Direct Medical Costs in the Care of Pediatric Patients with Non-Syndromatic Epilepsy: Using Levetiracetam and Valproic Acid

doi:10.21203/rs.3.rs-3228672/v1

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Research Article

Direct Medical Costs in the Care of Pediatric Patients with Non-Syndromatic Epilepsy: Using Levetiracetam and Valproic Acid

https://doi.org/10.21203/rs.3.rs-3228672/v1

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Background

The costs of treatments and medical technologies are variables health professionals and institutions can use in guiding decision-making and the improvement of health systems. Currently, few studies that address the economic impact of the clinical-therapeutic management of pediatric patients with epilepsy. This study aimed to determine the direct medical costs of the main monotherapies used in the pediatric population with nonsyndromatic epilepsy.

Methods

Observational, retrospective, longitudinal study, by capturing data and entering the database corresponding to the study variables from the records of patients who met the inclusion criteria, in a period of 10 years, and with an annual time horizon. Costs were determined by the microcosting method.

Results

400 complied with monotherapy therapy, in whom valproic acid (VPA, 46%) and levetiracetam (LEV, 25%) were the most prescribed antiepileptic drugs. Both drugs were considered broad spectrum in the treatment of epilepsy. 167 patients met the criteria for micro costing analysis. Absolute seizure control was observed in 77.9% of patients treated with LEV and 75.9% of those treated with VPA. The average annual cost per pediatric patient who was nonsyndromatic with monotherapy was $1,749.00 USD. Patients treated with VPA had a direct medical cost of $142,497.00 USD ($58,660.00 USD for clinical studies, $36,405.00 USD for consultation, $26,728.00 USD for hospitalization and $20,704.00 USD for medication), while the use of LEV represented a total direct medical cost of $149,511.00 USD ($63,759.00 USD for clinical studies, $15,499.00 USD in consultations, $31,196.00 USD in hospitalization costs and, $39,057.00 USD for the drug).

Conclusions

Regarding the costs of therapeutic schemes used in the pediatric population with nonsyndromic epilepsy, VPA was the less expensive medication per patient in monotherapy (of difference $18,353.00 USD).

Epilepsy

Direct medical costs

Antiepileptic Pharmacoeconomics

Valproic Acid

Levetiracetam

Epilepsy is one of the most frequent chronic neurological diseases¹, the prevalence was 6.38 per 1,000 persons² and incidence of epilepsy was 67.77 per 100,000 persons, with an incidence of 1.8% in children worldwide^3,4. Approximately 80% live in low- and middle-income countries, and it is considered a public health problem⁴. Epilepsy is characterized by an abnormal increase in the electrical activity of cortical neurons that is manifested by recurrent, spontaneous, excessive and unpredictable seizures⁵. In the initial treatment, the specific type of seizure suffered by the child should be determined, and if possible, a determination of epilepsy syndrome⁶. On the other hand, the WHO⁴ recommends phenobarbital as the treatment of choice for partial and tonic-clonic seizures in countries with restricted resources⁷.

In Mexico, clinical practice guidelines recommend the use of valproic acid (VPA), carbamazepine (CBZ) and topiramate (TPM) for focal seizures and VPA, TPM and lamotrigine (LTG) for generalized seizures in pediatric patients⁸. In addition to pharmacological treatment, the social aspect of the patient with epilepsy is essential for good control as well as the personal, occupational and academic development, which occurs when suffering from this pathology. At the National Institute of Pediatrics (NIP), in Mexico City, the most prescribed drug in both monotherapy and combination therapy is VPA; however, in recent years, there has been an increase in the use of levetiracetam (LEV) as an antiepileptic drug (AED) for the treatment of epilepsy⁹.

