Pharmacological Management of Neonatal Seizures

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Lithuanian University of Health Sciences

Faculty of Medicine

Department of Neonatology

Pharmacological Management of Neonatal

Seizures

Author: Femi Maria Varghese

Supervisor: Asist. Kristina Štuikienė

Final Master’s Thesis

Kaunas, Lithuania, 2021

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1. ABSTRACT

Author: Femi Maria Varghese

Title: Pharmacological Management of Neonatal Seizures

Aim: The aim of this article is to review the current studies and knowledge about the pharmacological

treatment of neonatal seizures and to assess the role of EEGs in their management.

Objectives:

1. To evaluate recent data to find the most efficacious pharmacological management of neonatal seizures

2. To assess the role of EEG monitoring and diagnosis on the treatment protocol

3. To compare the differences in pharmacological management of seizures according to the most common aetiologies

4. To assess the effect of combination therapy on the effectiveness of seizure control

Material and Methods: The collection of articles was carried out in accordance with the PRISMA

methodology. Included studies were collected from PubMed and Google Scholar databases using the key words: neonatal seizure, newborn, pharmacological treatment, and management. Initial search revealed 3225 articles between the two databases. Additional filters (human studies, English language and published between 2013 and 2021) were then applied, and the remaining articles were screened manually according to the eligibility criteria to reveal 21 articles that are included in this review.

Results: The 21 articles that were selected, consisted of both retrospective and prospective studies. 20

articles were clinical trials, and 1 article was a qualitative analysis based on a questionnaire. The studies included evaluated the effectiveness of phenobarbital, levetiracetam and other antiepileptic drugs by analysing seizure cessation and the short- and long-term effects and outcomes.

Conclusion and Practical Recommendations: Phenobarbital and levetiracetam were both evaluated as

the main pharmacological treatment strategies with the latter proving to be more efficacious and safer. EEGs are a crucial part of early diagnosis and treatment. Early detection led to less adverse effects and quicker time to seizure freedom, however, interpretation was shown to be difficult due to different factors and requires further study and education. The most common aetiology of these seizures is hypoxic-ischemic encephalopathy accounting for an overwhelming majority. The treatment principles, however, remain unchanged regardless of the aetiology. Time to seizure freedom was shown to be faster with multiple antiepileptic drugs when compared to monotherapy. Nevertheless, further research is needed to investigate the management efficacy. Furthermore, more studies are needed regarding the

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many aetiologies of neonatal seizures and to evaluate if there are any interactions between the aetiological treatment and seizure management.

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2. ACKNOWLEDGEMENTS

I would like to extend my sincere gratitude to my supervisor Asist. Kristina Štuikiene for her patience, guidance, and help throughout the writing of this final master’s thesis.

3. CONFLICT OF INTEREST

The author reports no conflicts of interest.

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4. TERMS

Gestation – the time between conception and birth. Gestation age is a measure of the age of a

pregnancy with the normal pregnancy ranging between 38-42 weeks.

Ictal – the time from the first symptom to the end of the seizure activity or seizure period. It is during

the ictal phase that intense electrical activity is taking place in the brain.

Neonate – an infant in the first 28 days after birth. Neonatal period – the first 4 weeks of a child’s life.

Preterm – babies born before 37 weeks of gestation. Also known as premature infants or babies. Term – term pregnancy are babies born after 37 weeks of gestation.

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5. ABBREVIATIONS

AED Antiepileptic drug

aEEG amplitude integrated electroencephalography

CNS Central nervous system

ECMO Extracorporeal membrane oxygenation

EEG Electroencephalogram

GABA Gamma-amino-butyric acid

HIE Hypoxic-ischemic encephalopathy

KCC2 Potassium-chloride cotransporter 2

LEV Levetiracetam

MRI Magnetic resonance imaging

NKCC1 Sodium-potassium-chloride cotransporter 1

NMDA N-methyl-D-aspartate

PHB Phenobarbital

PRISMA Preferred reporting items for systemic reviews and meta-analyses

SGA Small for gestation age

SV2A Synaptic vesicle protein 2A

TORCH Toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex

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6. INTRODUCTION

The neonatal period is the most vulnerable time period for a child’s survival [1]. Neonatal seizures are the most common neurological emergencies that can occur in this period. These seizures can seriously disrupt the development of the newborn’s brain which is already immature and can present as early signs of brain damage, potentially resulting in cognitive disorders, developmental delay, epilepsy or cerebral palsy[2].

These neonatal seizures manifest similar to other types of seizures as paroxysmal, repetitive and stereotypical events. However, the most frequent neonatal seizures are expressed as subtle because the clinical manifestations are often neglected [3]. As a result of this, clinical diagnosis and recognition of seizures is unreliable and challenging. The accurate and timely identification can be heightened by the use of electroencephalogram (EEG) monitoring and these are now a gold standard in diagnosing neonatal seizures in many neonatal intensive care units [3, 4].

