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ORIGINAL ARTICLE
Year : 2022  |  Volume : 70  |  Issue : 2  |  Page : 574-578

Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration


1 Department of Pharmacy Practice, Manipal College of Pharmceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Neonatology, Kasturba Medical College, Manipal, Karnataka, India

Date of Submission21-Apr-2020
Date of Decision04-Sep-2021
Date of Acceptance22-Sep-2021
Date of Web Publication3-May-2022

Correspondence Address:
Dr. Prasanna K Shetty
Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.344647

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 » Abstract 


Background: Management of neonatal seizures with available limited guidelines across different gestation can cause long-term neurological and cognitive impairment.
Objectives: To compare utilization and observe the efficacy of anti-epileptic drugs in the treatment of neonatal seizures. The association of hypoxic-ischemic encephalopathy with NS and the etiology of HIE were also determined.
Subjects and Methods: A retrospective cohort study was conducted at a tertiary care hospital for a period of one year. It was approved by IEC prior to initiation.
Participants: Neonates admitted for seizure management and perinatal asphyxia with hypoxic-ischemic encephalopathy were included in the study. Both term and preterm 267 neonates from January 2014 to July 2018 were retrospectively analyzed. The drugs with the fastest seizure resolution, least recurrence, and readmission rates were considered efficient. Phenobarbitone, levetiracetam, and phenytoin were compared as they were commonly prescribed. Inpatient medical records and hospital databases served as sources of information.
Results: Phenobarbitone was commonly utilized, followed by phenytoin and levetiracetam. The commonly prescribed combination was phenobarbitone (first-line agent) and phenytoin (second-line agent). Phenobarbitone immediately resolved seizures (97, 75.1%) and had the least cases of seizure recurrences (53, 41.1%) and readmissions (20, 15.5%), making it most efficient. The best second-line agent was phenytoin, with the least seizure recurrence (4, 8.51%), least readmissions (7, 14.8%), and fastest resolution (25, 53.1%). Levetiracetam was an efficient third-line agent. Hypoxic-ischemic encephalopathy was the most observed cause of neonatal seizures.
Conclusion: Phenobarbitone was observed as the most utilized and efficient anti-epileptic drug, followed by phenytoin and levetiracetam. Owing to limitations in this study, there is an alarming need for standardized clinical trials to establish thorough guidelines.


Keywords: Anti-epileptic drugs, neonatal seizures, neonates
Key Message: Phenobarbitone was observed as widely utilized due to its significant efficiency in managing neonatal seizures, in comparison to phenytoin and levetiracetam.


How to cite this article:
Thomas RB, Muttavarapu SS, Shetty PK, Lewis LE. Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration. Neurol India 2022;70:574-8

How to cite this URL:
Thomas RB, Muttavarapu SS, Shetty PK, Lewis LE. Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration. Neurol India [serial online] 2022 [cited 2022 Jun 25];70:574-8. Available from: https://www.neurologyindia.com/text.asp?2022/70/2/574/344647




Neonates are prone to seizures due to their juvenile brain; any hindrance can cause long-term impairment.[1],[2] Effective management of seizures is a neurological emergency.[3] WHO guidelines recommend phenobarbitone as the first-line and phenytoin as the second-line drug.[4] Levetiracetam and phenobarbitone are administered as first-line agents for neonatal seizure management, but their comparative efficacy is unknown.[5]

Due to the lack of established guidelines for treatment, this study was conducted to perceive the efficacy of anti-epileptics. The utilization of AEDs was assessed and correlated with their efficacy. Hypoxic-ischemic encephalopathy was the major etiology identified; other associated etiologies were also examined.


 » Subjects and Methods Top


A retrospective cohort study was conducted for a period of 1 year which included neonates admitted from Jan 2014 to July 2018. Ethical clearance was obtained from the lEC of the hospital. The data were collected from inpatient medical records and the hospital's online database using a case report form (CRF).