In 2007, spending on medicines in Mexico represented 24% of the total health expenditure (1.4% of gross domestic product). Most of this expense (75%) is out-of-pocket. The Mexican Social Security Institute concentrates 47.9% of public spending on medicines, followed by institutions that serve the uninsured population, with 26.8%¹⁰. Despite this, the information is limited; in Spain, they have reported cost-effectiveness ‘type’ studies in hypothetical cohorts (1,000 patients), with an annual medical cost of $184,274.00 USD in refractory focal epilepsy, indicating that pregabalin (PGB) provides a better cost-effectiveness than LEV for additional seizure-free days and quality-adjusted life years gained¹¹. García-Contreras et al. (2006) ¹² reported the direct medical cost of refractory focal epilepsy in patients > 12 years of age with more than two AEDs and a one-year follow-up and concluded that the annual health cost of 72 patients was $190,486.00 USD¹². Information on the annual health cost of nonsyndromatic epilepsy in pediatric patients is limited. Therefore, the application of the knowledge and techniques of economic evaluation in the pharmacological field allows focusing the analysis on the resolution of problems posed by an adequate prescription, from an effectiveness point of view, as well as in attaining efficiency at a reasonable cost. So that, this study was addressed to determine the direct medical costs of the main monotherapies used in the pediatric population with nonsyndromatic epilepsy (2008–2018).

Study population and variables

The costs evaluations were carried out by obtaining information on the study variables from the clinical records of patients with diagnosis of epilepsy (International Classification of Diseases-10 of G409), of nonsyndromic type, attended the NIP's outpatient neurology clinic, with complete adherence to antiepileptic treatment and consecutive therapeutic management, a minimum of six months of follow-up. All procedures performed for this observational, retrospective, longitudinal and analytical study were carried out in accordance with the Declaration of Helsinki and of the General Health Law on Research for Health, in Mexico, and were performed following the Protocol-NIP 059/2018, approved by the Research Board of the NIP (IRB00008065), and the Research Ethics Committee (IRB00008064) registered at the Office for Human Research Protection of the National Institute of Health (NIH).

Direct medical costs were determinate during a period spanning January 1, 2008 to December 31, 2018, with a one-year cost horizon, where the following clinical variables were reviewed: age, sex, type of seizures and etiology (according to the international classification of epilepsy) and seizure control (based on the number of seizures per month, absolute: absence of seizures; partial: decrease in seizures to 50%; no control: no change in the number of seizures). They also reviewed variables of direct medical costs: medical consultations, hospitalization, pharmacological treatment, laboratory expenses and other clinical studies including cabinet examinations.

Microcosting

The determination of direct medical costs was calculated by the microcosting method. Medical consultations (such as Neurology, Cardiology, Anesthesiology to perform Magnetic Resonance Imaging, Neurosurgery, Rehabilitation, Infectology, Genetics, Nutrition, Hematology, Audiology, Ophthalmology, Gastroenterology, Phoniatrics, Pulmonology, Human Communication, Urology and Stomatology services), hospitalization, laboratory and cabinet examinations (such as electroencephalogram, axial tomography, magnetic resonance imaging, and others), and the economic value was calculated using data obtained from the NIP, in Mexico City, quota tab corresponding to the last year of study, as managed in the Planning Direction of this Institute. The price of AEDs was taken from the drug price list granted by the Procurement Department and Inventories of the NIP, in Mexico City. Social work granted the socioeconomic classification, based on the program of Assignment of Socioeconomic Classification to the Users of the NIH, which considers the collection percentages according to the level assigned. Therefore, in the NIP, six levels were applied, whereby the last (6N) corresponds to 100%. The analysis alternatives for the study were conventional VPA therapy and alternative LEV therapy (first and second drugs frequently prescribed, respectively, during the period of this study)⁹.

Statistical analysis

The study was carried out through an analysis of direct medical costs, with a time horizon of one year, by the microcosting method, in which variable costs were calculated for each of the AEDs. The administrative system of costs that was used was specially designed for the preparation of this study and was called the Administrative System of Costs for Antiepileptic Drugs. It was based on the NIP Cost Tabulator, since this evaluation has an institutional perspective and corresponded to the last year of the study. Within the prices of the therapeutic approach of the patients, a variable was assigned for each cost, comprising the AED, clinical studies (laboratory studies, imaging and others) and hospitalization (drugs, supplies, procedures and professional fees). Labor was assigned as professional fees according to the number of consultations that the patient had within the institute. The price of the AED was calculated annually based on the weight of the patient at the time of the study and the indication from the Neurology Service. Initially, the subtotals corresponding to the cost of hospitalization, consultations, medications and clinical studies were obtained per individual file. Later, the total annual cost was calculated, as well as the average total cost of epilepsy in the NIP. This relative value of the intervention is usually expressed as the quotient obtained by dividing the net cost of the intervention by its effectiveness, which is the denominator and will be obtained based on the average of the effectiveness presented by each antiepileptic drug during the study period.