The management of neonatal seizures is crucial considering the many complications that can arise. Protocol differs between various healthcare professionals and healthcare centres regarding the antiepileptic drugs used. The most common antiepileptic drugs used are phenobarbital (PHB) and levetiracetam (LEV) with the latter gaining popularity over the recent years, however, controversy still exists about the optimal choice of treatment with regards to safety, efficacy and tolerability.

This article aims to review the current literature on the pharmacological management of neonatal seizures, to analyse which pharmacological method is the most efficacious and to also assess the value and role of EEG on the management.

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7. AIMS AND OBJECTIVES

Aim: This review aims to analyse literature to find the different pharmacological means of managing

and treating neonatal seizures.

Objectives:

1. To evaluate recent data to find the most efficacious pharmacological management of neonatal seizures

2. To assess the role of EEG monitoring and diagnosis on the treatment protocol

3. To compare the differences in pharmacological management of seizures according to the most common aetiologies

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8. LITERATURE REVIEW

8.1 Definition of neonatal seizures

A seizure can be defined as a paroxysmal electroclinical phenomenon that is characterised by the occurrence of transient signs and symptoms which develop due to an abnormal, excessive, or synchronous neuronal activity in the brain. When these transpire within the first 28 days after birth in a term neonate or before 44 weeks of gestational age in a preterm neonate, it is classed as neonatal seizures [5].

8.2 Epidemiology

Neonatal seizures are the most common neurological emergency in newborns. These seizures occur with the highest frequency within the first week of life (almost 60%) than at any other time[2].The exact incidence rate is hard to identify, however, various reports have estimated it to occur in 0.1% - 0.5% of newborns. Term infants have an incidence rate of 1.5-3.5 per 1000 live births and preterm infants have an incidence rate of 10-130 per 1000 live births.The incidence rate increases as the gestational age and the birth weight decreases [6]. It is reported to be approximately at 4.4 per 1000 live births for babies between 1500 and 2500g, 55-130 per 1000 live births for babies <1500g and up to 64 per 1000 live births in infants <1000g [7].

8.3 Risk Factors

The risk factors for neonatal seizures can be divided into three categories: maternal (nulliparity, diabetes mellitus – pre-existing or gestational), intrapartum (foetal distress, placental abruption, and chorioamnionitis) and infant (lower gestational age, low birth weight, post term >42 weeks, and male sex). In preterm infants the strongest risk factor is a birth weight of <1500g, which is followed by the male gender. In term infants, the most significant factors are low birth weight, caesarean section, and young maternal age [8].

8.4 Aetiology

The aetiology of neonatal seizures is diverse and extensive; however, the prevalence of the aetiological factors varies between developed and developing countries. This is dependent on the care and treatment available in both obstetric and neonatal departments, as well as access to electrodiagnostic techniques which leads to different rates of detection and diagnosis [3, 5]. A list of the main causes can be found in Table 1 together with their predominance in either term or preterm newborns. The majority of seizures in term newborns are due to hypoxic-ischemic encephalopathy (HIE), followed by stroke, and infections.

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12 For preterm newborns, the most common cause is intraventricular haemorrhage [5].Seizures due to HIE occur in the setting of birth asphyxia, respiratory distress or as a complication of various procedures such as extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass. The most common bacterial agents causing seizures include group B streptococcus and Escherichia coli. The nonbacterial causes include cytomegalovirus and intrauterine toxoplasmosis infections. Another common cause of neonatal seizures is due to malformations of cerebral development. The malformations that typically present with seizures include lissencephaly, polymicrogyria and focal cortical dysplasia [9].

Table 1: Aetiology of neonatal seizures [8 - 10]

Aetiology Frequency Term Preterm Acute Metabolic

Hypoglycaemia 0.1-5%

Hypocalcaemia, hypomagnesemia 1-4%

Rare inborn errors of metabolism (including pyridoxine responsive)

1-4% ++ +

Maternal drug withdrawal syndromes 4% ++ +

Cerebrovascular

Hypoxic-ischemic encephalopathy 40-60% +++

Arterial and venous ischemic stroke 6-17% +++ ++

Intracranial (intraventricular and periventricular) haemorrhage

7-18% + +++

CNS Infections

Bacterial meningitis/ septicaemia 2-14% +++ ++

Intrauterine (TORCH) infections

Malformations of cerebral development

3-17% ++ +

Idiopathic 2%

8.5 Pathophysiology

The pathophysiology of these seizures has been debated over the years and with the different aetiologies, it is hard to characterize into one specific mechanism. The main essence remains that the neonatal period is a time of increased physiological synaptic excitability. The balance between excitatory and inhibitory synapses are greatly towards the excitatory side. This model was seen in both humans and rodents, and

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there are increasing amounts of evidence to show that the neurotransmitter receptors are regulated according to development (Fig. 1) [9].