Participants

Neonates diagnosed with neonatal seizure and/or HIE (ICD-10-P-90 and ICD-10-P-91.60) (male and female) who were admitted at the study site from 2014 (Jan) to 2018 (July) were included. In other words, the 267 neonates in our study were either diagnosed with NS or status epilepticus to meet the primary objective. Neonates with HIE were also included in the study to determine its etiology and association with NS. Patients with incomplete records were excluded from the study.

Method of data collection

Detailed history of the neonates, that is, age at admission, birth weight, admission weight, history, and type of seizure, was recorded. The natal and post-natal history of the babies were collected. All available information regarding maternal medical and medication history were also recorded. Relevant laboratory investigations, such as complete blood count, blood glucose levels, serum calcium levels, serum electrolytes, and CSF analysis, were recorded in the study. Hypoglycemia was marked when glucose levels were <45 mg/kg in mature neonates. Calcium levels of <7.5 mg/dl indicated hypocalcemia. CSF analysis with CSF sugar less than serum sugar level, elevated protein levels, and CSF leukocytes more than 20 with predominant neutrophils were indicated as an abnormality.

Statistical analysis

The data were analyzed using Statistical Package for Social Sciences (IBM SPSS version 20.0). P < 0.001 is considered as statistically significant. All the categorical variables are expressed in proportion and analyzed by Chi-Square test. Continuous variables were expressed in terms of mean ± SD, and analysis was carried out by independent t test.

The etiology of HIE was checked by assessing categorical variables using the Chi Square formula and binary logistic regression. The association of HIE and neonatal seizures was measured using the Chi-square formula.


 » Results Top


General descriptive data

A total of 267 neonate's patient data were observed during the study, among which the majority were male (168, 62.9%). The mean and standard deviation of age (in days) of the study patients included was 4.17 ± 5.729. Out of 267 cases, 152 (56.9%) neonates had the diagnosis of only seizures, 38 (14%) with HIE, and 77 (28.8%) diagnosed with both neonatal seizures and HIE. The comorbidities (possible etiology) observed in subjects with seizures were metabolic abnormalities, infectious diseases, CNS abnormalities, respiratory disorders, HIE, hematologic abnormalities, and congenital malformations. Electroencephalogram was done for most of the neonates (191, 71.5%) and cessation seizures were confirmed clinically.[6]

Most babies (51.68%) had their first seizure episode within 24–48 h of life [Table 1]. The electroencephalography investigations for most babies were normal (as EEG was performed 24 h after a seizure due to unavailability of bedside EEG at the hospital) and 157 (58.8%) subjects were admitted for less than 10 days. The electrolyte abnormalities were monitored by recording hypoglycemia, hypocalcemia, and hypomagnesemia. Hyponatremia, hypernatremia, and hyperkalemia were included as the electrolyte abnormalities. However, hyperkalemia did not cause a seizure in most neonates.
Table 1: General demographics

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Utilization pattern of anti-epileptics drugs (2014–2018 (July))

When the frequency of overall drug utilization throughout the years was assessed, phenobarbitone was administered to 129 neonates, making this the commonly used anti-epileptic drug, especially in the year 2016. Phenytoin was the intermediately used drug and levetiracetam was the least used drug throughout. The utilization pattern of anti-epileptic drugs as first, second-, and third-line agents was observed. Phenobarbitone was commonly administered as a first-line agent along with phenytoin as a second-line agent. The drug least used as a first-line agent was phenytoin. There was a sudden rise in levetiracetam exposure to 23% in the year 2016 [Table 2].
Table 2: Anti-epileptic drug utilization

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Determination of the efficacy of AED (s) for neonatal seizures (a comparative observation)

The AEDs were compared based on their main outcomes, and phenobarbitone was prescribed in the highest number of cases where seizures were resolved within 24 h (97, 75.1%). It also had the least cases of seizure recurrences (53, 41.1%) and readmission (20, 15.5%). Phenytoin was the second-best first-line agent, making levetiracetam the least efficient first-line agent given its poor outcomes. Thus, we observed phenobarbitone as the most efficient first-line AED.

