic Trials

The limited evidence base for neonatal seizure treatment necessitates additional randomized controlled trials to determine optimal treatment strategies. Key questions include:

  • Which antiseizure medications are most effective and safe in neonates?
  • What is the optimal treatment approach for electrographic-only seizures?
  • Does aggressive seizure control improve long-term neurodevelopmental outcomes?

The conflicting results from trials examining treatment of subclinical seizures [30][31] highlight the need for larger studies with longer follow-up periods. Recommendations for the design of therapeutic trials for neonatal seizures have been developed to address these questions.[41]

Biomarkers and Prognostication

Development of biomarkers that can predict which neonates are at highest risk for adverse outcomes would allow for targeted interventions and more accurate counseling of families. Integration of clinical, electrophysiological, neuroimaging, and molecular biomarkers may provide improved prognostic models.

Genetic Discovery

Continued advances in genetic technologies will likely identify additional genetic causes of neonatal epilepsy syndromes [9][10]. Understanding the genetic architecture of neonatal epilepsies may lead to targeted therapies and precision medicine approaches. Population-based cost-effectiveness studies of early genetic testing in severe epilepsies of infancy have demonstrated value.[11]

Neuroprotective Strategies

Given the potential for seizures to contribute to brain injury,[5][5][6] development of neuroprotective strategies that address both the underlying injury and seizure-related injury represents an important goal. Animal models continue to provide insights into potential therapeutic targets.[13]

Technology and Monitoring

Advances in EEG technology, including automated seizure detection algorithms and improved portable monitoring devices, may enhance seizure detection and allow for more widespread implementation of continuous EEG monitoring. The impact of screening versus confirmatory EEG monitoring on seizure control[17] suggests that monitoring strategies themselves influence outcomes and warrant further optimization.

Standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates has been developed,[42] facilitating communication and research in this field.

Understanding Mechanisms

Deeper understanding of the pathophysiological mechanisms underlying neonatal seizures, including age-specific vulnerabilities and the relationship between seizures and brain development, will inform development of targeted therapies. The unique characteristics of the developing brain require age-specific approaches to treatment.