Figure 1: Glutamate and GABA receptors development in rodents and humans [9]

The excitatory neurotransmitter in the central nervous system (CNS) is glutamate and the major inhibitory neurotransmitter is Gamma-amino-butyric acid (GABA). In the mature, or adult brain, GABA causes hyperpolarisation of the neuronal membrane by inducing an influx of chloride ions. This makes the neuron unable to conduct an impulse. This mechanism of inhibition occurs due to the increased expression of potassium-chloride cotransporter 2 (KCC2) and decreased expression of sodium-potassium-chloride cotransporter 1 (NKCC1). In newborns, the proportion of expression is reversed with there being an increased expression of NKCC1 and decreased KCC2. This means that when GABA binds to its receptor, it causes an outflux of chloride ions, thereby depolarising the cell membrane and increasing the sensitivity of neurons to generate an action potential [2]. These structural changes and mechanism of depolarisation and hyperpolarisation can be seen depicted in Fig. 2.

In addition to that, the influx of chloride ions also activates N-methyl-D-aspartate (NMDA) receptors by triggering calcium currents. This in turn enhances the influx of calcium and sodium ions which increases brain excitability and therefore increases the risk of seizures [2, 9].

AMPA – α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, GABA – gamma-amino-butyric acid, NMDA – N-methyl-D-aspartate

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Figure 2: Mechanism of conduction and inhibition of impulses in immature and adult neurons [11]

8.6 Diagnosis

According to the World Health Organisation (WHO), the most accurate method of confirming whether a clinical event is of epileptic origin is through performing an EEG [12]. In neonates, the gold standard for diagnosis is video-EEG. The risk of doing an EEG on an infant is minimal – only slight discomfort and irritation of the scalp. However, in many neonatal units across the world there is limited or no access to an EEG. Therefore, a simplified tool called an amplitude integrated electroencephalography (aEEG) can be used. The aEEG displays a couple of the more commonly used channels of an EEG. This allows for faster assessment and diagnosis [13].

A review done by Okumaura [14] in 2012 evaluated the importance of conventional EEG and aEEG in the diagnosis of neonatal seizures. The review stated that studies that assessed these two modalities revealed that a large majority of neonatal seizures are not accompanied by any clinical symptoms and, in addition to that, in some cases where symptoms did occur, it did not correlate with the ictal EEG. These findings indicate that a phenomenon called electroclinical dissociation is an outstanding feature of neonatal seizures.

Cl-_{- Chloride ion, GABA}

A – Gamma-amino-butyric acid-A, KCC2 -

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Although recognition of these changes is a very significant factor in quick and early diagnosis and management, interpretation of both EEG and aEEG can be challenging as there may be many artifacts visible that could be misdiagnosed as seizures. The ictal EEG changes are characterised by sudden, repetitive, rhythmic events that consist of a clear beginning, middle, and end. These changes should also evolve in frequency and amplitude and, as well as that it should last for more than 10 seconds on two or more EEG channels [14, 15]. The ictal changes can be seen in Fig. 3.

Figure 3: Ictal changes in a conventional EEG [14] (Arrows indicate the foci of different ictal EEG loci)

8.7 Drug treatment of neonatal seizures

PHB is one of the most widely used antiepileptic drugs in the neonate for seizures. It belongs to a class of medications called barbiturates. The therapeutic range for PHB is 20-40ug/ml. It acts through stimulating GABA receptors in the CNS leading to a postsynaptic rise in chloride ions which in turn reduces the neuronal excitability. PHB remains in the body for a long time with a half-life of

approximately seven days [16]. It is metabolized by the liver and excreted mainly by the kidneys [17]. Phenytoin, an anticonvulsant is another drug commonly used in treating neonatal seizures. This drug works by preventing the spread of abnormal neuronal depolarization from the focus to the surrounding neurons. This is accomplished by delaying the neuronal recovery process, in which the Na+ channels transition from refractory to the responsive state. The peak concentrations of phenytoin are reached at 3 to 12 hours and the half-life ranges from 6 to 24 hours. Most of the phenytoin is eliminated as

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16 inactive metabolites in the bile, but it may also be secreted by the salivary glands which is a key

contributing factor for hyperplasia or gingival overgrowth that may occur [17, 18].

Another anticonvulsant used by many neonatologists is LEV. The pharmacokinetics of LEV differ slightly according to age. The half-life was found to be longer in neonates (approximately 8.9 hours compared to 6 to 8 hours in adults) due to lower clearance rates. The exact mechanism of action of LEV is unclear but current knowledge suggests that LEV binds to synaptic vesicle protein 2A (SV2A) which is a membrane bound protein that plays a role in the modulation of synaptic transmission. Stimulation of the presynaptic SV2A by LEV may inhibit the neurotransmitter release without affecting normal neurotransmission. It is absorbed very rapidly and has a reported absolute oral bioavailability of 100% which makes it a very efficient drug for the management of neonatal seizures [19].

