Diagnosis and Recent Advances in the Treatment of Neonatal Seizures: A Comprehensive Review
Dr Edwin Dias1*, Lathika A Nayak2
1. Professor and HOD, Department of Paediatrics, Srinivas Institute of Medical Sciences and Research Centre, Mangalore, Karnataka State, India.
2Final Year Pharm D, Srinivas College of Pharmacy, Valachil, Mangalore, Karnataka State, India, Orcid- ID: 0009-0007-7407-8280; E-mail: email@example.com.
*Correspondence to: Dr Edwin Dias, Professor and HOD, Department of Paediatrics, Srinivas Institute of Medical Sciences and Research Centre, Mangalore, Karnataka State, India, Orcid- ID: 000-0001-6266-795X; E-mail: firstname.lastname@example.org
© 2023: Dr Edwin Dias. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 09 October 2023
Published: 16 October 2023
Purpose: Neonatal seizures, defined as paroxysmal events associated with abnormal electrical activity in the neonatal brain, are a clinical emergency that requires immediate attention. Around 50 million people globally suffer with epilepsy, making it the third most common chronic brain ailments. It is a neurological condition that affects people of all ages and is non-communicable. This systematic review offers an overview of the most important pharmacological and non-pharmacological recommended treatments for neonatal seizures, as well as a description of the most recent clinical diagnostic considerations along with pharmacogenomic considerations supporting recent advances and recommendations of therapy.
Design/methodology/approach: Online databases and pertinent scholarly papers about the diagnosis and management of newborn seizures are used in the thorough review-based study. Using keywords, academic publications were generally retrieved from the PubMed database, Google Scholar, MEDLINE, as well as Web of Science, among other research database sites. The review-based analysis was conducted using the outcome papers, which included systematic reviews, research papers, and clinical guidelines in addition to the available pharmacogenomic data. Data from the selected articles were compiled and presented in accordance with various therapeutic modalities.
Findings/conclusion: Neonatal seizures distinct from those in infants and children in terms of their etiologies and electroclinical symptoms. Maximizing neurodevelopmental outcomes requires early detection, accurate diagnosis, and timely treatment of neonatal seizures. Due to the frequent application of continuous EEG monitoring, a correct diagnosis will lead to less unnecessary medical care and improved outcomes through quicker treatment. Numerous ongoing clinical trials have not yet had their findings published.
Keywords: Neonatal seizures, therapies, non-communicable, causes, treatment
Neonatal seizures are rather typical; in fact, this is the life stage at which they are most inclined to happen. They frequently appear as the very first symptom of severe brain dysfunction. Despite being frequently short-lived, they are nonetheless excellent warning signs of long-term developmental and cognitive dysfunction. [1,2]
Early recognition and treatment are crucial to prevent long-term neurological sequelae. Others have measured the incidence rate of neonatal seizure earlier, which ranges from 1.8 to 3.5 per 1000 births. Due to their immature brains and high risk of injury, newborns are most prone to developing seizures. The most prevalent neurological disorder, neonatal seizures, is linked to characterized by high mortality rates of up to 20%.  Depending on their etiologies and clinical results, neonatal seizures might result in long-term consequences like epilepsy, cerebral palsy, developmental abnormalities, and psychomotor impairments. [4,5] According to reports, term babies have a 1.5-5.5 per 1,000 live births incidence of newborn seizures, although preterm or extremely low birth weight babies likely to have greater incidences.  Children who have experienced newborn convulsions are at an 8–20% risk of experiencing another seizure, and those who experience seizures more frequently are more likely to experience post neonatal convulsions. Almost half of term infants with seizures are at risk of developing cerebral palsy, cognitive deficits, and epilepsy.  Neonatal seizures can be classified clinically into clonic, myoclonic, tonic, and mild seizures. Muscles in the limbs, face, or trunk contract in a repeated, rhythmic (1-4/s) manner during clonic seizures. They may be either focal or multifocal.  Preterm neonates are more likely to experience neonatal seizures (22.2%) than full-term newborns (0.5%).