References

  1. ↑ 1.0 1.1 Pressler RM, Cilio MR, Mizrahi EM, et al. The ILAE classification of seizures and the epilepsies: modification for seizures in the neonate: position paper by the ILAE Task Force on Neonatal Seizures. Epilepsia 2021;62:615-28.
  2. ↑ Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475-82.
  3. ↑ Shellhaas RA, Wusthoff CJ, Tsuchida TN, et al. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 2017;89:893-9.
  4. ↑ 4.0 4.1 4.2 Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: literature review. Eur J Paediatr Neurol 2015;19:6-14.
  5. ↑ 5.0 5.1 5.2 5.3 Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542-8.
  6. ↑ 6.0 6.1 6.2 Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50:445-54.
  7. ↑ Glass HC, Wusthoff CJ, Shellhaas RA, et al. Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study. Neurology 2014;82:1239-44.
  8. ↑ Plouin P, Anderson VE. Benign familial and non-familial neonatal seizures. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Epileptic syndromes in infancy, childhood and adolescence. 4th ed. Montrouge, France: John Libbey Eurotext, 2005:3-14
  9. ↑ 9.0 9.1 Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25-9.
  10. ↑ 10.0 10.1 Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71:15-25
  11. ↑ 11.0 11.1 Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 2018;59:1177-87.
  12. ↑ Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003;20:398-407.
  13. ↑ 13.0 13.1 Molinero I, Galanopoulou AS, Moshé SL. Rodent models: where it all started with these "truths." Eur J Paediatr Neurol 2020;24:61-5.
  14. ↑ Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837-44.
  15. ↑ 15.0 15.1 Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol 2003;28:277-80.
  16. ↑ 16.0 16.1 Jullien S, Smit G, Choonara I, et al. Brighton Collaboration Neonatal Seizures Working Group: neonatal seizures: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2019;37:7596-609.
  17. ↑ 17.0 17.1 Wusthoff CJ, Sundaram V, Abend NS, et al. Seizure control in neonates undergoing screening vs confirmatory EEG monitoring. Neurology 2021;97(6):e587-e596.
  18. ↑ 18.0 18.1 Bourel-Ponchel E, Querne L, Flamein F, Ghostine-Ramadan G, Wallois F, Lamblin MD. The prognostic value of neonatal conventional-EEG monitoring in hypoxic-ischemic encephalopathy during therapeutic hypothermia. Dev Med Child Neurol 2023;65:58-66.
  19. ↑ 19.0 19.1 Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG findings in hypoxic-ischemic encephalopathy predict outcomes at 2 years. Pediatrics 2009;124(3):e459-e467.
  20. ↑ Hellström-Westas L, Rosén I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med 2006;11:503-11.
  21. ↑ Shah DK, Mackay MT, Lavery S, et al. Accuracy of bedside electroencephalographic monitoring in comparison with simultaneous continuous conventional electroencephalography for seizure detection in term infants. Pediatrics 2008;121:1146-54.
  22. ↑ Rennie JM, Chorley G, Boylan GB, Pressler R, Nguyen Y, Hooper R. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child Fetal Neonatal Ed 2004;89:F37-F40.
  23. ↑ Toet MC, van der Meij W, de Vries LS, Uiterwaal CS, van Huffelen KC. Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates. Pediatrics 2002;109:772-9.
  24. ↑ Clancy RR, Legido A. The exact ictal and interictal duration of electroencephalographic neonatal seizures. Epilepsia 1987;28:537-41
  25. ↑ 25.0 25.1 Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed 2002a;86:F165-F170.
  26. ↑ 26.0 26.1 26.2 Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-9.
  27. ↑ 27.0 27.1 Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam versus phenobarbital for neonatal seizures: a randomized controlled trial. Pediatrics 2020;145(6):e20193182.
  28. ↑ 28.0 28.1 Malingré MM, Van Rooij LG, Rademaker CM, et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr 2006;165:598-604.
  29. ↑ 29.0 29.1 Weeke LC, Toet MC, van Rooij LG, et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: retrospective study of 413 full-term and preterm infants. Epilepsia 2016;57:e72-e77.
  30. ↑ 30.0 30.1 van Rooij LGM, Toet MC, van Huffelen AC, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics 2010;125(2):e358-e366.
  31. ↑ 31.0 31.1 Srinivasakumar P, Zempel J, Trivedi S, et al. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics 2015;136(5):e1302-e1309.
  32. ↑ 32.0 32.1 Fitzgerald MP, Massey SL, Fung FW, Kessler SK, Abend NS. High electroencephalographic seizure exposure is associated with unfavorable outcomes in neonates with hypoxic-ischemic encephalopathy. Seizure 2018;61:221-6.
  33. ↑ 33.0 33.1 Payne ET, Zhao XY, Frndova H, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014;137:1429-38.
  34. ↑ 34.0 34.1 Kharoshankaya L, Stevenson NJ, Livingstone V, et al. Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Dev Med Child Neurol 2016;58:1242-8.
  35. ↑ Pisani F, Cerminara C, Fusco C, Sisti L. Neonatal status epilepticus vs recurrent neonatal seizures: clinical findings and outcome. Neurology 2007;69:2177-85.
  36. ↑ Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbital, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed 2002b;86:F165-F170.
  37. ↑ Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008;39:77-9.
  38. ↑ Maitre NL, Smolinski C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol 2013;33:841-6.
  39. ↑ Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology 2004;62:486-8.
  40. ↑ Ramantani G. Neonatal epilepsy and underlying aetiology: to what extent do seizures and EEG abnormalities influence outcome? Epileptic Disord 2013;15:365-75.
  41. ↑ 41.0 41.1 Soul JS, Pressler R, Allen M, et al. Recommendations for the design of therapeutic trials for neonatal seizures. Pediatr Res 2019;85:943-54.
  42. ↑ Tsuchida TN, Wusthoff CJ, Shellhaas RA, et al. American Clinical Neurophysiology Society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates: report of the American Clinical Neurophysiology Society Critical Care Monitoring Committee. J Clin Neurophysiol 2013;30:161-73.

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