Effects of Long-term Antiepileptic Therapy on Carotid Artery Intima- Media Thickness.

BACKGROUND: Common first-line antiepileptic drugs (AEDs) used in children are valproate, phenytoin, and levetiracetam. Many side effects for these AEDs are reported including obesity, atherosclerosis, and metabolic syndrome. The aim of our study was to evaluate changes in carotid artery intima-media thickness (CIMT) in epileptic children and to correlate with lipid profile of those who are on long-term antiepileptic therapy.
MATERIALS AND METHODS: This case-control study was done over 18 months in department of pediatrics. Sample size was 84 with equal number of cases and controls. Epileptic children between 1 and 18 years of age receiving monotherapy with valproate, phenytoin, or levetiracetam for at least 6 months were included in the study. Measurement of CIMT was done by B mode ultrasonography. Lipid profile was analyzed. Statistical analysis was performed using one-way analysis of variance (ANOVA) test and Pearson correlation.
RESULTS: Among 42 cases of epilepsy, 30 were on valproate, 9 on phenytoin, and 3 on levetiracetam monotherapy. No significant difference was noted in body mass index (BMI) among children receiving AED compared with that of controls (P = 0.82). Mean value for CIMT was significantly higher among valproate (0.43 ± 0.04, P ≤ 0.001), phenytoin (0.44 ± 0.04, P ≤ 0.001), and levetiracetam group (0.43 ± 0.03, P = 0.01) compared to controls (0.39 ± 0.01). Significant correlation was noted between CIMT and total cholesterol (P = 0.034), triglyceride (P = 0.011), low-density lipoprotein (P = 0.008), and very low-density lipoprotein (P = 0.011).
CONCLUSION: Children on long-term monotherapy with valproate, phenytoin, and levetiracetam have significantly abnormal CIMT. This might be associated with atherosclerotic changes, and these children may require close follow-up to prevent cardiovascular and cerebrovascular risks. Copyright:

INTRODUCTION

Epilepsy is a condition of recurrent, spontaneous unprovoked seizures arising from aberrant electrical activity within the brain. Objectives of treating epilepsy in children are to prevent recurrence and to minimize the acute and chronic side effects of drugs used in treatment. Antiepileptic drugs (AEDs) are the mainstay of treatment either in single or in combination. First-generation AEDs are phenobarbitone, phenytoin, valproate, and carbamazepine, and second generation are levetiracetam, lamotrigine, and oxcarbazepine.[1] Valproate is the most common AED used in children because of its broader spectrum of activity and tolerability. Phenytoin, extensively used drug in past decade, has been replaced by valproate and levetiracetam. Levetiracetam is a newer drug for epilepsy and has good safety profile.[2] Adverse and some serious effects noted during treatment with valproate include overweight, abnormal liver function, pancreatitis, and metabolic syndrome.[34] Valproate modulates pancreatic islet cell insulin secretion, thereby increasing appetite and energy storage. This possibly results in weight gain in children on prolonged valproate therapy.[5] Similarly, it can also increase the levels of serum leptin, thus causing alteration in lipid profile.[67] Phenytoin, being an enzyme inducer, increases the activity of the hepatic cytochrome P450 system, which can affect lipid profile.[89] Children on levetiracetam do not have side effects related to overweight, but behavioral changes and psychotic disturbances can be seen.[10] Weight gain and adiposity are known risk factors for developing premature-onset cardiovascular diseases. The measurement of carotid artery intima-media thickness (CIMT) can be used as surrogate marker to detect and monitor premature atherosclerosis. In clinical studies, CIMT measurements parallel the significance of cardiovascular risk factors.[11] Detection of CIMT is a noninvasive tool, which can guide in reviewing children on long-term AEDs for their cardiac and vascular adverse effects.[12] Our objectives were to estimate intima-media thickness of common carotid artery in children on long-term AEDs and to correlate between CIMT and individual lipid profile in turn to assess the atherogenic property of these drugs.

MATERIALS AND METHODS

Study setting

This was a case–control study conducted in department of pediatrics of a tertiary care hospital in south India from January 2018 to June 2019.