This systematic review offers an overview of the most important pharmacological and non-pharmacological recommended treatments for neonatal seizures, as well as a description of the most recent clinical diagnostic considerations. It is anticipated that this study will aid researchers in detecting and comprehending new initiatives regarding the application of numerous existing and novel medicines, as well as pharmacogenomic considerations for accurate disease diagnosis and treatment, as well as serving as a medium of reference for ongoing research.
Online databases and pertinent scholarly papers about the diagnosis and management of newborn seizures are used in the thorough review-based study. Using keywords, academic publications were generally retrieved from the PubMed database, Google Scholar, MEDLINE, as well as Web of Science, among other research database sites. The review-based analysis was conducted using the outcome papers, which included systematic reviews, research papers, and clinical guidelines in addition to the available pharmacogenomic data. Data from the selected articles were compiled and presented in accordance with various therapeutic modalities.
4. DIAGNOSTIC CONSIDERATIONS:
According to clinical definitions, newborn seizures are abnormal, stereotyped, and paroxysmal central nervous system dysfunctions arising within 44 weeks of delivery. Due to their numerous clinical features and overlapping presentations, newborn seizures are difficult to diagnose. A thorough evaluation is necessary to accurately recognize and categorize the seizures in newborn seizures.
Clinical Presentation: Neonatal seizures can present with various clinical manifestations. Seizures may be focal or generalized and can involve various body regions. Common seizure types observed in neonates include tonic seizures (sustained muscle stiffening), clonic seizures (repetitive jerking movements), myoclonic seizures (brief muscle twitches), and subtle seizures (subtle changes in movement, behavior, or autonomic function). Some seizures may be present at birth or shortly thereafter. Seizures in neonates can be brief or prolonged, ranging from a few seconds to several minutes. Some seizures may occur in clusters or have a repetitive pattern. Neonates with epilepsy may exhibit additional symptoms or signs that can provide clues to the underlying cause. These may include abnormal eye movements, changes in heart rate or breathing patterns, abnormal movements or postures, altered consciousness, poor feeding, irritability, or lethargy. 
Electroencephalography (EEG): EEG is an essential tool for diagnosing and characterizing neonatal seizures. Continuous video-EEG monitoring is preferred as it allows for simultaneous observation of clinical events and EEG patterns. EEG findings may include focal or generalized electrographic seizures, burst suppression patterns, or interictal epileptiform discharges. In the NICU situation, noninvasive EEG-based diagnostics offer an excellent temporary option with little risk of scalp irritability since they are simple to set up, portable, useful for bedside testing, and noninvasive. Routine EEG, continuous EEG monitoring (cEEG), video-EEG monitoring, and amplitude integrated EEG (aEEG) are some of the EEG approaches that can be used. Neonatal seizures have different EEG characteristics than seizures in older children and adults. Despite the possibility of electrical seizure activity in neonates before 34–35 weeks after conception (CA), premature infants are less likely to experience it than term babies. Within a single electrical seizure or from one infant to the next, frequency, voltage, and morphology can all vary significantly. Except for the generalized activity connected to some forms of myoclonic jerks or epileptic spasms, all electrical seizure activity in neonates starts out focally. In neonates, the central or temporal region of one hemisphere or the midline central region is where electrical seizure activity most frequently manifests. The occipital and frontal areas are less frequent locations of start. The motor manifestations of clinical seizures are based on the cortical region where the electrical seizure activity is present. Patients with vascular injury or electrolyte imbalance may experience focal discharges, those with vitamin-related illnesses may experience multifocal discharges, and those with severe epileptic encephalopathies may experience suppression-bursts, showing unique relationships between ictal EEG patterns and underlying etiologies. [12,13]
