Literature Review On Neonatal Seizures: Pharmacological Treatment & Cooling Method

Search Strategy

The treatment processes for neonatal seizures are quite limited within 2 to 4/1000 in North American births, which is not up to the level of expectancy of experts, and paediatric doctors around the world as neonatal seizures are quite common. Nearly 19 to 58/1000 infants are born with less than 1500 grams of birth weight (Slaughter Patel and Slaughter 2013). However, different new antiepileptic medications are introduced almost every year to treat the infants. As per the experts, besides new antiepileptic the necessity of treatment is also as important as the process of treatment required for a certain newborn infant. The most common medication used by experts are Phenobarbital and phenytoin/fosphenytoin which have efficiency of approximately 50% which is way to less than required effectiveness. The main concerns related to this medication process are the side effects, interaction of the medication with the patient body, continuous monitoring of the blood flow level besides the consequences of potential negative neurodevelopment. However, according to different reports, the increment in the usage of antiepileptic medications is the result of these limitations of phenytoin and phenobarbital. As per the research and analysis of different expert neurologists on the other hand, nearly 73% of levetiracetam and/ or topiramete in the treatment of neo natal seizures are used in treatment of neonatal seizures because of their less adverse effects and the easiness of usage.

To develop the database for this research (see appendix 1) different databases like Medline, PubMed Central, NCBI and Google Scholar are used. To complete the research, ample time is important to ensure the significance of the work and the results obtained from this. 22 qualitative research papers were approved which are summarized in Appendix 2. The study consists of systematic analysis and meta-synthesis review techniques. The three most predominant themes immerged in the literature review in this paper have been formulated as the subdivisions of this study paper to develop it. The three recurring themes will be debated in the next sections of this paper.

Pharmacological treatment

To perform this research nearly 557 articles had been identified from the MEDLINE database by the team of researchers. The whole texts of the rest of the 64 articles have been reviewed. During this, the abstract and the titles of the manuscript are eliminated, as they do not serve the purpose of paper analysis. After the analysis of these articles and the references involved with them 14 additional articles are taken to review. After the analysis of total 78 full texts with 16 research papers involving investigations with EEG (electro encephalogram) to diagnose seizure and treatment observations are taken in considerations as they are fulfilling the required criteria (Slaughter Patel and Slaughter 2013).