Benzodiazepines, although used primarily as sedative or antianxiety drugs, can be used to treat seizures in the neonatal period, especially, midazolam. It also interacts with the GABA receptor similar to PHB but is largely used when PHB or other drugs are ineffective. It has a short half-life in neonates with doses up to 0.3mg/kg/h being used for antiepileptic reasons which is more than the dosage required for sedation (approximately 0.1mg/kg/h). [16]

In addition to that, lidocaine an anesthetic has also been known to be used as a second- or third-line drug when the seizures are not responding to traditional therapy. Lidocaine is metabolized mainly in the liver and in neonates, it has an elimination half-life of 3 hours. This increases up to 4 to 8 hours after long-term intravenous administration [20].

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9. RESEARCH METHODS AND METHODOLOGY

9.1 Data Sources and Searches

Published literature that were relevant to the topic of pharmacological management of neonatal seizures were extracted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) method. The PubMed database and Google Scholar search engines were used for the collection of the articles. A combination of the following terms was used to formulate the primary search: (‘neonatal seizure’ OR ‘newborn seizure’) AND (‘pharmacological management’ OR ‘pharmacological treatment’). Then additional filters were applied to both data sources as illustrated in Table 2.

Table 2: Filter parameters in primary data sources

PubMed Google Scholar

o Humans o English

o Newborn: birth – 1 month o Between 2013 to 2021

o Between 2013 to 2021

9.2 Inclusion and Exclusion Criteria

After the initial filters were applied, the studies were manually screened according to the inclusion and exclusion criteria listed in Table 3. Firstly, the abstracts were analysed and then the full article was read to select the articles that were eligible for the review.

Table 3: Inclusion and Exclusion Criteria

Inclusion Exclusion

o Data from original studies o Full text available

o Neonatal seizures specified o Pharmacological therapy

specified o Cohort study

o Case or clinical trials o Human studies o English language

o About adult seizures o Duplicate publications

o Abstract or no full text available o Literature or systematic review o Meta-analysis

o Animal or non-human studies o Not focused on management o Pharmacological therapy not

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9.3 Data Extraction

For each study selected for the review, the following data was extracted: author’s last name, year of publication, country of origin, study design, sample size, method of diagnosis and monitoring, the pharmacological drug/s evaluated, and results summary. All this information was systematised and arranged into Table 6.

9.4 Study Selection

The process of study selection involved four stages which can be seen depicted in Fig. 3. as a PRISMA flow chart. The initial search on PubMed database and Google Scholar search engine identified a total of 3225 articles. After that, filters were applied that narrowed down the article number to 642. There were 2 duplicates that were found immediately and after elimination of those, the abstracts of the remaining 640 articles were screened manually according to the inclusion and exclusion criteria (Table

3). This stage eliminated 579 studies as they adhered to the exclusion criteria. The remaining 61 articles

were then read fully and from that, 21 articles were found to be relevant to the topic and therefore, included in this review.

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Fig 3. PRISMA flow diagram showing the study screening and selection process

Articles identified through PubMed database searching (n = 2901) S cr ee n in g In clu d ed E li g ibi li ty Id en tif icat

ion _{Articles identified through Google}

Scholar (n = 324)

Articles excluded after reading title and abstracts

(n = 579) Full-text articles assessed

for eligibility (n = 61)

Full-text articles excluded, with reasons

(n = 40) Studies included in review

(n = 21) Articles identified after application

of filters (n = 478)

Articles identified after application of filters

(n = 164)

Articles after elimination of duplicates and abstracts assessed for eligibility

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10. RESULTS AND THEIR DISCUSSION

The reviewed articles and studies all confirmed the need for rapid administration of antiepileptic medication, as the onset of the seizure comes with the highest seizure burden and can contribute to adverse neurodevelopmental outcomes. Some antiepileptic drugs have emerged in multiple studies as efficient in treating this neonatal emergency.

10.1 Phenobarbital (PHB)

The most common antiepileptic drugs used to treat neonatal seizures are PHB and phenytoin. In this review, 17 of the articles had neonates who had received PHB either as first line or second line therapy. Spagnoli, et al. [21] Dwivedi, et al. [22] Nataraja, et al. [23] and Low, et al. [24] assessed PHB on its own, looking at either the response rate, the short-term effects or the effect of withholding maintenance. Spagnoli, et al. [21] investigated 91 newborns who had received PHB. 62.6% of them responded completely to the treatment and 16.5% responded partially (an additional PHB bolus was necessary). Low, et al. [24] revealed similar results that showed that a loading dose of PHB resulted in significantly reduced seizure burden within 1 hour of administration. 65% of cases had seizure cessation when the dose administered was 20mg/kg. However, this reduction was shown to be temporary and was likely to return beyond 4 hours of administration. Low, et al. [24] also found that doses at 20mg/kg showed significantly more effectiveness in reducing seizure burden than doses at 10mg/kg.

