Exploring the Correlation between Seizure Control and Serum Levels of Antiepileptic Drugs in Pediatric Patients with Epilepsy in Ethiopia: A Retrospective Cross-Sectional Study

doi:10.21203/rs.3.rs-5208377/v1

Introduction: Antiepileptic drugs (AEDs) are frequently used to treat seizures; however, in settings with limited resources, the relationship between seizure control and the plasma levels of these medications in the paediatric population is still not well understood.

Purpose: This study investigated this correlation, aiming to optimize treatment strategies and enhance the well-being of children with epilepsy.

Methods: A retrospective cross-sectional design was employed in three Ethiopian hospitals from September 2021 to February 2022. Data from 81 participants were analysed, with a focus on sociodemographic and clinical characteristics and AED serum levels.

Results: Boys composed 69.1% of the sample, with an average age of 8.56 ± 4.35 years. Generalized seizures were predominant (54.3%). TDM was performed for valproic acid (13.7%), phenytoin (11.7%), phenobarbitone (8.7%), and carbamazepine (1.3%). Post-TDM, 48% of the patients underwent therapeutic interventions. A chi-square test revealed no significant relationship between seizure control and AED concentration (p=0.920). Correlation analysis revealed a fourfold increase in the odds of poor seizure control with antiepileptic polypharmacy (AOR=4.162, p=0.046) and a sevenfold increase with increasing seizure frequency (AOR=6.711, p=0.027). Fisher's exact test indicated a significant correlation between TDM results and AED effectiveness for phenobarbitone, phenytoin, and valproic acid. The lack of a direct correlation between AED concentrations and seizure control emphasizes the multifactorial nature of epilepsy management.

Conclusions: This study emphasizes the need for personalized treatment for pediatric epilepsy, considering factors such as seizure frequency and antiepileptic polypharmacy. This suggests that caution should be taken in antiepileptic polypharmacy and regular seizure frequency assessment. Further research is recommended for improved treatment guidelines.

Antiepileptic Drugs (AEDs)

Therapeutic Drug Monitoring (TDM)

Seizure Control

Antiepileptic Polypharmacy (APP)

Epilepsy is a neurological disorder caused by an abnormal connection of neurons in the brain that affects populations of all ages worldwide ^1-3. It affects approximately 10 million children worldwide, and its prevalence is high in the developing world due to paediatric exposure to infectious diseases such as meningitis, onchocerciasis, malaria, neurocysticercosis, encephalitis and HIV infections ^4-6. Approximately 4–10% of children who experience a seizure within the first two decades of life, 1% of whom develop epilepsy ³^,⁷.

Epilepsy is a significant health concern in Ethiopia, particularly among pediatric patients ⁸. While antiepileptic drugs (AEDs) are commonly used for seizure management, there is a need to investigate the correlation between seizure control and the serum levels of these drugs in the pediatric population ⁹. Understanding this relationship is crucial for optimizing treatment strategies and improving the overall well-being of children with epilepsy ¹⁰. This allows healthcare providers to optimize treatment efficacy, tailor drug dosages, and move towards personalized medicine ¹¹. Maintaining AED serum levels within the therapeutic range is essential for controlling seizures while minimizing adverse effects ¹². Elevated AED serum levels can lead to drug toxicity, resulting in adverse effects and potentially exacerbating seizures ¹²^,¹³.

Monitoring and adjusting AED doses on the basis of serum levels can help prevent toxicity and promote patient safety ¹⁴. Serum level monitoring can also help identify nonadherence, explore potential pharmacoresistance, inform clinical decision-making, and enhance the quality of life for individuals with epilepsy ¹⁵. Understanding the correlation between seizure control and AED serum levels can guide the implementation of therapeutic drug monitoring (TDM) practices in clinical settings ¹⁶^,¹⁷. This study aimed to investigate the correlation between seizure control and the serum levels of AEDs in pediatric patients with epilepsy in Ethiopia. Additionally, research has sought to evaluate the factors that influence the levels of AEDs in this particular population.