Painter and his team focused on the phenobarbital and phenytoin and their research work is the only one in this field in 1999. After this research study, a trail with 59 patients were arranged. In this trail, patients were given a level of 25mg/l Phenobarbital and 3 mg/L of phenytoin in addition to an alternative medication in case the process fails. EEG of the patients were performed continuously. The effectiveness of the phenobarbital and phenytoin were obtained as the seizures came in control of 43% for both matured and premature infants. The results were obtained in both the cases with phenobarbital and phenytoin (P=1) which is nearly 45% with a seizure ratio controlled by these medications is 57:62 respectively for P=0.67. Therefore, the results obtained shows that both of the medications are equally effective with no adverse side effects for the infants. This significant development is considered as the cause of seizure reduction up to 80% relative to complete seizure cessation, this rate of efficiency improved to 80% and 72% respectively. The observations of adverse effects are almost none. However, the patients were shuffled for better research; still the research of Painter and his team consists of some insignificant restraints. The research is carried on only single centre with expert physicians, well aware EEG technicians to carry out the observation and research method. The usage of disparity among groups and the only single-blinded regarding baseline characteristics was present.
In 2004, boylan and his team had performed a research on randomised trial of lidocaine versus a benzodiazepine dip after the failure of Phenobarbital. During the research, the experts performed EEG of the patients continuously. Lidocaine was used at a dosage at a rate of mg/kg then infused at a rate of 2 mg/kg/hr. 60 micrograms/kg of midazolam were dozed after 150-300 micrograms/kg/hr infusion. In addition to this Clonazepam, dosing has been used. The statistical analysis required for this research was prevented due to the major restriction of its small size. There are certain cases, which were randomized including five cases to lidocaine group, 6 to benzodiazepines (3 for midazolam, 3 for clonazepam). The responses varied with each other. Benzodiazepine groups came up with no responses and in case of lidocaine, 3 out of 5 patients responded to the treatment. In the second case, among 3 patients one had 80% seizure reduction and two were seizure free. It is clear that from the results that the neurodevelopment among patients were very poor for over the period of a year for the research. However, no adverse effects were noticed in a short period. Particularly the 50% of the patients under observation responded to the phenobarbital, which is consistent with the reports of Painter and his team.
A research on second-line midazolam usage after up to 40 mg/kg phenobarbital to a historical phenobarbital and or phenytoin treated neonatal seizure patients by the team of Castro-Condeet in 2005. Continuous EEG was done for multiple hours then intermittent EEG at an interval of 24-hours was done to assure no seizure reversion occurs. Midazolam was administered up to twice at a rate of 150 mg/kg when required at a rate of 60-1080 mg/kg/hr injection. The dosage is way to higher than the dosage used by Boylan and his team in 2004 or any other expert team for that matter. The midazolam rate brought remarkable response of 100%. The seizures were totally controlled within an hour for nearly 10 to 13 patients in the treatment group. However, no gap differences of any year has been observed in case of neurodevelopmental results. If the results are compared between group 1 with no responders (seizures continued even after administration of phenobarbital or phenytoin) and the 2^ndgroup which is treated with midazolam, surprisingly the number of patients assessed as normal after treatment showed significant differences in terms of percentage in favour of midazolam. As the difference contains the previous troop, the results are considered to be biased as of the changed practice between this time period which is not related to midazolam. In numerical view, it has seen that in every 4 out of 13 infants have decreased consciousness as side effects for nearly 10 to 15 minutes further leading to midazolam bolus hypertension with multisystem organ failure because of acute hypoxic-ischemic injury (HIE). Tin case of 2 infants the conditions are not related to midazolam administration.
After dosage of 40mg/kg of phenobarbital and /or IV diazepam or lorazepam in a single dosage, the comparison between second and third line treatment with lidocaine versus midazolam for mature and premature babies with neonatal seizure cases has been conducted by Shany and his team in 2007. The research also consists of the historical cohort based on the hypoxic-ischemic encephalopathy of such cases. The Amplitude based EEG has been conducted on the students continuously. The 2mg/kg of lidocaine dosage was administered at a rate of 4-6 mg.kg.hr infusion. Midazolam was also injected at a rate of 60-200 mg.kg/hr without loading as a dosage. This group of patients in the first case responded up to 77% however, there were 50% cessation with the seizure activity rate less than 6 hours. The second group showed 50% response with a seizure activity rate also less than 6 hours of completion of cessation. The non-responders were passed by the alternative medication agents leading towards the overall response consists of 81% lidocaine and 67% of midazolam with no adverse effects in this short period. The comparative investigation was limited due to the absence of midazolam loading dose.
After that about 20 infants were treated with lidocaine (dosing protocol: 2 mg.kg load, 6mg/kg/hour for 12 hours then 2 mg/kg/hours for again 12 hours.) prospectively. Malingre and his team develop the process in 2006. The research work is significant after the failure of phenobarbital and either midazolam or clonazepam. The reduction in the seizures was noticed at 76% with 52% with seizure cessation. The aim of this research was to minimize the cardiac effects with an optimal lidocaine dosing. The dose was reduced following this research from 6 mg/kg/hour for 6 hours versus up to 12 hours.). This gave a similar response rate of 78% affectivity with no adverse result notices.
Another research is done on the usage of levetiracetam of 10-20 mg/kg load with a rate of 80 mg/kg/hour divided twice daily leading to 45mg/kg/hour everyday among 23 neonates in comparison with phenobarbital and phenytoin. The research is conducted by Abend and his team in 2011. Result of this research shows a reduction of 50% in the number of seizures treated by levetiracetam recorded among 35% neonates. No adverse effects had been noticed. It is stated in the discussion that with the passage of time some of the seizures may have been secondary.
Another research is done by reviewing 22 patients acquiring first and second line levetiracetam of 10-50 mg/kg intravenous load at an infusion rate of 50 mg/kg/hour. The result of this research showed 86% reduction in seizure cessation. 100% improvement was recorded in case of 7 patients among 22 which is 32% after the heavy dosage. The side effect was noticed in one patient it was just an irritability, which was cured by following pyridoxine supplement.