Finally, the distribution of the data was determined and the statistical program SPSS version 21 was used for the statistical analysis.

From January 2008 to December 2018, 1362 files from the study population were reviewed, and 682 had a diagnosis of epilepsy, of which 605 patients had nonsyndromic epilepsy. Four hundred of these complied with monotherapy treatment. The frequencies of all AEDs in monotherapy were identified: VPA 46% (n = 184), LEV 25% (n = 100), oxcarbazepine (OXC), 11.5% (n = 46), carbamazepine (CBZ), 5% (n = 20), phenytoin (DFH), 4.75% (n = 19), phenobarbital (PB), 3.7 (n = 15), TPM 2.5% (n = 10), LTG 0.7% (n = 3), and vigabatrin (VGB), 0.7% (n = 3). Pharmacologic treatment distribution varied, depending on the type of seizure (Table 1)

Table 1

Distribution of the clinical characteristics of the microcosting population (LEV, VPA) in patients with nonsyndromic epilepsy (n = 167).
Variables
Variables	n (%)
Sex
Male	94 (56.3%)
Diagnosis age	2.52 (+/-0.17)
Socioecoomic level
1N	56 (33.5%)
1X	12 (7.2%)
2N	73 (43.7%)
3N	22 (13.2%)
Seizures control
Absolute	128 (76.6%)
Partial	36 (21.5%)
No control	3 (1.8%)
Type of seizures
Focal	112 (67.1%)
Generalized	26 (15.6%)
Secondary Generalized Focal	27 (16.2%)
Not specified	2 (1.1%)
Etiology
Structural-metabolic	100 (59.9%)
Unknown	30 (18.0%)
Genetics	19 (11.4%)
Not specified	18(10.8%)
Psychomotor development
Normal	6 3 (37.7%)
Abnormal	96 (57.5%)
Not specified	8 (4.8%)

The two most prescribed AEDs were obtained, comprising a total of 284 files, 184 corresponding to VPA and 100 files to LEV; however, only 167 met the criteria for microcost analysis (VPA n = 109, LEV n = 58) from which the statistical analysis for this study was performed. Of the population studied, 56.3% (n = 94) were male and 43.7% (n = 73) were female with an average age of 2.52 years. Regarding the socioeconomic level of NIP health users, the first three strata represented 97.6%. The pathological personal antecedents were prenatal 10.8% (n = 18), perinatal 12.6% (n = 21), postnatal 18% (n = 30), prenatal and postnatal 1.2% (n = 2), and other background 2.4% (4) (Table 1). Finally, frequency of the subspecialty queries and cabinet studies are described in the Table 2.

Table 2

Frequency of the main microcosting variables of the study population (LEV, VPA) in patients with nonsyndromic epilepsy (n = 167).
Main drug	VPA (n = 109)	LEV (n = 58)	TOTAL
Number of Subspecialty Queries Neurology Cardiology Anesthesiology to perform Magnetic Resonance Imaging Neurosurgery Rehabilitation Infectology Genetics Nutrition Hematology Audiology Ophthalmology Gastroenterology Phoniatrics Pulmonology Human Communication Urology Stomatology	117 52 1 1 4 1 10 5 5 4 1 7 6 8 1 2 4 1 4	116 55 1 2 4 2 12 5 5 4 1 4 4 4 3 1 4 1 4	233 107 2 3 8 3 23 10 10 8 2 11 10 14 4 3 8 2 8
Prehospital emergency number	75	21	96
Hospitalization Number	195	195	390
Number of Electroencephalograms	50	50	100
Magnetic Resonance Number	15	15	30
Simple CAT Number	9	9	18
CAT number simple and contrast	5	11	16
**Valproic Acid (VPA), Levetiracetam (LEV), Computed axial tomography (CAT)

In the analysis of bivariate frequencies for pharmacological treatment and crisis control variables, LEV presented a higher percentage of absolute control with 77.5% (n = 45), while VPA presented 76.1% (n = 83) of absolute and 22.9% (n = 25) in partial control, and both drugs had lower frequencies of No Control, LEV 3.4% (n = 2), VPA 0.91% (n = 1) (Fig. 1).