Study design, setting and period

The study uses a retrospective cross-sectional design to gather data on TDM from patient charts, complementing the larger research on pediatric epilepsy management.

The study was carried out in three Ethiopian hospitals, namely, Tikur Anbessa Specialized Hospital (TASH), Saint Paul's Hospital Millennium Medical College (SPMMC), and Yekatit 12 Hospital Medical College (Y12HMC). TASH is the largest referral hospital in Ethiopia, with 700 beds, and is currently being expanded to 2000 ¹⁸. TASH is the main teaching center for preclinical and clinical training in most fields in the country. Furthermore, this hospital offers specific therapeutic treatments that are unavailable from other public or private facilities to the entire nation. In addition to having more than 1000 contracts and permanent, administrative, and support staff, TASH employs more than 900 health professionals. Moreover, TASH collaborates with most regional and federal hospitals in Addis Ababa to provide clinical care and education ¹⁹. The SPMMC was established in 1968, and it is Ethiopia's first integrated modular and hybrid problem-based undergraduate medical education institution. It is governed by the Federal Ministry of Health and has grown rapidly, with over 2800 clinical, academic, and administrative staff. The college provides healthcare and training to students in various departments. It also sees an average of 1200 emergency and outpatient clients daily ²⁰. Y12HMC was formerly known as Bethesda Be-Teferi Mekonnen and was established in 1915 by His Majesty Haile Selassie. The college provides healthcare and training to students in various departments. It also provides clinical services in emergency, outpatient, and inpatient units ²¹.

This study was conducted from September 2021 to February 2022.

Study population

The study included children up to 18 years old with epilepsy who were receiving TDM for at least one antiseizure drug.

Patient selection

This study considered all TDM patients from a single, unpublished study that gathered information from the three referral Ethiopian hospitals. Data were extracted from all AED serum level reports.

Sampling method and sample size determination

Among the 314 participants tracked in three hospitals for the study, 81 individuals were on TDM. Hence, the sample size for this study was 81 participants (Figure 1). TDM measures were obtained from 35.9% of TASH, 28.1% of SPMMC, and 10.5% of Y12HMC.

Data analysis and interpretations

For the purposes of the chi-square test analysis, only patients who had a single ASM level completed were included; one patient had two ASM concentrations and different findings, with one being normal and the other being abnormal. The data were checked for completeness and then coded, entered, and cleaned via Epi data version 4.6.6 and then analysed via Statistical Science for Social Science (SPSS) version 25 (IBM Corp., NY, USA).

Descriptive statistics (frequency, percentage, mean, and standard deviation) were used to collect data on illnesses, medications, and sociodemographic variables. Owing to the limited sample size, the relationship between the blood levels of antiseizure medications and the state of seizure control was investigated via the chi-square test of independence.

Sociodemographic and clinical characteristics of the patients

The study analysed demographic and clinical variables among pediatric patients diagnosed with epilepsy. The average age of the study participants was 8.56 ± 4.35 years. The majority were aged 5-10 years, with a higher prevalence among males (69.1%). The most common form of seizure was generalized type 44 (54.3%). Comorbidities were present in 38.3% of the participants (Table 1).

Table 1: Sociodemographic and clinical characteristics of the patients

Variables	Categories	Number (n)	Percentage (%)
Age	1-5 years	20	24.7
	5-10 years	33	40.7
	10-15 years	23	28.7
	15-18 years	5	6.2
Sex	Male	56	69.1
	Female	25	30.9
Type of seizures	Focal	16	19.8
	Generalized	44	54.3
	Mixed	18	22.2
	Unclassified	3	3.7
Frequency of seizure attacks (last 1 year)	None	17	21
	1-5 times	30	37
	6-10 times	15	18.5
	Greater than 10 times	19	23.5
Age at Diagnosis of epilepsy	Less than 1 years	30	37.0
	1-5 years	37	45.7
	6-10 years	8	9.9
	Greater than 10 years	6	7.4
Health facility	TASH	46	56.8
	SPHMMC	27	33.3
	Y12HMC	8	9.9
Commorbidity	Yes	31	38.3
	No	50	61.7