Neuroimaging: The detection of structural brain pathology, such as hemorrhage, infarction, or anomalies of cortical development, requires the use of neuroimaging. Brain MRI provides excellent anatomic resolution and is extremely sensitive for detecting cerebral anomalies, ICH, stroke, and ischemia alterations. When a vascular etiology is suspected, MR angiography and venography should be carried out. The diagnosis of inborn metabolic abnormalities can often be facilitated by magnetic resonance spectroscopy. Due to its lesser resolution than MRI and substantial ionizing radiation exposure, computed tomography is typically avoided in newborns. Due to its portability and ease of use at the bedside, cranial ultrasonography is the most often utilized neuroimaging technique in newborns. It produces images of the brain using high-frequency sound waves. The use of cranial ultrasound can be used to spot structural anomalies including hemorrhage, ischemic damage, or congenital deformities. MRI provides detailed images of the brain and is useful for assessing the structural and functional aspects of neonatal brains. It can detect various conditions related to neonatal seizures, including brain malformations, ischemic or hypoxic injury, and metabolic disorders. MRI is particularly helpful when cranial ultrasound findings are inconclusive or if a more detailed evaluation is needed. Cross-sectional images of the brain are produced by CT scans using X-rays. The neonate is exposed to ionizing radiation during a CT scan, which can result in speedy findings but should be avoided in this population. When an MRI is not an option or when there is an urgent need, CT scans could be considered. Through the detection of variations in blood flow and oxygenation, fMRI analyses brain activity. It can assist in locating the seizure focal and identifying brain regions that become active during seizures. [14,15]
Metabolic and Genetic Investigations: In cases where there is suspicion of an underlying metabolic or genetic disorder, laboratory investigations may be conducted. Metabolic disorders such as inborn errors of metabolism can cause seizures in neonates. Initial laboratory examinations for neonatal convulsions ought to look for short-term metabolic changes such hypoglycemia, hypocalcemia, or electrolyte imbalance. Complete blood count, blood culture, CSF analysis, urine culture, toxicological testing, TORCH (toxoplasmosis, rubella, CMV, herpes simplex, and HIV) screening, metabolic testing, and ophthalmologic evaluation should all be part of such evaluation. Serum amino acid levels (glycine and serine), ammonia, lactate, pyruvate, very long chain fatty acids, urine organic acid, biotinidase, pipecolic acid, CSF lactate, CSF amino acids, CSF chromatogram for folinic acid/pyridoxine-dependent seizures, and CSF pyridoxal-5-phosphate (active form of vitamin B6) are possible additional laboratory tests. 
In neonates with epilepsy for whom an acute provoked seizure etiology is not detected on the initial history, examination, and neuroimaging, genetic testing should be highly explored. More than 75% of patients with newborn epilepsy may be able to determine the potential etiology of their epilepsy using genetic testing. The discovery of a genetic cause has ramifications for both the course of treatment as well as prognostications, genetic counselling, and the avoidance of further thorough etiologic testing. Because of the clinical overlap of several genetic epilepsies, full exome sequencing is recommended when genetic testing is carried out utilizing a gene panel for epileptic encephalopathies and brain abnormalities. [17,18]
Maternal and Obstetric History: A detailed maternal and obstetric history is important in identifying potential risk factors for neonatal seizures. Maternal factors such as infection, substance abuse, or medication use during pregnancy, as well as obstetric complications like maternal hypertension, placental insufficiency, or intrauterine growth restriction, may contribute to neonatal seizures.
Neonatal epilepsy risk can be increased by obstetric variables such birth trauma, such as protracted labour, the use of forceps or vacuum extraction, or delivery problems. Epileptic episodes may start soon after delivery or in the early neonatal period as a result of birth trauma. A risk factor for newborn epilepsy can be maternal epilepsy itself. Pregnancy-related seizure activity may raise the newborn's risk of developing seizures. Additionally, the developing fetus may be at danger if the mother uses specific antiepileptic drugs while she is pregnant. Neonatal epilepsy risk can be increased by maternal infections during pregnancy, such as maternal herpes simplex virus (HSV) or cytomegalovirus (CMV) infection. These illnesses may cause swelling and damage to the growing fetus's brain. Neonatal epilepsy is more likely to occur if the mother abuses drugs, alcohol, or tobacco while she is pregnant. These drugs may be harmful to the developing brain, causing abnormalities and an increased risk of seizures. Neonatal epilepsy risk may be elevated in cases of maternal hypertension diseases like preeclampsia or eclampsia. These diseases can hinder fetal brain development and result in placental insufficiency, which may induce seizures. HIE (Hypoxic-ischemic encephalopathy) happens when the baby's brain receives insufficient oxygen and blood during delivery. Complications include placental abruption, issues with the umbilical cord, or maternal hypotension may cause this syndrome. HIE is a recognized risk factor for newborn epileptic episodes and may have long-term neurological effects. [17,18] Testing for transitory metabolic changes including hypoglycemia, hypocalcemia, or electrolyte imbalance should be part of the initial laboratory evaluation for neonatal convulsions.