In the 167 patients studied, the annual costs generated by this pathology were determined by the microcosting method, and a total amount of $292,008.00 USD was obtained during the studied period. Therefore, an average annual cost per patient of $1,749.00 USD was generated. Of the total amount spent, the cost of consultations was $51,904.00 USD; the hospitalization cost reached $57,924.00 USD, the annual cost per medication was $59,761.00 USD. Of the four main costs reported, the highest was the cost of auxiliary clinical studies, which amounted to $122,419.00 USD (Table 3).

Table 3

Annual costs (mean) derivate of the attention of patients with nonsyndromic epilepsy.
Principal AEDs	Average cost per patient	Hospitalization cost	Cost of consultations	Cost of clinical studies	Cost of medication	Total
VPA (n = 109)	$1,307.00	$26,728.00	$36,405.00	$58,660.00	$20,704.00	$142,497.00
LEV (n = 58)	$2,578.00	$31,196.00	$15,499.00	$63,759.00	$39,057.00	$149,511.00
Total		$57,924.00	$51,904.00	$122,419.00	$59,761.00	$292,008.00
*Valproic Acid (VPA), Levetiracetam (LEV)

Patients who used VPA as a base drug (65.3%) spent $58,660.00 USD in clinical studies, with $36,405.00 USD in consultations and $26,728.00 USD in hospitalization. The cost of VPA as a drug was $20,704.00 USD. In total this medicine generated $142,497.00 USD spent for this pathology during the study period. The patients with LEV as treatment (34.7%) spent $15,499.00 USD in consultations, $31,196.00 USD in hospitalization costs, and $63,759.00 USD in clinical studies. The cost for the drug was $39,057.00 USD. Therefore, the LEV treatment incurred an expense of $149.511.00 USD. Based on the average cost per patient, there is a savings of $1,271.00 USD with the use of VPA.

The study population had a wide age distribution; from the neonatal period to adolescence, but the largest group were younger infants (35.5%), which coincided with the frequency of presentation of the convulsive phenomenon in the first year of life^1,13–15. A male predominance was found in the population (56.3%, n = 94), which matches that reported since the males are generally predominantly affected^13,16. Therefore, the population studied complied with the characteristics of an open population, considering that the NIP is a third-level hospital, and consequently, more specific cases come to our consultation¹⁷. Deficiencies or intermittency in the provision of AEDs by health services or lack of means of the patients themselves to pay for their treatment may arise due to the economic situation of the country. It is estimated that only up to 20% of the population in Latin America has private health insurance, and most of them do not include the cost of medicines^18,19. In cases where the cost of the drug is borne by the NIP and not by the patient, a discount percentage is maintained depending on the socioeconomic classification, which ranges from 97.5% for the 1N level to 0.0% for the 6N level (Dates provided by NIP, 2018). It is important to highlight that in the distribution by socioeconomic level, the first three strata represented 97.6%; based on this, the expense generated per patient was $34,513.00 USD for epilepsy treatment. On average, a patient must pay $21,075.00 USD per year for medication in the case of VPA and $39,058.00 USD for LEV. In addition, there is a difference in the price between first-generation AEDs (VPA, CBZ, DFH, PB) and the newer AEDs, which implies they are become up to 100 times more expensive¹⁹.

As regards the frequencies and costs reported in this study, VPA was the most widely used antiepileptic drug in monotherapy and polytherapy, within the population between 2008 and 2018 (605 patients), however, by reducing the population for economic analysis (167 patients), LEV had a higher frequency at 16.5%. LEV has a broad-spectrum activity and minimal interactions with other medications, hence has become a common option for the first-line treatment of epilepsy in early life, although others medications are equally reasonable and the option must be individualized²⁰. However, these data suggest the change in the trend of prescription regimens, due to the use of new AEDs, with less side effects, good availability and efficacy in the last 10 years²¹; nevertheless, VPA is described as the most used antiepileptic drug followed by CBZ⁹.

When analyzing the costs of epilepsy, the current trend tends to assess the so-called direct medical costs. The NIP reports a total amount of $292,008.00 USD from the January 1, 2008 to December 31, 2018 period. By subdividing the total cost, we can appreciate that $59,761.00 USD corresponds to the drug, while the cost of medical consultations was $51,904.00 USD; and the cost per hospitalization reached $57,924.00 USD. Of the four main costs reported in this study, the highest (nearly half of the total cost) were the cost of clinical and auxiliary studies, which amounted to $122,419.00 USD.