Sample size

Children between 1 and 18 years of age with epilepsy were recruited as cases. Sample size was calculated on openepi.com/SampleSize/SSMean.htm for the power of 80% and 95% confidence interval with ratio of cases/controls of 1:1.[13] Total of 84 children formed the study group. Forty-two children diagnosed with epilepsy were enrolled into the study.

Study participants

All the cases recruited had abnormal electroencephalogram (EEG) at diagnosis. They were receiving one of the three AEDs, that is, valproate, phenytoin, or levetiracetam as monotherapy for a minimum duration of 6 months. Children were classified by type of seizure and AED.[14] Those children who were not compliant with therapy were excluded. Equal number of healthy children of same age and gender without underlying chronic and metabolic illnesses were recruited as controls. Children with body mass index (BMI) more than >95th centile, and those receiving drugs such as statins, antipsychotics, and danazol, which can alter lipid profile, were excluded for both the groups. Institutional ethics committee approval was obtained before the initiation of the study. Written informed consent from parents was obtained, and in addition, assent was taken for children aged 7 years and above.

Data collection and definition

All the data were entered in the case pro forma. Anthropometric data were obtained for each child. Height was measured with a stadiometer (for children aged more than 2 years), length by infantometer (for children aged less than 2 years), and the body weight was measured on a standard weighing scale. BMI was calculated as weight (in kilogram) divided by the square of the height or length (in meter) and plotted on the standard World Health Organization (WHO) growth charts.

Measurements

B mode ultrasonography was used to measure CIMT with ultrasound scanner and linear probe. To minimize the subjective variations, single radiologist performed the scan. Subjects were in supine position with the head slightly extended and rotated to the other side during the ultrasound examination. Both left and right common carotid arteries were scanned. The distance between the leading edge of first bright line (lumen-intima interface) and the leading edge of the second bright line (media-adventitia interface) was taken as the intima-media thickness. CIMT was defined as the mean of the three measurements (distal, middle, and proximal segments) from carotid artery [Figure 1]. Fasting blood sample of 3 mL was collected from the cases.

Figure 1

Intima-media thickness of distal segment of common carotid artery

Analytical methods

Lipid profile included total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low-density lipoprotein (LDL), Very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo A1). Lipid profile was analyzed using CFAS (Calibrator for automated systems) lipid calibrator, and Apo A1 levels were analyzed using Tina-quant Apo A1 test in a standard laboratory. Standard reference values were taken as follows: TC (<170 mg/dL), TG (<90 mg/dL), HDL (>45 mg/dL), LDL (<110 mg/dL), VLDL (<30 mg/dL), and Apo A1 levels (>120 mg/dL).[15]

Outcome measures

Primary outcomes studied were mean CIMT in cases of different groups of AEDs and controls. Secondary outcome was measured as correlation between lipid profile and CIMT.

Statistical analysis

Baseline characteristics and laboratory parameters were reported using descriptive statistics. For categorical data, frequency (n) and percentages (%) were calculated. For quantitative data with normal distribution, mean standard deviation or median with interquartile range were calculated. Student’s t test was applied to compare the data between cases and controls. For comparison between and within three groups of children on different AED, one-way analysis of variance (ANOVA) test was used. Pearson correlation was used to analyze relation between CIMT and individual lipid parameter. A P value of < 0.05 was considered significant. Statistical analysis was done using the software Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM, Armonk, New York) and EpiInfo version 6.0 (Center for Disease Control and Prevention, Atlanta, Georgia).