Clinical characteristics

The study revealed that the mean serum levels of antiepileptic medications varied, with phenytoin, phenobarbitone, valproic acid, and carbamazepine all falling outside the reference range. Phenytoin had a mean concentration of 11.7 µg/ml, phenobarbitone had a mean concentration of 41.9 µg/ml, and valproic acid had a mean concentration of 74.4 µg/ml. These findings provide insights into the distribution of serum levels, highlighting both adherence to and deviations from established reference ranges, which is crucial for optimizing therapeutic outcomes and effective management of epilepsy in the studied population (Table 2).

Table 2: Serum concentrations of phenytoin, phenobarbitone, valproic acid and carbamazepine in Addis Ababa, Ethiopia

Medications	Mean serum level	Within reference range	Out of reference range	Reference range
Phenytoin	11.7	10 (3.4%)	25 (8.4%)	10-20 µg/ml
Phenobarbitone	41.9	14 (4.7%)	12 (4%)	10-40 µg/ml
Valproic Acid	74.4	23 (7.7%)	18 (6%)	50-100 µg/ml
Carbamazepine	8.54	0 (0%)	4 (1.3%)	6-12 µg/ml

A post-TDM investigation revealed that 48% of the subjects underwent therapeutic interventions, with the prescribed doses in 34 (42%) patients remaining unchanged. The distribution of interventions varied for each medication, with 41.9% continuing their current regimen, 27.2% experiencing escalation, 28.4% decreasing dosage, and 2.5% switching to an alternative. These findings highlight the importance of TDM in epilepsy treatment (Table 3).

Table 3: Therapeutic interventions following therapeutic drug monitoring, n=81

Therapeutic Interventions	Valproic acid	Phenobarbitone	Phenytoin	Carbamazepine	Total
Continued	16 (19.7%)	9 (11.1%)	8 (9.8%)	1 (1.2%)	34 (41.9%)
Escalated	12 (14.8%)	4 (4.9%)	4 (4.9%)	2 (2.5%)	22 (27.2%)
Decreased	6 (7.4%)	8 (9.9%)	8 (9.9%)	1(1.2%)	23 (28.4%)
Switched	2 (2.4%)	0	0	0	2 (2.5%)
	36 (44.4%)	21 (26%)	20 (24.7)	4 (4.9%)	81 (100%)

The analysis revealed that among participants whose serum drug levels were within the reference range, 78.3% had uncontrolled seizures, whereas 21.7% had controlled seizures. Similarly, for those with serum drug levels outside the reference range, 77.1% had uncontrolled seizures, and 22.9% had controlled seizures. The comparison of seizure control status between these two categories of serum drug levels yielded a p value of 0.920. The lack of statistical significance (p = 0.920) indicates that there is no substantial association with seizure control status (Table 4).

Table 4: Relationships between seizure control status and serum concentrations of AEDs among children with epilepsy in Addis Ababa, Ethiopia

Variable		Categories	Seizure control status		P value
			Uncontrolled n (%)	Controlled n (%)
Serum drug level	Within the reference range		18 (78.3%)	5 (21.7%)	0.920
	Out of the reference range		27 (77.1%)	8 (22.9%)