The patients treated with VPA (65.2%) spent $58,938.00 USD, $36,677.00 USD in clinical studies and $26,728.00 USD in hospitalizations due to uncontrolled seizures. Where 43.5% of this patients were hospitalized, and 76.1% presented absolute crisis control. The annual cost of buying this drug was $21,075.00 USD, in total this drug generated $143,318.00 USD cost for this pathology. While for patients using LEV as the main AED (34.7%), they spent $63,759.00 USD, $ 9,058.00 USD, and $31,196.00 USD in hospitalization costs, clinical studies and consultations, respectively. The annual cost for LEV was $39,058.00 USD. Therefore, the LEV treatment produced an expense of $149,512.00 USD, which resulted in a more expensive alternative considering that the percentage of seizure control is only 77.5% and the hospitalization percentage was 47.4%, no doubt the increase in this therapeutic alternative lies in the cost of the drug, since that is where the maximum increase is observed compared to VPA. Based on this, there was a difference in the average cost per patient of $1,263.00 USD between the alternatives. Hence, the results of the model showed that VPA obtained more favorable cost values than those corresponding to LEV in the pharmacological treatment of patients with nonsyndromic epilepsy.

As reported in literature, LEV is an epileptic medication with good efficacy and safety profile, plus it is licensed as monotherapy for adults and children over 16 years of age with focal seizures, with or without secondary generalization. However, it is increasingly used off-label in younger children²². The LEV prescription rate increased by 10% within 8 years after 2000 in the United Kingdom and 8% within 10 years in Wales. In Taiwan, the LEV prescription rate increased from 0% in 2003 to 18% in 2007²³. In a systematic review, LEV in 30 trials of complementary therapy in the pediatric population presented a crisis reduction between the reference and treatment periods that ranged from 10.5–31.2% in children²⁴. On the other hand, in a randomized, double-blind trial conducted in children with refractory focal seizures (198 patients), it was found that the average percentage of crisis reduction was 43.8% in children treated with LEV as adjunct therapy, compared to 23.3% for the placebo-treated group²⁵. In a randomized, placebo-controlled, double-blind, multicenter trial with 38 patients who were enrolled to assess the efficacy of LEV in children and adolescents with epilepsy recently diagnosed childhood and juvenile absence seizures, it was observed that 23 patients (7%) ceased having absence seizures. In the placebo group, 4.8% of the patients were free of seizures; nonetheless, the result was not statistically significant²⁶.

In an open study of 20 patients, VPA resulted in a more than 50% reduction in the frequency of epileptic seizures, and in 3 patients, VPA halted seizures²⁷. In a randomized, open-label parallel-group design, 38 children (19 children taking VPA and 19 taking LTG) were included. After 12 months, 13 children taking VPA (68.4%) and 10 taking LTG (52.6) were seizure free. Side effects were mostly mild and transient, and were recorded in 2 (10.6%) children treated with VPA and in 6 (31.8%) children treated with LTG²⁸.

Based on the studies described above, the efficacy measures of LEV were consistent with an average crisis reduction of 27.1% (0.27), with efficacy intervals from 10.5–43.8%, in the 88 patients who were treated. In the case of VPA, efficacy intervals from 50–68.4% were recorded with an average efficacy of 59.2% (0.59) within the population studied and a demonstrated effectiveness of -0.32. This shows that VPA is the least expensive alternative and has proven its effectiveness as a dominant therapy.

A limitation of this study is not having estimated the drop-out rate due to adverse drug reactions, which were considered within the study variables; however, the reported incidence was 1.1% (n = 2) (without indicating the type of reaction or its severity). Still, we do not know the impact that this would have had on the control of the seizures and on the quality of life of the patients. There could be a bias in the indication of antiepileptic drugs, since it is unknown under what criteria each doctor decided to prescribe one or another drug. It may be that because of its broader spectrum, doctors tend to use LEV frequently in more severe or complicated cases, which may affect their response and efficacy, as well as the doses used. In the same way, it cannot be ruled out that the doctors had decided to use LEV in cases in which the patients had better economic means. Last, as a general limitation, the populations studied were patients of a third-level hospital and therefore, the reported cases were more serious.