One study compared the response rate of PHB and phenytoin. Pathak, et al. [25] randomly allocated 109 infants into two groups (55 to phenytoin and 54 to PHB). The results were significant for PHB. Only 14.5% of neonates who received phenytoin had seizure cessation, while 72.2% of neonates who received PHB achieved seizure cessation. This superiority of PHB was evident as a single drug and even after crossover with phenytoin.

10.1.1 Withholding PHB maintenance

PHB in neonates may be associated with adverse neurological outcome following long-term administration, therefore, the continuation or withdrawal of PHB has been debated. This review found three articles (Jindal, et al. [26] Saxena, et al. [27]Natarajan, et al. [23]) that investigated the effect of early withdrawal of PHB. Jindal, et al, [21]reported similar incidence rates of seizure recurrence in the PHB withdrawal and PHB continued groups. The study was conducted with neonates who had initially received a loading dose of PHB of 20mg/kg and remained seizure free after 12 hours of the loading dose.

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Saxena, et al. [27] also presented with the conclusion that there was no significant increase in the occurrence of clinical breakthrough seizures after withholding PHB maintenance. Both studies randomised the allocation of maintenance and withdrawal for the enrolled babies. An important finding in the study by Saxena, et al. that was noted, was that, there was a lower survival rate in the PHB withdrawal group when compared with the PHB maintained group (50.9% and 65.1% respectively) however, the author commented that it may be due to more severe illness being present in the withdrawal group.

Natarajan, et al. [23] found that the duration of PHB treatment depended on the duration of seizures with the period shortening if an additional medication was given. This study was also consistent with the other two studies in the suggestion that longer PHB treatment does not prevent seizure recurrence.

10.2 Levetiracetam (LEV)

The use of LEV has been gaining popularity over the recent years even though the data on efficacy and guidelines are inadequate [28]. Sedighi, et al. [29] evaluated 50 infants who were given LEV in a prospective non-blind, clinical trial in Iran. Of the 50 infants evaluated, 47 infants were seizure free at the end of the first week and 46 remained seizure free when followed up at 11 weeks. Additionally, there were no adverse effects observed. The 47 infants that became seizure free had received LEV doses of 20mg/kg/day for a few days. Others needed dosage up to 40mg/kg/day.

A retrospective study of 15 neonates done by Hnaini, et al. [28] evaluated the tolerability and effectiveness of high dose LEV. The study concluded that neonates who do not respond to the typical dosage, could be considered for further escalation. In 7 neonates a high dose LEV regimen of 80-100mg/kg/day was given. No adverse effects of any sort were noticed in any of the neonates and LEV did not need to be discontinued due to intolerance or inefficacy. This was consistent with findings of previous studies as well. Hnaini, et al. concluded that LEV is safe even at higher than standard doses and that it may add to seizure control although prospective studies are needed to confirm these findings.

10.2.1 Phenobarbital vs levetiracetam

A questionnaire sent out in the UK by Gossling, et al. [30]to clinical professionals found that 97.8% of unit guidelines recommended PHB as first-line. Not all those professionals that were questioned agreed that it was the most efficacious because 47.7% thought LEV was equally as effective. The reason given for this discrepancy was that it was because of tradition and familiarity. Sharpe, et al. [31] in a randomised controlled trial found that PHB was more effective then LEV, but this came with greater adverse effects on administration of PHB. Lui, et al. [32]compared the short-term efficacy between PHB

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22 and LEV and found that there was no significant difference in efficacy, but the cumulative survival rate of the LEV group was better. This study also showed that LEV had a better effect on the neurodevelopmental level after 16 weeks of treatment than PHB.

10.3 Midazolam and lidocaine

Midazolam is another effective antiepileptic drug (AED) for acute seizures in infants. A study conducted in Switzerland assessed the tolerability of midazolam as first-line treatment. It is theorised to be useful and effective due to its ease of administration (intranasal route), short onset of action and short half-life. In the study, 12 out of 72 (16.7%) infants responded well to the drug, whilst 25 of 72 were considered partial responders. Hypotension was the most frequent and notable adverse effect, affecting 7 patients, however, midazolam was not exclusively given to all of them (1 patient had also received PHB). [33] Another study conducted by Weeke, et al. [34] investigated the response rate of patients who received lidocaine and midazolam as second- or third-line AEDs. Both full-term and preterm infants were evaluated with results showing lidocaine being significantly less effective in preterm neonates. When comparing the two drugs, lidocaine showed a significantly higher response than midazolam as second-line and third-second-line AED (p = 0.049 and p = 0.086 respectively). Nonetheless, midazolam still had a high response rate as a third-line drug. This finding, in combination with midazolam being less prone to sedation than PHB and phenytoin, and there being no major potential for any drug - drug interactions makes midazolam very important in clinical practice, as most newborns with seizures are under polymedication [33].