A second-line AED is required in a scenario where the first-line AED fails to effectively control seizures. When the efficacy of drugs as a second-line agent was compared, phenytoin manifested as the best choice. It had the least seizure recurrence (4, 8.51%), readmissions (7, 14.8%), and fastest resolution in 24 h (25, 53.1%). In contrast, levetiracetam proved itself as the worst second-line agent [Table 3].
Table 3: Comparison of AEDs as first- and second-line agents

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The efficacy of AEDs as a third-line agent was also assessed and compared. Levetiracetam and phenytoin were the prominently observed third-line agents in this study. Levetiracetam was the better third-line choice with the fastest recovery in 48 h (6, 60%) and least admissions (2, 20%).

Determination of association between hypoxic-ischemic encephalopathy and neonatal seizures

A highly significant association was found between HIE and neonatal seizures with P < 0.05; it was determined statistically by applying Chi-square formula (df = 1, P < 0.05).

Etiology of HIE

The possible etiology of HIE was remarked using Chi-square formula (df = 1, P < 0.05) and binary logistic regression, for the association of HIE and the neonatal factors and maternal medical history.

We observed that metabolic abnormalities and birth asphyxia and PV leakage in mothers were significant etiologies of HIE, with P < 0.05.


 » Discussion and Conclusion Top


Newborns have a juvenile brain, which may be one of the many reasons why a coexisting etiology (HIE, Intracranial hemorrhage, sepsis, etc.) may cause a seizure.[1]

The efficacy of antiepileptic drugs was assessed by comparing three main outcomes of each AEDs. The main variables that were measured to evaluate the AEDs were the time taken to resolve seizure, seizure recurrence, and readmission. The AED that took the shortest time to resolve a seizure, yielded the least cases of seizure recurrence after administration, and required the least readmissions was considered most efficient.

Phenobarbitone was extensively prescribed as a first-line drug in 2014, with a gradual decrease especially in 2017 and higher in 2018. The explanation as to why it was commonly prescribed was obtained when its efficacy was observed. It was the fastest to resolve seizures with lease recurrences and readmissions. These outcomes were the best when compared with levetiracetam and phenytoin. Phenobarbitone was the second-best when used as a second-line agent and was never administered as a third-line agent in our study.

Ahmad et al.[5] conducted a retrospective cohort study among 9134 neonates who were diagnosed with seizures. There was a 98% phenobarbitone exposure observed, making it the commonly used AED during the study period. However, the study had stated a lot of safety concerns based on a single-center review, which established an association between phenobarbitone use, worsened 24-month cognitive/motor scores, and cerebral palsy.

Torolira et al.[7] also confirmed that phenobarbitone had revealed widespread neonatal injury during a study on rat pups. A study by Gowda et al.[8] concluded that there were 10 adverse events reported with phenobarbitone and none for levetiracetam group among 122 neonates. Long-term effects and possible adverse reactions of phenobarbitone use must be addressed and not just the anticonvulsant properties.

Levetiracetam had contractual changes in its use as a first-line agent. Its poor efficacy could explain the reduced utilization [Table 3]. In the present study, levetiracetam was observed as an efficient third-line agent. However, its minimized use at the hospital could predispose these results when observed therapeutic outcomes were statistically determined. Neubauer et al.[9] concluded that it is an effective adjunctive AED (second or third-line agent) for seizure control in newborns. Randomized controlled trials conducted by Sharpe et al.[10] revealed that phenobarbitone was more effective than levetiracetam along with higher levels of adverse effects. The trial recommended using higher doses of levetiracetam to reach desired therapeutic goals. A study conducted by Dias et al.[3] observed that levetiracetam is a better alternative to phenobarbitone in neonates where NS is associated with HIE. Neonates diagnosed with HIE may be phenobarbitone resistant, leaving levetiracetam as the better first-line drug in such scenarios.[11]

In contrast, a study was conducted by Grinspan et al.[2] on the comparative effectiveness of levetiracetam and phenobarbitone in the management of neonatal seizures. It concluded that levetiracetam had the least monotherapy failure and had less developmental delay, whereas neonates treated with phenobarbitone had a much greater number of monotherapy failures and poorer cognitive outcomes in otherwise healthy subjects, further reminding the necessity for clinical trials to generate systematic guidelines to treat neonatal seizures and unravel the dilemma.

