Treatment of neonatal seizures: from guidelines to precision therapy
- Open Access
- 01.12.2025
- Correspondence
Erschienen in:
Overview
Neonatal seizures represent one of the most common neurological emergencies in newborns, with significant implications for long-term neurodevelopmental outcomes. Current management strategies, as outlined in Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures, advocate for a stepwise approach [1]. These recommendations prioritize the administration of phenobarbital as the first-line therapy for initial seizure control, followed by consideration of alternative anti-seizure medications (ASMs) in refractory cases [1, 2]. However, it is critical to note that even when phenobarbital effectively controls seizures, it does not exclude underlying causes that may require targeted precision therapies. Among these alternatives, therapies considered precision-based include pyridoxine (vitamin B6) for pyridoxine-dependent epilepsy, sodium channel blockers such as carbamazepine or oxcarbazepine for suspected channelopathies and specific interventions for metabolic disorders identified through biochemical screening [3]. Precision therapies are considered transformative as they directly address the underlying pathology, altering the disease course and improving outcomes [4]. Pyridoxine, in particular, exemplifies an early and effective form of precision therapy, demonstrating the profound impact that such treatments can have on the natural history of the disease.
Current guideline-based therapy
Current guidelines emphasize the use of phenobarbital, given its long-standing history, relative safety profile, and efficacy in neonatal seizure suppression [1, 2, 5]. However, the drug’s use is not without limitations, including concerns regarding its impact on neuronal development and cognitive outcomes [6‐9]. In cases where phenobarbital fails to control seizures, second-line agents such as phenytoin, levetiracetam, or midazolam are recommended [1, 2]. Pyridoxine supplementation is also specifically highlighted as a targeted therapy in neonates suspected of having pyridoxine-dependent epilepsy, a rare but treatable cause of refractory neonatal seizures.
Anzeige
While these guidelines provide a structured framework for managing neonatal seizures, they are rooted in a generalized appr. oach. This “one-size-fits-all” strategy, in search for the holy grail- a single medication that works for all seizures- often delays the initiation of individualized treatments that may yield superior outcomes. Precision therapies, by directly addressing the underlying etiology of seizures, have the potential to change the disease's natural course, improving not only seizure control but also long-term neurodevelopmental outcomes. Their transformative impact underscores the necessity of integrating such approaches earlier in the management algorithm to ensure timely, etiology-specific interventions [4].
The need for precision therapy in neonatal seizures
Emerging evidence underscores the heterogeneity of neonatal seizures, which often arise from diverse etiologies such as hypoxic-ischemic encephalopathy (HIE), metabolic disorders, structural abnormalities, genetic channelopathies, and neonatal seizures secondary to stroke. A deeper understanding of these underlying mechanisms is reshaping the paradigm of neonatal seizure management. Precision therapy aims to tailor treatments based on the individual’s specific etiological, genetic, and biochemical profiles.
With genetic etiologies accounting for > 50% of neonatal-onset epilepsies, the current role of early genetic testings’ application in clinical practice, such as whole exome sequencing (WES)/whole genome sequencing (WGS) or more rapid panels of next generation sequencing (NGS), has been clearly stated, even though a diagnosis and, hence, a treatment is often initiated based on clinical and electrographic features [10‐16].
For instance, in cases of suspected channelopathies—even in the absence of definitive clinical or diagnostic features—the early use of sodium channel blockers (e.g., carbamazepine or oxcarbazepine) could potentially prevent further neurological damage [17, 18]. Studies have shown that carbamazepine and oxcarbazepine are effective in controlling seizures related to sodium channelopathies in up to 70–80% of cases, particularly in conditions like gain-of function SCN1A, SCN2A, SCN8A, early onset epileptic encephalopathies and KCNQ2 loss-of function epilepsies [17‐20].
Anzeige
This success rate underscores the importance of these drugs in mitigating seizures and preventing long-term neurological sequelae [10]. This highlights the need for a shift from reactive to proactive therapy, where the initial management is informed by diagnostic considerations rather than a trial-and-error approach.
Clinical clues for early etiology-specific therapy
Recognizing specific clinical and diagnostic indicators can enable clinicians to initiate etiology-specific therapy early, rather than relying on a generalized pharmacological approach. Enhancing diagnostic performance requires a detailed consideration of expanded clinical clues for various conditions [21]. Key clinical clues include:
1.
Metabolic Disorders:
-
◦ Persistent metabolic acidosis or elevated lactate levels, often indicative of mitochondrial dysfunction or other metabolic deficiencies.
-
◦ Hypoglycemia or hyperammonemia detected in blood tests, suggesting disorders like glycogen storage diseases or urea cycle defects.
-
◦ Specific triggers such as fasting, illness, or dietary protein load, which may precipitate metabolic crises.