10.4 Hypoxic – ischemic encephalopathy (HIE)

HIE is the most common aetiology of neonatal seizures in all the articles reviewed. Three of the articles specifically assessed the control of seizures associated with HIE. Lekha, et al. [35] retrospectively identified 44 neonates with mild to severe HIE who had underwent therapeutic hypothermia. The neonates received either PHB (n=13), LEV (n=18), LEV followed by PHB (n=21), or PHB followed by LEV (n=10). In this study, the time to seizure freedom was investigated and although LEV exhibited faster time to freedom and superior efficacy, it was noted that the severity of HIE was an independent predictor of longer duration to seizure freedom. Another observation that was found was that the newborns who received PHB first, exhibited higher severity scores and were more likely to exhibit short-term mortality.

Venkatesan, et al. [36]conducted a study with a larger cohort (n=127) of which 32 neonates were given LEV. This was including a mixture of first, second, and third – line therapies and the results showed

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84% of infants achieved seizure freedom with the addition of LEV within 72 hours. PHB was the drug given when LEV wasn’t first–line and, in this study, the evaluation of those that received PHB revealed worse neurodevelopmental outcomes than those who received LEV. This was especially evident in cognitive and motor areas.

Findings in Dwivedi, et al. [22] were also in agreement with the previous two studies. The author found that nonresponse to PHB in their study was associated with a higher seizure score, and on MRI investigation, it was revealed that the severity of brain injury was also associated with PHB nonresponse. All three articles suggest that although PHB has been used as first–line therapy, LEV is a good choice in those that develop neonatal seizures secondary to HIE.

10.4.1 Neonatal seizure treatment interactions with hypothermia

Therapeutic hypothermia has been linked with improving neurological outcomes in infants with moderate-to-severe HIE. Core rectal temperature of 33.5°C ± 0.5°C, can be achieved with both selective head cooling and whole-body cooling.If initiated within the first 6 hours of life, it decreases severe long-term neurodevelopmental disabilities and mortality [37]. Since hypothermia and the antiepileptic drugs administered for neonatal seizures may enhance the neuroprotective properties of each treatment, it was crucial that this was explored. Dwivedi, et al. [22] noted that, in their study, there was decreased seizure burden in neonates that were treated with hypothermia. Furthermore, those undergoing hypothermia also responded better to PHB. Although this didn’t reach statistical significance due to small sample size (n=50), it is a marker for further studies into this aspect of management. Sharpe, et al. [31] also suggested that Midazolam may be useful in neonates undergoing hypothermia as its metabolic clearance is less affected by the therapeutic hypothermia. [31]

10.5 Treatment in preterm neonates

Han, et al. [38]and Khan, et al. [39]evaluated the management of preterm neonates with seizures, whereas Kurtom, et al. [40] concentrated on extremely preterm neonates (<28 weeks of gestation). In all three studies LEV was mainly used in the treatment. Khan, et al. [39] analysed 12 neonates who were treated with intravenous LEV of whom 82% had achieved seizure freedom within 24 hours and 91% of neonates included had seizure freedom within 48 hours. The study concluded that intravenous LEV is efficient in managing the seizures in preterm neonates with no immediate or long-term adverse effects. It was also noted that 8 of the 12 patients received LEV because of failure of previous antiepileptic drugs and so it was suggested that intravenous LEV may be effective in preterm neonates when other medications may have failed.

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24 The same conclusion was reached in the study by Han, et al. [38]which also showed LEV as being efficacious and with no adverse effects occurring in the preterm neonate. This study however had results of only 57% of neonates demonstrating seizure cessation within 24 hours. Such variations in the efficacy could be due to many factors such as type of seizure, aetiology, and diagnosis and this would need further investigation.

Kurtom, et al. [40]who evaluated extremely preterm neonates presented drastically different results. Only 16% of the neonates in the cohort responded to LEV therapy alone and 45% needed additional medications. It was also highlighted that, of the infants in the study who were small for gestation age (SGA), none responded to monotherapy with LEV. Although, this study differed in the conclusion of effectiveness of LEV, it agreed with the previous two studies in reporting no presence of any adverse effects after administration of LEV.

10.6 Monotherapy vs combination therapy

Most of the studies reviewed in this article report of treatment response and adherence of monotherapy of the AED used. On the other hand, in the case of Soul, et al. [41]the trial was conducted to test the doses of bumetanide (n=27) given in conjunction with PHB in comparison to a control group (n=16) which was given normal saline. The author found no significant difference in the adverse events between treatment with bumetanide and the control, furthermore, there was greater reduction in seizure burden related to the dose and exposure of the additional drug. This indicates that there might be added benefits to administering a combination of drugs. As to which drugs are best used together or have the best efficacy, currently no studies were found, however, this is a great indicator for further research.