Therapeutic hypothermia is a powerful and clinically accessible treatment for neonatal hypoxic-ischemic encephalopathy or HIE. Various animal quantitative researches have shown that this type of hypothermia treatment can diminish seizures and epilepsies action in the setting of hypoxia-ischemia. However, recent clinical information in human babies has been proving different from this. Three observational quantitative studies demonstrated a diminished frequency and seriousness of seizures among neonates with HIE who were treated with therapeutic hypothermia. Furthermore, two quantitative research studies demonstrated a much lower burden for the electrographic seizures by EEG observing: (1) among neonates with direct encephalopathy and (2) subsequent to representing severe mind damage on MRI. In addition this, in cohort studies, neonates were treated with therapeutic hypothermia and as a result it was found to have blood vessel ischemic stroke on
MRI having a much lower probability of seizure when contrasted with those neonates with stroke who were not given cooling treatment. Interestingly, meta-examinations of randomized controlled trials of cooling therapy for neonatal HIE have neglected to demonstrate a relationship between cooling therapy and diminished seizures. The potential effects of epileptogenic impacts of cooling therapy possess critical clinical ramifications. Since some of the seizure, medicines have restricted viability in infants and hence, may prove harmful.
The connection between cooling therapy and the combined occurrence of seizures was inspected by examining neonate’s cohorts either with seizures who were admitted to various health centers previously o rafter the start of the cooling treatment. Among the enrolled infants incorporated into the study nearly 151 were getting treatment for hypothermia. The seizure monitoring in study subjects who were born before the onset of the cooling therapy were mainly at discreation of all appointed treating physician, however, on the other hand, cooled newborns were having continuous monitoring both with conventional video EEG as well as amplitude-integrated EEG. It was done from time of admission until completion of the rewarming treatment after giving therapeutic hypothermia. All the cooled infants suffering from direct encephalopathy substantially were much less prone to suffer from either electrographic or clinical seizures compared with the non-cooled babies (the cooled ones: 26 % vs. the non-cooled: 61%, P<0.001). However, there was still no distinction in risks of seizures mainly among the infants having extreme encephalopathy’
As the observation of ceaseless EEG was performed closely by hypothermia, it was most probably possible that the recurrence of EEG seizure was more or less under-evaluated in non-cooled amass whenever checking was more constrained and at the tact of the treating doctor.

According to quantitative findings of – a study, neonatal period (the initial 28 days of life) has the highest frequency of seizures over the life expectancy at 1.8 to 3.5 for every 1,000 live births. The most widely recognized reason for neonatal seizures is hypoxic-ischemic Encephalopathy, which happens in around 1 to 2 for each 1,000-1ive births. In the neonates, a wide scope of central nervous system and systematic disorders can give rise to neonatal seizures. Evaluation of cause and treatment normally happens simultaneously. The most basic need is distinguishing treatable reasons underlying seizures, including metabolic disturbances (hypocalcaemia, hypo glycaemia and hypomagnesaemia) as well as inflammation due to infection attack. The overwhelming reason is to some degree due to the neonate basic setting. A detailed quantitative investigation from a tertiary care referral neonatal ICU was done in which around 66% were found to be related to hypoxic-ischemic encephalopathy and cerebrovascular disarranges
In spite of the fact that the term baby is at high hazard for seizures, it is progressively perceived that seizures can be a major issue for the preterm newborn children. A recent quantitative study of extremely low birth-weight children in Israel was analyzed showing a general rate of neonatal seizures of around 5’6%’ A much younger male sex, gestational age, along with other major foundational (such as sepsis) and neurological comorbidities (either intraventricular drain or periventricular (leukomalacia) were all considered as autonomous indicators of neonatal seizures.
Newborn children with complex innate coronary illness are at high hazard for seizures in the perioperative period. Different but less common reasons for neonatal seizures incorporate formative irregularities, natural mistakes of digestion, and other hereditary disorders that are examined in detail in reference studies

Thorough assessment of the adequacy of antiepileptic drugs treatment in neonates is very challenging. In perspective of the difficulties characteristic in behavioral findings, incorporation of the constant EEG observing can be referred to as a quality level for investigations of the therapeutic efficiency. A consensus exists that as of now the anticonvulsants used are regularly ineffectual for the treatment of neonatal seizures (Sanker and Painter 2005). Painter and associates’ in 1999 quantitative investigation revealed that in babies with EEG-affirmed seizures, the loading doses for both phenobarbital and phenytoin were similar but deficiently viable, and that either of these alone controlled seizures in less than the half. Moreover, variable viabilities has been reported for midazolam as the second line of pharmaceutical.
Lidocaine is a viable treatment for neonatal seizures; however, issues related to the heart danger have restricted broad reception of this in infants. A similarly imperative quantitative finding regarding AED treatment in neonates was whether treatment as fruitful method of treatment for seizures justified. In encephalopathy newbom children, the seizures unexpectedly wind down before the finishing of first 7 days of life; in spite of the fact that it is obscure whether continuation of AED treatment is of advantage, this practice is very normal. Quantitative investigations of early-life anticonvulsant treatment on both psychological as well as neurological improvement are constantly confounded by numerous reasons for neonatal seizures, and it will be important to formulate thorough methodologies for the generally homogeneous clinical populaces for such examinations.

Main body

Proving a technique to be the best with 100% positive result in case of treating seizure is not possible as a very few proof about the finest treatment for natural seizure in medicine is available. One out of two scattered trails, which have been conducted for this research was worthy and big enough to give numerical analysis. There are only few more researches available with potential of non-scattered study by experiments and two legions of demonstrations done before this research. Those papers also provide thorough study on effects of different types of treatment methods for neonatal seizures. The description of the first exposure seizing infants related to novel medications was revolutionary in terms of the historical cohort of neonatal seizure treatment. However, hazards and advantages are very lesser known as per recent data about anti-epileptic drugs comprising the scarcity of control or comparability group.