Neurological Examination: A thorough neurological examination helps in assessing the overall neurological status of the neonate, identifying any focal deficits, abnormal movements, or signs of encephalopathy. It aids in determining the severity of the seizures and potential underlying brain injury.
A common phenomenon with babies is jitteriness. It is characterized by rhythmic, involuntary tremors in the limbs towards the middle of the body, which stop when the affected limb is tightly gripped.  There are a few distinctions between clonus and myoclonus, while tremors can resemble them. In general, tremors have a higher rate and a smaller amplitude. A slower rebound and faster movements are hallmarks of seizures. Tremors start after the first day of life in roughly 50% of cases and persist an average of 7.2 months, or even longer if they are more severe. There are no discernible distinctions between symptoms that appear later and those that appear from postnatal day 1 on.
Three categories of jitteriness in newborns can be recognized: When the baby cries, the tremor is (1) light; when the baby wakes from sleep, (2) moderate; and (3) severe, when the tremor becomes evident even when the baby is sleeping soundly or awake.
Metabolic conditions like hypoglycemia or hypocalcemia, systemic issues like an infection or thyroid disease, and nervous system damage like hypoxic-ischemic encephalopathy or intraventricular hemorrhage may all result in severe tremors. The use of anesthetics or other medicines, difficult labour, fetal distress, and placental insufficiency are a few factors that have been linked to tremor. Other factors include a history of maternal or perinatal illness such as maternal diabetes, thyrotoxicosis, sepsis, hemorrhage, or other conditions.
The newborn could display hyperexcitability and tremors due to withdrawal if the mother uses medicines such serotonin reuptake inhibitors (fluoxetine, fluvoxamine, sertraline), haloperidol, benzodiazepines, opiates, cannabis, and cocaine, thus caution must be exercised. Likewise breastfeeding practices should be examined. Infant hyperexcitability may be linked to chocolate, caffeine, and mate tea. [24,25] Deficiencies in vitamin D, carminatives, heavy metals, and pesticides must all be taken into account.
b) Neonatal sleep myoclonus:
Myoclonus is identified by bodily trembling as you sleep. Clinically, it is frequently seen on both sides throughout stages II to III of NREM sleep, and it totally vanishes after awakening. Arms and legs are usually affected by synchronous or asynchronous myoclonus. Rarely does it affect just one region of the body; it usually affects the entire body. The face, head, or abdomen are not frequently impacted. Usually, sleep myoclonus starts before two weeks after delivery. Nearly 95% of the time, myoclonus tends to grow over the first 3–4 weeks after birth before declining until age 6. A large number of myoclonus episodes take place during NREM (non-rapid eye movement) sleep and last for around an hour on average.
A relatively rare kind of hypertonia called hyperekplexia results by waking up from hypotonia while sleeping or from external stressors. It can happen at birth or at some point in life, and in the mild case, it may be followed by startle. Apnea, cyanosis, and hypertonia in the extremities are all signs of severe cases, and they last for many seconds. A sudden visual or aural stimulus may cause it. By the age of three, hypertonia has improved, although it can reappear in teenage years or later as a result of abrupt stimulus, cold, or pregnancy. Patients may respond to mild dosages of clonazepam, valproic acid, and levetiracetam if their intellectual faculties are intact. A brain disability or developmental delay may be present in some situations, necessitating watchful monitoring. 
d) Sleep apnea: It is characterized by breathing pauses of at least 10 to 15 seconds during sleep. In premature infants, it is usually noted within the first two months of life. It can result from a premature brain, gastric reflux, or medication use. Regular tracking may be necessary for several months until symptoms resolve since in severe circumstances, it can result in sudden newborn death. 
5. PHARMACOLOGICAL TREATMENT:
5. 1. FIRST LINE AED’S:
Gamma-aminobutyric acid (GABA) receptor-based first-line therapy, such as phenobarbital and benzodiazepines.