Finally, it should be considered that both drugs have a broad spectrum, and that VPA has been in use since the 1970s, unlike LVT, whose use began 20 years later, consequently there is a greater variety of brands and prices for the VPA, in addition to the fact that there is greater knowledge of the unwanted and adverse effects that occur when treating the patient with this medication. It is worth mentioning that this study is based on what is described in the clinical records of the study population and that these variables, such as the variety of brands and prices, may influence the existence of a much cheaper presentation and it can impact the direct medical cost. We must also consider that although we did not find in this series, due to the age of the population studied, frequently the patient treated with VPA is subjected to frequent studies where plasma VPA levels, blood biometry and liver function tests are determined, as well as in adolescents treated with VPA, they may present more frequently with obesity, gastritis, thrombocytopenia and greater interactions with other medications. On the other hand, LVT has been associated with behavioral alterations, and the adverse effects and drug interactions, that this medication could induce are still under study.

The direct medical costs incurred by epilepsy care was $292,830.00 USD, in patients treated with monotherapy, where it was observed that LEV represented almost double that generated by VPA. In this economic analysis, VPA turned out to be a dominant medicine as it was more economical, relative to the cost exerted by LEV. However, subsequent, more exhaustive studies will have to be conducted to determine the effectiveness the VPA and determine whether this drug results in a higher cost-effectiveness or a better quality of life for the patient. Although the direct cost is important, so is the safety and efficacy profile. VPA is a drug with significant side effects that limit its use, especially in young women of reproductive age. Based on this analysis, it is would be valuable to continue pharmacoeconomic studies to determine the true effectiveness of VPA as a monotherapy in these patients. This economic evaluation can contribute to the updating of information and in this way provide evidence that helps health professionals, as well as the corresponding health institutions, improve the decision-making process to choose appropriate therapeutic treatment options within this population.

VPA

Valproic acid

LEV

Levetiracetam

USD

United States Dollar

WHO

World Health Organization

CBZ

Carbamazepine

TPM

Topiramate

LTG

Lamotrigine

NIP

National Institute of Pediatrics

AED

Antiepileptic Drug

AEDs

PGB:Pregabalin

AEDs

Antiepileptic Drugs

NIH

National Institute of Health

OXC

Oxcarbazepine

CBZ

Carbamazepine

DFH

Phenytoin

Phenobarbital

VGB

Vigabatrin.

Ethics approval and consent to participate

The results presented correspond to the retrospective part of the Protocol 059/2018. It was approved by the Research Board of the National Institute of Pediatrics (IRB00008065), and the Research Ethics Committee (IRB00008064) registered at the Office for Human Research Protection of the NIH. In addition, the methods carried out in this research are in accordance with the Declaration of Helsinki and adheres to the ethical aspects described in chapter 1 of the General Health Law on Research for Health, in Mexico, 2023. It is worth mentioning that according to article 17, chapter 1 of this Law, this research is considered a risk-free research, since there is no intentional intervention or modification of the individual's variables, in addition to the fact that although the information presented comes from the analysis of the clinical record, personal data are treated with confidentiality, with prior anonymization, through coding and with the generation of specific collection formats for this study, therefore, by not complying with article 22, chapter 1, of this Law, informed consents are not applicable for this study.

Consent for publication

Not applicable.

Availability of data and materials

The data used to support the findings of this study are available from the corresponding author upon request.

Competing interests

The all authors declare that they have no competing interests.

Funding

We appreciate the support received from Protocol 059/2018, Program-E022 of the National Institute of Pediatrics (Ministry of Health, Mexico), and Scholarship No. 706968 (CONACyT, Mexico), which supported studies by Diana L. Pérez-Lozano of the Doctoral Program of the Medical, Dental and Health Sciences, Clinical Experimental Health Research, Clinical Pharmacology, UNAM, Mexico.

Authors' contributions

LC-A and DLP-L conceived and interpreted the studies included; DLP-L, LC-A, MT-V, SG-DP, MP-B, PM-M, TEJ-Z. LR-E and EC-U collected and analyzed the data; DLP-L, LC-A, MR-G, MT-V, SG-DP, MP-B, PMM, TEJ-Z, LR-E, HM-C and EC-U wrote and critically revised and corrected the manuscript; and all authors approved the final manuscript.

Acknowledgments

We thank Mr. Sergio Humberto Larios-Godínez, Ms. C. Aristides III Sampieri-Hernández, and Dr. Noemi Cárdenas-Rodríguez for providing technical assistance.

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No competing interests reported.

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Direct Medical Costs in the Care of Pediatric Patients with Non-Syndromatic Epilepsy: Using Levetiracetam and Valproic Acid

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