The use of levetiracetam in a study conducted by Ahmad et al, showed an increase from 1.43% to 14.3%. This is because of its newly found benefits in monotherapy and as a second-line drug.[5] An association between levetiracetam use in each population and worsened cognitive and motor scores was observed. However, it was lesser than the reports obtained from phenobarbitone safety studies.

Phenytoin was least prescribed as a first-line drug throughout the study, but was the commonly administered second-line agent, which was justified by its efficacy as the latter. Phenytoin exposure was seen in neonates diagnosed with seizures and HIE. Based on the pharmacokinetics of phenytoin, Neubauer et al.[9] suggested its use for acute management and long-term maintenance.

Painter et al.[12] compared the effectiveness of phenobarbitone and phenytoin in neonatal seizures. They concluded that both drugs had equal effectiveness but are still not adequately competent AEDs. In contrast, Pathak et al.[13] conducted an open clinical trial and concluded that phenobarbitone was more efficacious than phenytoin in treating neonatal seizures.

In many subjects, midazolam was coadministered with phenobarbitone, probably for its dual advantage as an AED and as a sedative for investigational procedures. In a study by Kang et al.,[6] midazolam and levetiracetam were administered to neonates diagnosed with refractory seizures and HIE.

Dao et al.[14] did a study that reported a few adverse reactions only when midazolam was coadministered with phenobarbitone; when higher than necessary doses were administered, neonates were to be found in serious conditions, such as malformations and brain hemorrhage. However, no serious adverse reactions were reported in the present study.

The association of HIE and neonatal seizure was observed among subjects. As a result, we witnessed a significant association between HIE and NS. In a population study, Ronen et al.[15] observed neonatal seizures that were triggered by HIE. Kang et al.[6] conducted a study that strongly stated that HIE is a crucial etiology since it may lead to a comorbidity.

When levetiracetam was administered prophylactically to neonatal rats diagnosed with HIE, a significant improvement in hypoxic activity was observed. In a study by Mruk et al.,[16] levetiracetam showed a direct disease-modifying effect on HIE, reducing the risk of developing seizures. Early diagnosis and specific treatment are important as most neonates with HIE are phenobarbitone resistant.[6] Study findings by Kossoff[17] showed that there is a twofold risk of developing seizures in neonates diagnosed with severe HIE. Neonatal seizure occurs in approximately 1–2 per 1000 live births according to a study by Silverstein et al.,[18] thereby emphasizing the importance of quick HIE management and prevention in order to prevent seizures.

Birth asphyxia, metabolic acidosis, and maternal para-valvular leakage were concluded as significant etiologies of HIE. In a study by Thornberg et al.,[19] the incidence of birth asphyxia with HIE in neonates was estimated as 1.8 per 1000 live births, thus indicating that birth asphyxia is an important etiology of HIE. Metabolic abnormalities such as hypoglycemia and hypocalcemia were confirmed as possible etiology of HIE in a study by Hahn et al.[11] According to a study conducted by Itoo et al.,[20] maternal factors can trigger HIE in neonates.

To conclude, phenobarbitone was most utilized and observed as an efficient anti-epileptic drug for neonatal seizures. Levetiracetam was the least used and the least efficient AED. Phenytoin was the best second-line drug and the second-best AED in the study. HIE was observed to commonly cause seizures, making its prevention and effective management more crucial.