-
◦ Poor feeding, lethargy, hypotonia, or vomiting within the first days of life, potentially pointing to inborn errors of metabolism.
-
◦ Characteristic “metabolic smells” such as a sweet, maple-like odor (maple syrup urine disease) or a musty smell (phenylketonuria).
-
◦ Unusual seizure patterns such as myoclonic jerks or burst suppression on EEG.
-
◦ Elevated plasma or CSF glycine levels, indicating nonketotic hyperglycinemia.
-
◦ Low CSF serine levels in serine deficiency after nonketotic hyperglicinemia.
-
◦ Newborn screening abnormalities including organic acidurias or aminoacidopathies, providing diagnosis to inherited metabolic disorders. Hence, not all centres can rely on specialized metabolic labs to provide rapid results; in these cases, a treatment based on clinical/EEG features and response to treatment should be considered.
-
◦ Targeted metabolic screening revealing enzyme deficiencies or genetic mutations.
-
◦ Abnormal neuroimaging findings like white matter abnormalities or basal ganglia lesions, often associated with metabolic encephalopathies.1.1Early-onset vitamin-dependent DEE
-
◦ Refractory seizures (focal, multifocal, epileptic spasms, generalized tonic/clonic, tonic-clonic seizures) often non-responding to first-line ASMs.
-
◦ Family history of neonatal seizures or consanguinity.
-
◦Improvement with empirical pyridoxine or pyridoxal phosphate (PNPO gene), folinic acid (FOLR1 gene).
-
◦ Laboratory findings indicating elevated alpha-aminoadipic semialdehyde and pipecolic acid in urine, plasma or cerebro-spinal fluid (CSF).
-
◦ Genetic testings revealing pathogenic variants in ALDH7A1 or PLBP (pyridoxine-dependent DEE) or PNPO gene (pyridox(am)ine-5’-phospatase-DEE).
-
2.
Structural Brain Abnormalities:
-
◦ Focal seizures with concordant findings on cranial ultrasound or MRI.
-
◦ Prenatal history of infections, ischemic events, or brain malformations.
-
◦ Macrocephaly or microcephaly noted at birth.
-
◦ Hemorrhagic events.
3.
Hypoxic-Ischemic Encephalopathy (HIE):
-
◦ Onset of seizures within the first 24 hours of life.
-
◦ History of perinatal asphyxia or low Apgar scores.
-
◦ MRI showing diffusion-restricted lesions consistent with hypoxic injury.
4.
Monogenic and Chromosomal Syndromes
-
◦ Dysmorphic features or congenital anomalies associated with syndromic causes.
-
◦ MRI showing possible association with brain abnormalities (though, often not already altered in early stages of specific disorders).
-
◦ Lack of response to first and second-line ASMs, often “drug-resistant seizures”.
-
◦ These clinical clues, in conjunction with targeted investigations, allow for early differentiation of seizure etiologies and the timely initiation of appropriate therapies, though future efforts must focus on achieving faster genetic testings and results.
5.
Neonatal-Onset Genetic Epilepsies:
-
◦ Tonic, myoclonic, tonic spasms, focal clonic, apnea or subtle automatisms seizures
-
◦ Refractoriness to first-line ASMs.
-
◦ Limited response to traditional ASMs, some syndromes (e.g. KCNQ2, SCN2A) may respond to sodium channel blockers.
-
◦ Interictal EEG: burst suppression or multifocal discharges, diffuse slowing.
-
◦ Normal development and neurological examination at onset, which rapidly evolves into abnormal neurological exam including hypotonia, poor suck or altered consciousness.
-
◦ Developmental delay or regression.
-
◦ Family history of epilepsy or neonatal death.
-
◦ Normal neuroimaging early on.
-
◦ Metabolic workup needed to rule out inborn errors of metabolisms: plasma aminoacids, urine organic acids, CSF studies, lactate, ammonia
Limitations of the current approach
The reliance on phenobarbital as a first-line agent reflects its historical role rather than its’ superiority in achieving optimal neurodevelopmental outcomes, though it must be said that no newer ASMs have proven, to date, to be overall more effective in treating neonatal seizures. Studies have shown that phenobarbitals’ efficacy in neonatal seizure control is limited, with seizure cessation in only 50–60% of cases [1, 2, 5, 22]. Furthermore, its potential neurotoxic effects raise concerns about its long-term use, particularly in vulnerable neonatal populations [6‐9].
A shift towards early precision therapy
The future of neonatal seizure management lies in the integration of precision medicine principles from the onset of clinical presentation. This approach requires:
1.