10.7 Role of EEGs in diagnosis and management of neonatal seizures

EEG monitoring was a staple in the diagnosis and monitoring of all the reviewed articles except one. Jindal, et al. [31]reported that the EEG facility was not available in their unit and so it could not be done. The other studies all used either the video-EEG or aEEG. In a study done by Rennie, et al. [4]

they extensively assessed neonates with and without electrographic seizures. In their study each seizure episode was classed as those recorded on the EEG with 2 hours interval between them. In this way it was easier to have a standard in the administration of AED which was considered appropriate if done within 60 minutes of the start of the episode. Although, in theory, this method was good, when it came to the results, the author noted that the use of AEDs was not always at the correct time or was not appropriate. This reflects how difficult EEG interpretation is, even for experienced users. The difficulty stems from the doctors having to look through hours of continuous EEG quickly and being able to

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differentiate between the artefacts that could be present. In the study mentioned, only on 11% (24 out of 221) of the occasions presented was an AED given within the time frame of 1 hour since seizure onset. This is a testament to the fact that even if video-EEGs and aEEGs are readily available, neonatal seizures are not always recognised and treated promptly.

10.8 Study Limitations

Study limitations are factors that could have negatively affected the quality and effectiveness of the review. The identified limitations for this review are mainly associated with the collection and selection of the articles that were used. Only two databases (PubMed and Google Scholar) were analysed, thereby decreasing the number of available studies. As well as that, by limiting the studies with the application of filters such as time period (2016 – 2021), English language, and age group, this further limits the number of studies available and there is an increased risk of missing relevant studies. Furthermore, only one author manually reviewed the data which increases the bias. Limitations within the evaluated studies were also seen as the majority of the studies included only had a small cohort of patients, which again leads to increased bias.

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Table 6. Summary of included studies for the pharmacological management of neonatal seizures

No Author Country Type of Study Number of Patients Diagnosis and monitoring Special Considerations Antiepileptic drugs used Conclusions 1 Rennie JM, et al. 2018 [4] UK, Sweden, The Netherlands, Ireland Prospective and retrospective, Multi-centre 214 Continuous EEG PHB (n=104) Midazolam (n=4) Lidocaine (n=2) LEV (n=1)

Even with access to cEEG monitoring, seizures occur very often and are difficult to treat 2 Spagnoli C,

et al. 2016 [21]

Italy Retrospective 91 Clinical,

continuous video-EEG Neonates with electrographically confirmed neonatal seizures PHB 62.6% complete response (n=57) No response in 20.9% (n=19). Background EEG activity and seizure type were to be predictors of effectiveness 3 Dwivedi D, et al. 2019 [22] USA Retrospective, Single-centre

50 EEG, MRI Neonates included

all had perinatal asphyxia or HIE

PHB PHB responders (n=30), PHB

nonresponders (n=20).

Severity of brain injury found on MRI was associated with

nonresponse to PHB. 4 Nataraja N,

et al. 2017 [23]

USA Qualitative 83 Clinical,

EEG, aEEG Neonates with symptomatic seizures whose seizures were controlled within 30 days PHB Early discontinuation of PHB is

supported and shows no increase in risk of postnatal seizures

5 Low E, et al. 2016 [24]

Ireland, UK Cohort 19 EEG Neonates with

electrographic seizures

PHB PHB significantly reduced

seizures within 1 hour, however reduction is not permanent 6 Pathak, G, et al. 2013 [25] India Open-label randomised controlled trial 109 EEG Phenytoin (n=55) PHB (n=54)

PHB more efficacious than phenytoin irrespective of aetiology 7 Jindal A, et al. 2021 [26] India Open-label randomised controlled trial 221 (PHB withdrawal n=112, PHB

Clinical Neonates selected were clinically stable term and near-term

PHB (n=93) Phenytoin (n=25) LEV (n=14)

Early withdrawal of PHB maintenance was not associated with statistically significant

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continued n=109)

increase in rate of seizure recurrence 8 Saxena P, et al. 2016 [27] India Randomised, double-blind trial 152 Clinical, EEG Neonates included were those that remained seizure free for 12 hours after initial therapy with PHB

PHB (n=77) Control (n=75)

Clinical breakthrough seizures not likely to increase significantly following withholding PHB maintenance after loading dose

9 Hnaini M, et al. 2020 [28]

Lebanon Retrospective, Cohort

15 Video-EEG LEV LEV was found to be safe at

higher than standard doses and no adverse effects were found

10 Sedighi M, et al. 2016 [29] Iran Prospective, Clinical trial 50 Clinical, EEG

LEV (n=50) LEV effective in controlling neonatal seizures (n=47) with no immediate or long-term side effects 11 Gossling L, et al. 2020 [30] UK Questionnaire 100 Video-EEG, aEEG PHB LEV Phenytoin

PHB was generally found to be first line treatment, however, doctors were willing to change to LEV if it was found to be equally as effective as PHB 12 Sharpe C, et al. 2020 [31] USA Multicentre, randomised blind phase IIb trial

83 Continuous

video-EEG

Term neonates with a weight of at least 2.2kg selected

LEV (n=53) PHB (n=30)

Greater efficacy was achieved with PHB, however, PHB also came with more adverse effects. Rate of LEV efficacy increased with dose increment