Phenobarbitone has the potential to decrease myocardial function and produce respiratory depression. Phenobarbitone, up to a maximum loading dose of 30 mg/kg in divided doses, should be used aggressively to treat prolonged newborn seizures (longer than one minute) or frequent seizures (more than two in one hour), followed by a single loading dose of phenytoin (20 mg/kg).  When provided to asphyxiated term newborn infants at danger of convulsions, phenobarbitone (40 mg/kg) dramatically decreased severe neurodevelopmental disability or death compared to those who received it after seizures became apparent.  Learning deficiencies are caused by lower brain capacity in infancy after prenatal exposure to phenobarbitone or phenytoin. Phenobarbitone can also worsen anxiety-related behaviour and is linked to substantial motor and cognitive impairments.
Sedation is a severe side effect of benzodiazepines, particularly midazolam, which may cause respiratory depression and intubation. Midazolam might be thought of as a second- or third-line therapeutic option, particularly in newborns who have already been intubated. [35,36] Midazolam, loading dose of 0.05–0.2 mg/kg in 10 minutes, then increasing doses of 0.1–0.5 mg/kg/hour (maximum 1.0 mg/kg/hour). A continuous infusion of midazolam, which is increasingly used to sedate infants and children receiving intensive care and seems to have good safety margins, may be the most effective way to manage ongoing seizures.
Compared to diazepam or midazolam, lorazepam has a longer half-life, requiring less frequent administration and intermittent dosing (minimizing cumulative exposure to hazardous excipients). This may be the reason lorazepam is frequently chosen over other benzodiazepines. Because of its metabolic route, which leads to the formation of pharmacologically active metabolites, midazolam is short-acting and has a quicker onset of action. Loading dose of lorazepam, 0.05-0.15 mg/kg over 5 minutes, no maintenance doses (loading dose repeatable). 
Clonazepam has been successful in treating newborns who are resistant to phenobarbitone and phenytoin. In one trial, phenobarbital (more than 30 mg/kg) and phenytoin (15–20 mg/kg)-resistant individuals experienced seizure cessation within 120 minutes of receiving clonazepam. Major adverse consequences include reduced awareness, hypotension, and multiorgan failure (particularly at high doses). Clonazepam, which is loaded with a 0.1 mg/kg bolus dosage and then given up to five times within a 24-hour period at 0.01 mg/kg doses. When phenobarbitone and phenytoin-unresponsive babies are concerned, clonazepam has also proved successful. In one trial, clonazepam was administered to two patients who had failed phenobarbital (more than 30 mg/kg) and phenytoin (15–20 mg/kg), and after 120 minutes, the patients' seizures had stopped.
5. 2. SECOND LINE AED’S:
Due to its success in treating neonatal seizures, levetiracetam, an antiseizure drug of second generation, is receiving more and more attention. It is one of the few FDA-approved antiepileptics for children as young as one month old, does not require blood-level monitoring, and is simple to maintain as outpatient therapy. Levetiracetam or phenytoin as a second-line treatment have not shown better outcomes. Levetiracetam has a neuroprotective effect that makes it appealing, however a recent study found that it had inferior seizure termination effectiveness when compared to phenobarbital. Use of levetiracetam (10–20 mg/kg load, followed by 10–80 mg/kg/day divided into two doses each day; average dose: 45 mg/kg/day) following phenobarbital and, in rare cases, phenytoin, as first-, second-, or third-line treatment in 23 neonates. Within 24 hours of starting levetiracetam, 35% of newborns experienced a reduction in seizures of more than 50%, and 88% of them stopped having seizures altogether. No significant negative effects were reported.
Levetiracetam dosage for neonatal seizures can change depending on the infant's age, weight, renal function, and the intensity of the seizures, among other variables. It is crucial to remember that a healthcare provider with knowledge of managing neonatal seizures should always decide on the precise dosing. The following details give a comprehensive overview of levetiracetam dosage recommendations for newborns:
Dosing based on age and weight:
- Term Neonates (≥37 weeks gestational age) and Infants: The recommended starting dose is typically 20 mg/kg/day, divided into two equal doses given every 12 hours.