Comprehensive Diagnostic Workup: multidisciplinary readily available approach including neurophysiological monitoring performed by trained and skilled personnel, advanced genetic testing, metabolic screening, and neuroimaging should be implemented early to identify specific etiologies and guide treatment [12, 13]. In particular, a multigene approach with WES/WGS or rapid NGS when available, should always be considered and, ideally, readily available in neonatal intensive care units (NICUs) [12, 15, 16]Comprehensive Diagnostic Workup: multidisciplinary readily available approach including neurophysiological monitoring performed by trained and skilled personnel, advanced genetic testing, metabolic screening, and neuroimaging should be implemented early to identify specific etiologies and guide treatment [12, 13]. In particular, a multigene approach with WES/WGS or rapid NGS when available, should always be considered and, ideally, readily available in neonatal intensive care units (NICUs) [12‐16].
2.
Etiology-Driven Therapies: For example, pyridoxine should be administered early in neonates with unexplained seizures, given the potential for complete seizure resolution in pyridoxine-dependent epilepsy. Similarly, the use of sodium channel blockers in suspected channelopathies could significantly alter outcomes [4, 17‐20]. Etiology-Driven Therapies: For example, pyridoxine should be administered early in neonates with unexplained seizures, given the potential for complete seizure resolution in pyridoxine-dependent epilepsy. Similarly, the use of sodium channel blockers in suspected channelopathies could significantly alter outcomes [4, 17‐20].
3.
Biomarker Development: Identifying reliable biomarkers for specific seizure etiologies would facilitate rapid, targeted interventions [26]. Along with traditional biomarkers, including both genetic, metabolic (e.g. lactate, plasma aminoacids, serum glucose), electrophysiological, imaging and neurobiochemical markers such as S-100B (S100 calcium-binding protein-beta), NfL (neurofilament light chain protein) and NSE (neuron-specific enolase), emerging biomarkers are currently being exstensively studied and include CSF neurotransmitters (such as in pyridoxine-dependent epilepsy), proteomics/metabolomics, microRNAs and transcriptional markers [27, 28]. Biomarker Development: Identifying reliable biomarkers for specific seizure etiologies would facilitate rapid, targeted interventions [26]. Along with traditional biomarkers, including both genetic, metabolic (e.g. lactate, plasma aminoacids, serum glucose), electrophysiological, imaging and neurobiochemical markers such as S-100B (S100 calcium-binding protein-beta), NfL (neurofilament light chain protein) and NSE (neuron-specific enolase), emerging biomarkers are currently being exstensively studied and include CSF neurotransmitters (such as in pyridoxine-dependent epilepsy), proteomics/metabolomics, microRNAs and transcriptional markers [27, 28].
4.
Minimizing Neurotoxicity: though current evidences still support the use of Phenobarbital as first-line treatment in neonatal seizures [1, 5, 14, 29], the use of alternative and potentially less neurotoxic treatments based on disease mechanisms should always be considered when available, especially in cases where clinical features suggest or genetic tools enable clinicians to early identify etiology specific phenotypes; in such cases precision therapies including early initiation of sodium-channel blockers in specific genetic channelopathies, early vigabatrin in tuberous sclerosis complex should be considered not only to treat seizures but to reduce the risk of progressing to epilepsy and high seizure burden’s consequences [14]. Minimizing Neurotoxicity: though current evidences still support the use of Phenobarbital as first-line treatment in neonatal seizures [1, 5, 14, 29], the use of alternative and potentially less neurotoxic treatments based on disease mechanisms should always be considered when available, especially in cases where clinical features suggest or genetic tools enable clinicians to early identify etiology specific phenotypes; in such cases precision therapies including early initiation of sodium-channel blockers in specific genetic channelopathies, early vigabatrin in tuberous sclerosis complex should be considered not only to treat seizures but to reduce the risk of progressing to epilepsy and high seizure burden’s consequences [14].
Conclusions
The management of neonatal seizures is at a critical juncture, where traditional guideline-based therapies must evolve to incorporate the principles of precision medicine. By focusing on individualized, etiology-specific treatments from the onset of seizures, we can potentially improve both acute seizure control and long-term neurodevelopmental outcomes. This paradigm shift requires a collaborative effort among clinicians, researchers, and policymakers to refine diagnostic algorithms, prioritize early genetic and metabolic testing, and ensure the availability of targeted therapies. In particular, the integration of genetic and molecular advancements with NGS, WES, WGS readily available in a growing number of settings, telemedicine and artificial intelligence application, is completely changing the management of neonatal and infantile epilepsies, fostering precision-driven care. Continued research and innovation are essential to refine these strategies, optimize patient outcomes, and establish new, readily available, easy to access standards of care [13‐16].
Anzeige
Precision therapy is not merely the future of neonatal seizure management—it is an urgent imperative for improving the lives of affected neonates and their families.
Acknowledgements
We wish to thank AI for contributing in writing the paper and the authors in the reference list who contributed to our review providing information about their patients.
Declarations
Competing interests
The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