Exploring the associations between TDM and seizure control

The proportion of participants who underwent TDM was 81 (27%). As shown in Table 5, participants identified as male exhibited an increased likelihood of poor seizure control, with a crude odds ratio (COR) of 2.571, 95%CI (1.074-6.156), p = 0.034). However, after adjusting for other factors (AORs), the association became nonsignificant, with an odds ratio of 1.321 (95% CI: 0.283–6.173, p = 0.723). Older patients (≥ 5 years) were significantly associated with poor seizure control, with a COR of 2.812 (95% CI: 1.590-4.976, p < 0.001, whereas those with identified triggers had a greater likelihood of poor seizure control. Comorbidities were also associated with poor seizure control, but the association became nonsignificant after adjustment. A higher frequency of seizures (less than one week) was also associated with poor seizure control, with a COR of 18.500 (95% CI: 4.459-76.757, p < 0.001) and an AOR of 6.711, 95% CI (1.239-36.346), p = 0.027) after adjustment. Interventions following TDM results were significantly associated with poor seizure control, as indicated by a COR of 3.700 (95% CI: 1.840-7.440, p < 0.001). After adjustment, the association became nonsignificant, with an AOR of 0.873 (95% C. I: 0.239-3.186, p = 0.837).

Table 5: Factors associated with poor seizure control in pediatric patients.

Variables	Seizure Control		COR	95% C.I		P. Value	AOR	95% C.I		P. Value
Variables	Poorly Contr’d	Well Contr’d	COR	Lower	Upper	P. Value	AOR	Lower	Upper	P. Value
Sex(m)	18 (72.0%)	7 (28.0%)	2.571	1.074	6.156	0.034	1.321	0.283	6.173	0.723
Age (≥ 5yrs)	45 (73.8%)	16 (26.2%)	2.812	1.590	4.976	<0.001	0.978	0.149	6.430	0.982
Age at Diagnosis of epilepsy (≥5 year)	10 (71.4%)	4 (28.6%)	2.500	0.784	7.971	0.121	1.604	0.313	8.216	0.571
Triggers	46 (86.8%)	7 (13.2%)	6.571	2.967	14.554	<0.001	3.175	0.937	10.757	0.063
Comorbidities	26 (83.9%)	5 (16.1%)	5.200	1.997	13.541	0.001	1.831	0.432	7.769	0.412
Adverse effects	36 (75.0%)	12 (25.0%)	3.000	1.561	5.766	0.001	0.527	0.136	2.039	0.353
Antiepileptic Polypharmacy			7.600	2.991	19.309	<0.001	4.162	1.029	16.835	0.046*
frequency of seizure (less than a week)	37 (94.9%)	2 (5.1%)	18.500	4.459	76.757	<0.001	6.711	1.239	36.346	0.027*
Duration with AEDs (≥1 year)	52 (75.4%)	17 (24.6%)	3.059	1.769	5.289	<0.001	0.525	0.079	3.475	0.504
Intervention after TDM result	37 (78.7%)	10 (21.3%)	3.700	1.840	7.440	<0.001	0.873	0.239	3.186	0.837

*significant, P<0.005;

Table 6 shows the correlation between the AED intervention and the TDM results. According to Fisher's exact test, the TDM results and the effectiveness of the AEDs are statistically correlated for phenobarbitone, phenytoin, and valportic acid. The Mantel‒Haenszel test further eliminates all potential sources of confounding. Therefore, the analysis is more reliable and provides a more comprehensive explanation of the statistical link between TDM results and the efficacy of AEDs when both tests are used.

Table 6: Association of therapeutic drug monitoring results with interventions for phenobarbitone, carbamazepine, phenytoin, and valproic acid

AEDs		Intervention after TDM Result		Fisher's Exact Sig. (2-sided)	Mantel‒Haenszel (2-sided)
AEDs		Yes (%)	No (%)	Fisher's Exact Sig. (2-sided)	Mantel‒Haenszel (2-sided)
Phenobarbitone	No	36 (52.2)	33 (47.8)	0.011	0.031
Phenobarbitone	Yes	11 (91.7)	1 (8.3)	0.011	0.031
Carbamazepine	No	44 (56.4)	34 (43.6)	0.260	0.368
Carbamazepine	Yes	3 (100.0)	0 (0.0)	0.260	0.368
Phenytoin	No	26 (43.3)	34 (56.7)	<0.001	<0.001
Phenytoin	Yes	21 (100.0)	0 (0.0)
Valproic Acid	No	29 (47.5)	32 (52.5)	0.001	0.002
Valproic Acid	Yes	18 (90.0)	2 (10.0)