13 Liu BK, et al. 2019 [32] China Retrospective, Cohort 125 Clinical, EEG Neonates selected were all given PHB or LEV for at least 3 days

PHB (n=66) LEV (n=59)

No significant difference between PHB and LEV in efficacy in the short term, however, LEV group showed better long-term efficacy 14 Dao K, et

al. 2018 [33]

Switzerland Retrospective 72 Clinical,

aEEG Neonates were included who received midazolam as first-line treatment

Midazolam 16.7% responders (n=12) and 48.6% non-responders (n=35). However, its well tolerated and no severe adverse reactions

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28 15 Weeke L C, et al. 2015 [34] The Netherlands Retrospective, Cohort 413 (full-term n=319, preterm n=94) Continuous aEEG Neonates were included who received Lidocaine as second- or third-line AED Lidocaine Midazolam

In full term, response to lidocaine as second-line was significantly better than midazolam. Both had higher response rate as third-line 16 Lekha M. Rao, et al, 2018 [35] USA Retrospective, Single-centre cohort 44 Continuous video-EEG

Infants with HIE undergoing therapeutic hypothermia PHB (n=13) LEV (n=18) PHB followed by LEV (n=10) LEV followed by PHB (n=3) Seizure free (n=34) Died (n=10)

Initial treatment with LEV predicted a shorter interval to seizure freedom. 17 Venkatesan C, et al. 2016 [36] USA Retrospective, Single-centre, Cohort 127 Continuous video-EEG (not used in all) Neonates with seizures due to HIE

PHB (n=80) PHB followed by LEV (n=32) LEV as 3rd line (n=2)

Seizure cessation was achieved within 72 hours in 84% of neonates that had LEV added

18 Han J Y, et al. 2018 [38]

South Korea Retrospective 37 Clinical,

Continuous video-EEG All neonates included were preterm (<37 weeks) LEV (n=21) LEV and PHB (n=9) LEV and PHB and other (n=7)

Seizure cessation within 24 h in 57% with just LEV. No adverse reactions occurred, and LEV was tolerated well

19 Khan O, et al. 2013 [39]

USA Retrospective 12 Continuous

video-EEG

Preterm neonates treated with IV LEV

LEV 82% seizure cessation after 24

hours with no adverse effects 20 Kurtom W, et al. 2019 [40] USA Retrospective, Cohort 61 Continuous video-EEG Neonates <28 weeks of gestation age only were included in cohort

LEV LEV monotherapy was not

successful for seizure control in 74% of extreme preterm neonates. Those SGA had no response with LEV monotherapy 21 Janet S. Soul, et al. 2020 [41] USA Randomised, double-blind trial 43 Continuous video-EEG Neonates after initial therapy with PHB

Bumetanide (n=27)

Control – saline (n=16)

Addition of Bumetanide showed a statistically significant benefit over monotherapy with PHB

UK – United Kingdom, EEG – electroencephalogram, PHB – phenobarbital, LEV – levetiracetam, USA – United States of America, MRI – magnetic resonance imaging, HIE – hypoxic-ischemic encephalopathy, IV – intravenous, SGA – small for gestation age

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11. CONCLUSION

1. In practise, phenobarbital is widely used, and it was found to be the first-line drug in the majority of centres and studies analysed. The efficacy and safety of phenobarbital, however, was discovered to be lower than that of levetiracetam which has been gaining popularity over the recent years. Midazolam and lidocaine were also analysed but concluded to be better as second or third-line antiepileptic drugs.

2. EEGs and/or aEEGs were used for diagnosis and monitoring and was found to be a crucial part of early diagnosis as most seizures in the neonatal period remain asymptomatic and hence overlooked. However, interpretation of an EEG has revealed to be complicated and so, many seizure episodes are missed in diagnosis, leading to untimely management. Conventional EEG remain the gold standard, even though aEEGs are more readily available and can be done faster.

3. The most common aetiology of neonatal seizures is hypoxic-ischemic encephalopathy with an overwhelming majority. Administration of therapeutic hypothermia in the cases of hypoxic-ischemic encephalopathy revealed greater treatment adherence although this was without statistical significance and requires further investigation.

4. Administration of a combination of phenobarbital and bumetanide showed great promise in seizure burden reduction, but unfortunately no other studies or articles were found to back up this finding. This reiterates the requirement for further investigations into the management of neonatal seizures.

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12. PRACTICAL RECOMMENDATIONS

Although more studies are emerging, there is still a lack of randomised controlled trials to evaluate the efficacy of multiple antiepileptic drugs and to formulate a protocol of therapy wherein the first-, second-, and third-line drugs are known and universal. In addition to that, there is an urgent need for more studies regarding the many aetiologies of neonatal seizures and to evaluate if there are any interactions between the aetiological treatment and seizure management. Further education of EEG reading should also be made available for medical professionals to enable them to have a clear, precise, and early diagnosis of neonatal seizures. This will also help to minimise the risk of missed seizure episodes.

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