Even after different study suggesting against phenobarbital, it has been found from different research papers that the first line of medication should be phenobarbital. This is because it is included as RCT, which is the first line treatment of neonatal seizure. As in animals, it is the most analyzed anti-epileptic drug, which makes it historically precedent for neonates. It has also been found that the proof of the impact of phenobarbital on futuristic neonatal neurodevelopment is very little. In addition, the U.S Food and Drug Administration (FDA) have put bindings on the usage, which includes no approval of usage of such drugs in communities with large number of patients. The reasons of such bindings is not clear. However, in other researches, Phenobarbital was been considered as a better medication for neonatal antiepileptic, even though Painter and his team gave equal importance to phenytoin. The probability of side effects, capricious metabolism in neonates besides the requirement of continuous monitoring blood flow level are the major reasons, which suggest the opposite of this.

There are treatments, which are not that much responsive to Phenobarbital for neonatal seizures and can be used as second-line treatment includes Levetiracetam, Phenytoin/fosphenytoin, and

Lidocaine. Although there is no comparison within the same structural study in two different studies. It has been observed that Levetiracetam has minimized the seizure. It is recommended for all age groups and does not require any type of blood observations. Therefore, for this research, as per the stipulations of Lidocaine and fosphenytoin/phenytoin, it has been considered as the second line of medication. However, it is not recommended as there are not many thorough studies done taken in regards to the first moth life cycle especially. If the usage is compulsory at any circumstances, it is not recommended to use more than 40-50 mg/kg bolus in line. This is also recommended by the team of Khan. It has been found from the study that this measurement shows continuous progress.

Pharmacological treatment

In addition, neonatal seizures are related to the morbidity and mortality. Hypoxic-ischemic

encephalopathy (HIE) is a widely recognized cause behind seizures in beizuresabies. Neonatal models using cooling therapies for animals show better results to diminish seizures and epileptic-form among hypoxia-ischemia, however information from human examinations have poor results. In this regard,discoveries of recent examinations exhibited a diminished seizure number in infants with direct HIE treated with hypothermia. This research also confirms to clinical trial information that showed that infants with encephalopathy could benefit the most from therapeutic hypothermia (Gano et al., 2014). Furthermore, more study is required to reveal the components that underline the decreased risks of seizures related with cooling therapy in babies with HIE, and the potential risks of epileptogenic for hypothermia in other clinical settings (Silverstein and Jensen, 2007).

In spite of the fact that, many researches and innovations of procedures are now available for neonatal seizures. Numerous functional difficulties must be routed to smoothen the clinical trials of AEDs in neonates. Involving consistent EEG checking into clinical investigations of neonatal seizure treatment is an overwhelming task. However, it will likewise be fundamental to survey AED effectiveness with different treatments (such as instigated hypothermia) in newborn children.

The criteria involved in this research do not include any articles as treatment options, which comprise of Phenobarbital coma and status epileptics for infants. Resultantly it cannot be used as reasons about the recommendation of the trail of phenobarbital in effected infants who have not responded to our pharmacological therapies.

Conclusion and Recommendation

The research is conducted on the review of popular research works depicting different treatment method for neonatal seizure with respect to antiepileptic medication. The aim of this research is to bring out the most suitable method of them. The data used for this research is topiramate in neonates is quite low. The adaptation of the futuristic approach includes the seizure diagnosis and verification of cessation via amplitude-integrated EEG can be considered one of the most effective of all. The focus of this method is on the condition of the patient and etiologist. Irregular but controlled experimentation showed better results with medications without any side effects. However financing such researches is a major concern for any researchers. The collaboration of different neonatal care units of different hospitals is also necessary for such researches, as this will help in financing of the projects. In addition to this, the collaboration will ample the statistical power of data collection and help to cope with the difficulties of reports related to the enrolled neonates in medical experiments of antiepileptic and offer a minimal amount of protective means for treatment and randomization. A detailed group formation for patients is necessary to enlist details of those infants whose parents have denied randomization for different researches. This is why collaboration of different centres with networks to ensure funding and permission to perform tests on neonatal seizure medication. On the other hand, this will help the researchers to use large amount of statistical and medical reports and analyse more data to ensure more accuracy of the research. The success rate of the research will be more than conducting research on patients of a single centre.

Subject: Management of Neonatal Seizures

Search Time Frame: 1999-2018

Selected databases & Sources:

PubMed Central (Results 20/saved 15)

Google scholar (Results 45/saved 8)

Springer (Results 2/1 )

Elsevier (Results 5/saved 2)

Range of search terms:

Synonyms: epilepsy, fits, newborn/infants, treatment

Acronyms: AED, HIE, EEG, FDA

Other search terms: women, mother, neurological problem, epilepsy, causes, management, short and long term effects, recommendations.

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