It is necessary to understand the clinical and sociodemographic characteristics of paediatric epileptic patients to understand the dynamics of treatment response and therapeutic approaches ²². Boys made up 69.1% of the sample in this study, with an average age of 8.56 ± 4.35 years. In terms of the distribution of seizure types, generalized seizures accounted for the majority (54.3%), followed by mixed (22.2%), focal (19.8%), and unclassified seizures (3.7%). These findings are in line with earlier studies on the occurrence and distribution of different seizure types in paediatric populations ²³. Nonetheless, several studies support the notion that focal seizures are more common in adults and children than are generalized seizures ²⁴^,²⁵. This could be because seizure types can be determined by several underlying causes, such as diagnosis, treatment plans, genetic variations, and predisposing factors ²⁴^,²⁵.

With respect to clinical aspects, the most frequently monitored AEDs for which TDM was used were carbamazepine, phenytoin, valproic acid, and phenobarbitone. These results highlight how crucial it is to keep an eye on drug levels to maximize therapeutic results. When unsatisfactory serum levels are detected, modifying treatment schedules is useful for guaranteeing successful seizure control ¹⁷^,²⁶. In our instance, a single TDM test was used to correlate with seizure control. However, we feel that multiple tests—at least five—are necessary to produce the desired outcomes; consequently, our findings offer insight into the subjects who, in a typical scenario, would be permitted to undergo TDM monitoring owing to treatment nonresponsiveness.

In the second instance, since the TDM service was provided through outsourcing, the sole element influencing the decision is the doctor's willingness to achieve the intended result and make the required therapy improvements. During our inquiry, studies carried out following TDM revealed that more than half of the subjects received therapy, including adjustments to their dosage. Notable modifications in medication substitution, dosage reduction, and escalation indicate that treating epilepsy in young individuals is a dynamic process ²⁷^,²⁸.

The chi-square test of independence revealed no statistically significant relationship between serum AED concentrations and seizure control status. The implication emphasizes how difficult it is to manage epilepsy in children by suggesting that variables other than serum concentrations may be involved in seizure management ²⁹^,³⁰.

The correlation analysis revealed a noteworthy finding: those receiving antiepileptic polypharmacy (APP) had a fourfold increased likelihood of experiencing inadequate seizure control. This result is in line with several findings ³¹^,³². This statement discusses the positive changes in seizure control and quality of life for individuals with medically refractory epilepsy who switched from APP to monotherapy. This change was primarily due to the difficulty in controlling seizures and the need for a simpler treatment regimen. Switching from polypharmacy to monotherapy has resulted in simplified treatment, fewer side effects, and increased overall efficacy.

Furthermore, a higher seizure frequency was associated with a sevenfold increase in the likelihood of having insufficient seizure control, according to our data. This finding has also been supported by related studies ³³^,³⁴. This emphasizes how important it is to treat seizure frequency as a crucial component of treatment planning.

Three AEDs were shown to have statistically significant connections when the relationship between TDM results and AED effectiveness was examined via Fisher's exact test: phenobarbitone, phenytoin, and valproic acid. Confounding variables were eliminated to better validate the Mantel‒Haenszel test results. These findings suggest that TDM results could provide useful information for tailored treatment strategies and be a reliable predictor of AED efficacy ¹⁶^,³³. More erratic serum blood concentrations from the three drugs listed above were observed in our study since the intervention following the TDM resulted in changes in therapy or medication dose. Several studies have shown that AEDs with variable pharmacokinetics or narrow therapeutic windows—such as phenobarbital, ethosuximide, carbamazepine, valproic acid, and phenytoin—need TDM ³⁵^,³⁶.