- Preterm Neonates (<37 weeks gestational age): Lower doses may be considered based on gestational age and individual patient factors. The starting dose can range from 10 to 20 mg/kg/day, divided into two equal doses given every 12 hours.
- Levetiracetam dosage can be gradually increased based on clinical response and tolerability. The dose is typically raised once every two to three days until seizure control is attained or the maximum dosage is reached.
- The dose increments during titration can range from 10 to 20 mg/kg/day. The maximum recommended daily dose is generally 60 mg/kg/day.
- During titration, the dose increments might be between 10 and 20 mg/kg/day. The maximum dose that is often advised is 60 mg/kg/day.
Modification of Renal Function:
- Levetiracetam is mainly excreted by the kidneys, hence renal function should be taken into account when choosing a dosage.
- To prevent medication buildup in newborns with compromised renal function, dosage modifications may be required.
Individualized Dosing and monitoring:
- It is crucial to closely evaluate the infant's clinical response, seizure frequency, and any potential side effects in order to optimize the dosing schedule.
- Levetiracetam is not frequently monitored for serum drug levels. Therapeutic drug monitoring, however, may be taken into consideration in some situations where there are questions about efficacy or toxicity.
b) Phenytoin: Phenytoin was found to be as effective, but due to the possibility of adverse effects, the unpredictable nature of neonatal metabolism, and the requirement for frequent blood-level monitoring, we are unable to suggest it as a first-line treatment. Second-line phenytoin (15–20 mg/kg) was administered after phenobarbital (40 mg/kg), and phenytoin caused seizure cessation to occur within 120 minutes of its addition. Phenytoin is known to cause cardiac arrhythmia and hypotension. Phenytoin was introduced as a second-line therapy for seizures that were resistant to phenobarbital, and this improved seizure control in an extra 10-15% of patients. Phenytoin (phosphenytoin) is typically not advised for long-term maintenance due to its distinct pharmacokinetics and is only advised for acute treatment.
c) Lidocaine: Compared to benzodiazepines, lidocaine looks to be more effective; nonetheless, it has a limited therapeutic window, the potential to result in cardiac arrhythmias or hypotension, and, at high doses, can cause seizures. Phosphenytoin/phenytoin should not be administered after lidocaine since it may have additional cardio-depressive effects. In a recent trial, lidocaine was found to be moderately effective as second-line therapy after benzodiazepines for refractory seizures.
Neurosteroids, such as allopregnanolone, have shown promise in preclinical studies for their anticonvulsant effects. These compounds enhance GABAergic neurotransmission and exert neuroprotective effects, making them potential candidates for the treatment of neonatal seizures. The creation of progesterone and other precursor hormones by the placenta, which are then quickly converted to pregnane steroids like allopregnanolone in the fetal brain till birth, is what causes the high levels of neurosteroids in the brain before birth. Both brexanolone and allopregnanolone, often referred to as 5-pregnan-3-ol-20-one or 3-, 5-tetrahydroprogesterone (3-, 5-THP), positively regulate the GABAA receptor, which results in a general suppression of CNS activity. In order to find potential neuroprotective drugs, we carefully looked at the neurosteroid synthesis route after hypoxia-ischemia. In addition to promoting brain development and preventing hypoxic injury in fetuses, allopregnanolone also provides a tonic suppression of brain activity, as seen by EEG, as well as fetal mobility and breathing patterns. After the placenta is removed, the neurosteroid-induced suppression of brain activity at birth quickly disappears, and neurosteroids like allopregnanolone, whose half-life is estimated to be 10 minutes, are quickly eliminated from the neonate's circulation. The healthy term foetus "wakes up" once the tonic inhibition of in utero neurosteroids has been removed following delivery, which is the physiological sense of this rapid alteration of CNS neurochemistry. The lack of this physiological inhibition, however, exposes the post-hypoxic fetus's brain to oxidative stress and other neurochemical alterations that raise excitability, potentially leading to the beginning of seizures. The growth-promoting environment that neurosteroids provide in utero is lost for a protracted period of time for the prematurely born kid in addition to the immediate loss of protective inhibition. When it comes to administering steroids to infants, there appears to be a higher risk of cerebral palsy if it happens after birth as opposed to a reduced risk if it happens during the antenatal stage. [48,51]
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