Lack of clinical studies focusing on long-term side effects, follow-up, and missing data are the limitations of this study. The safety of the AEDs was not assessed in the neonatal population due to lack of follow-up as this was conducted retrospectively. Owing to limitations in this study, there is an alarming need for standardized clinical trials in order to establish thorough evidence-based guidelines for the treatment of neonatal seizures.[3]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Saral S, Ghangoria P. Assessment of developmental outcome of neonatal seizures at NICU of tertiary care center hospital. Int J Contemp Pediatr 2017;4:100-4.  Back to cited text no. 1
    
2.
Grinspan ZM, Shellhaas RA, Coryell J, Sullivan JE, Wirrell EC, Mytinger JR, et al. Comparative effectiveness of levetiracetam vs phenobarbital for infantile epilepsy. JAMA Pediatr 2018;4:352-60.  Back to cited text no. 2
    
3.
Dias E, Mithun S, Varghese GS. Management of neonatal seizures- A focus on neuropharmacological aspects. Pediatr Neonat Biol 2018;3:131.  Back to cited text no. 3
    
4.
Guidelines on Neonatal seizures- WHO 2011.  Back to cited text no. 4
    
5.
Ahmad KA, Desai SJ, Bennett MM, Ahmad SF, Ng Y-T, Clark RH, et al. Changing antiepileptic drug use in neonatal intensive care units from year 2014 to 2015. J Perinatol 2017;37:296-300.  Back to cited text no. 5
    
6.
Kang SK, Kadam SD. Neonatal seizures: Impact on neurodevelopmental outcomes. Front Pediatr 2015;3:101.  Back to cited text no. 6
    
7.
Torolira D, Suchomelova L, Wasterlain CG, Niquet J. Phenobarbitone and midazolam increase neonatal seizure associated injury. Ann Neurol 2017;82:115-20.  Back to cited text no. 7
    
8.
Gowda VK, Romana A, Shivanna NH, Benakappa N, Benakappa A. Levetiracetam versus phenobarbitone in neonatal seizures- A randamized clinical trial. Ind Pediatr 2019;56:643-6.  Back to cited text no. 8
    
9.
Neubauer D, Salamon SA, Orsedkar D, Paro-Panjan. Management of refractory seizures. Research and Reports in Neonatology. 2014;4:17-29.  Back to cited text no. 9
    
10.
Sharpe C, Reiner GE, Davis SL. Levetiracetam versus phenobarbitone for neonatal seizures: A randomized controlled trail. Pediatrics 2020;6:145.  Back to cited text no. 10
    
11.
Hahn JS, Olson DM. Etiology of neonatal seizures. Neo Rev 2004;5:327-35.  Back to cited text no. 11
    
12.
Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-9.  Back to cited text no. 12
    
13.
Pathak G, Upadhyay A, Goel SP. Phenobarbitone versus phenytoin for treatment of neonatal seizures: An open ended randomized controlled trial. Indian Pediatr 2013;50:753-7.  Back to cited text no. 13
    
14.
Dao K, Giannoni E, Diezi M, Perez ER, Lebon S. Midazolam as first line agent for neonatal seizures: Retrospective study. Pediatr Int 2018;60:498-500.  Back to cited text no. 14
    
15.
Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in newfoundland: A population-based study. J Pediatr 1999;134:71-5.  Back to cited text no. 15
    
16.
Mruk AL, Garlitz KL, Leung NR. Levetiracetam in neonatal seizures: A review. J Pediatr Pharmacol Ther 2015;20:76-9.  Back to cited text no. 16
    
17.
Kossoff E. Neonatal seizures due to hypoxic-ischemic encephalopathy: Should we care? Epilepsy Curr 2011;5:147-8.  Back to cited text no. 17
    
18.
Silverstein FS, Jensen FE. Neonatal seizures. Ann Neurol 2007;62:112-20.  Back to cited text no. 18
    
19.
Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: Incidence, clinical course and outcome in a Swedish population. Acta Paediatr 1995;84:927-32.  Back to cited text no. 19
    
20.
Itoo BA, Al-Hawsawi ZM, Khan AH. Hypoxic ischemic encephalopathy: Incidence, risk factors in North Western Saudi Arabia. Neuroscience 2003;8:113-9.  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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