In summary, this study clarifies the clinical and sociodemographic features of young epileptic patients, highlighting the importance of individualized and adaptable treatment approaches. The results highlight the influence of seizure frequency and antiepileptic polypharmacy on treatment outcomes, and the relationship between TDM results and AED efficacy suggests that TDM may play a role in optimizing therapeutic interventions for improved seizure control in paediatric populations. It is necessary to perform additional research to investigate other factors impacting treatment response and to improve our knowledge of the individualized management of epilepsy in children.

This study highlights the importance of gender-specific treatment planning for pediatric patients with epilepsy, with boys being the predominant group. The study also highlights the dynamic nature of treatment interventions in pediatric patients, with adjustments in prescribed doses. The lack of a significant relationship between seizure control status and antiepileptic medication concentrations suggests that factors beyond drug levels contribute to seizure outcomes. Antiepileptic polypharmacy and increased seizure frequency are significant factors influencing poor seizure control, emphasizing the need for tailored treatment approaches. This study suggests that clinicians should exercise caution when considering antiepileptic polypharmacy in pediatric patients and regularly assess and manage seizure frequency for optimal treatment outcomes.

Further research is needed to determine which other factors influence the efficacy of therapy for pediatric patients with epilepsy. Additional research on the connection between TDM results and long-term clinical outcomes can help to enhance treatment guidelines. Continued research efforts to understand the intricate nature of paediatric epilepsy will contribute to the development of specialized and effective treatment modalities.

ADEs Adverse Drug Events

AEDs Antiepileptic Drugs

AEMs Antiepileptic Medications

AOR Adjusted Odds Ratio

ASDs Anti-seizure Drugs

ASMs Anti-seizure Medications

CI Confidence Interval

EEG Electroencephalogram

MRI Magnetic Resonance Imaging

OR Odds Ratio

SUDEP Sudden Unexpected Death in Epilepsy

SPHMMC Saint Paul’s Hospital Millennium Medical College

TASH Tikur Anbessa Specialized Hospital

TDM Therapeutic Drug Monitoring

Y12 HMC Yekatit 12 Hospital Medical College

VPA Valproic Acid

WHO World Health Organization

Acknowledgements

We want to express our sincere gratitude and appreciation to Addis Ababa University, the data collectors and all parents who participated in the study.

Funding

Addis Ababa University

Data availability statement

The data supporting the findings of this study are available at the following link and can be accessed online: https://etd.aau.edu.et/items/10198a42-b73f-482d-a33b-dbb829d1f037. Researchers and interested parties can access the dataset through this link for further analysis and verification.

Author contributions

BMM: Proposal development and writing of the manuscript;

AMB: Review of proposal, supervision, and review of the manuscript;

MAL: Review of proposal, supervision, and review of the manuscript;

MAW: Review of proposal, supervision, review of draft and final manuscript, and approval for publication.

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical consideration

Ethical approval for the study was obtained from the Ethical Review Committee of the School of Pharmacy, Addis Ababa University (Ref no: ERB/SOP/247/13/2021) and from each participating hospital. Consent was sought from patients or caregivers for data extraction from medical records. All methods adhered to relevant guidelines, including the Declaration of Helsinki, and complied with institutional and national standards for retrospective studies. Patient confidentiality and data protection were strictly maintained throughout the research.

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No competing interests reported.

Exploring the Correlation between Seizure Control and Serum Levels of Antiepileptic Drugs in Pediatric Patients with Epilepsy in Ethiopia: A Retrospective Cross-Sectional Study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study design, setting and period

Study population

Patient selection

Sampling method and sample size determination

Data analysis and interpretations

Results

Sociodemographic and clinical characteristics of the patients

Clinical characteristics

Exploring the associations between TDM and seizure control

Discussion

Conclusions

Recommendations

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1