RESULTS

The demography of cases is described in Table 1. Among the AED, 71.4% were on valproate, 21.4% were on phenytoin, and 7.2% on levetiracetam monotherapy. Highest and lowest ages among the cases while recruiting were 192 and 12 months, respectively. Median age at onset of seizures was 48 months. Majority of the children were males (59.5%). Less than half of cases had abnormal magnetic resonance imaging (MRI) findings such as cortical dysplasia/atrophy and diffuse gliosis. Duration of AED therapy before recruiting cases and analysis was between 6 months and 1 year in 58%, 1–2 years in 30% and more than 2 years in 12% children. None of the children had BMI more than 95th centile. BMI and CIMT between cases and controls were compared and shown in Table 2. Though average BMI was higher among children receiving AED compared with that of controls, there was no statistical significance (P = 0.83). Correlation between duration of AED and CIMT was not significant (P = 0.973, r = 0.005). Mean value for CIMT was significantly higher among valproate (P ≤ 0.001), phenytoin (P ≤ 0.001), and levetiracetam group (P ≤ 0.001) compared to controls. Comparison of individual parameter of lipid profile between three groups of AEDs has been shown in Table 3. Lipid profile was abnormal in 28 cases of valproate group. When individual parameter was compared between and within groups, significance was noted for TC (P ≤ 0.001), TG (P = 0.04), LDL (P ≤ 0.001), and Apo A1 levels (P = 0.005). Pearson correlation was done between CIMT and individual lipid profile, and significance was noted for TC (P = 0.034, r = 0.279), triglyceride (P = 0.011, r = 0.329), low-density lipoprotein (P = 0.008, r = 487), and very low-density lipoprotein (P = 0.011, r = 0.329).

Table 1

Demography of cases

Variables	Valproate, n = 30 (%)	Phenytoin, n = 09 (%)	Levetiracetam, n = 03 (%)
Median age (months)	79	84	72
Median age at onset of seizures (months)	49	48	36
Gender
Male	21 (70)	05 (56)	01 (33)
Female	09 (30)	04 (44)	02 (67)
Type of seizure
Generalized	24 (80)	09 (100)	02 (67)
Partial	06 (20)	-	01 (33)
Development delay	08 (27)	05 (56)	02 (67)
Microcephaly	05 (17)	03 (33)	02 (67)
Abnormal neurological examination	07 (23)	04 (44)	02 (67)
MRI abnormality	10 (33)	04 (44)	01 (33)

Table 2

Comparison of BMI and CIMT between cases and controls

Variables	Controls (n = 42)	Valproate, n = 30 (%)	Phenytoin, n = 09 (%)	Levetiracetam, n = 03 (%)	P value
BMI (kg/m2)	14.7 ± 2.2	15.3 ± 3.3	15.3 ± 2.8	15.2 ± 1.7	0.828
Right CIMT (mm)	0.38 ± 0.06	0.43 ± 0.04	0.44 ± 0.05	0.43 ± 0.03	0.001
Left CIMT (mm)	0.39 ± 0.01	0.43 ± 0.04	0.44 ± 0.04	0.43 ± 0.02	<0.001
Mean CIMT (mm)	0.39 ± 0.01	0.43 ± 0.04	0.44 ± 0.04	0.43 ± 0.03	<0.001

Table 3

Serum lipid profile among the cases in comparison with standard reference range

Lipid profile	Reference value[15]	Valproate, n = 30 (71%)	Phenytoin, n = 09 (22%)	Levetiracetam, n = 03 (7%)	P value
TC (mg/dL)	<170	143.3 ± 26.9	174.3 ± 53	161 ± 44.5	<0.001
TG (mg/dL)	<90	120.8 ± 65.6	105.5 ± 65.9	100.3 ± 52.2	0.041
HDL (mg/dL)	>45	45 ± 12.8	53.2 ± 11.8	44.3 ± 19.9	0.122
LDL (mg/dL)	<110	101 ± 90.1	113.8 ± 53	107.7 ± 28	<0.001
VLDL (mg/dL)	<30	23.6 ± 13.2	21.1 ± 13.2	20.1 ± 10.4	0.20
Apo A1 (mg/dL)	>120	102.7 ± 38.3	97.8 ± 30.8	94.2 ± 5.1	0.005

DISCUSSION

In this case–control study on epileptic children, we showed that individual AED can have atherogenic property by subtly changing the lipid parameters and in turn resulting in vascular remodeling. Alteration in lipid profile values as well as increased CIMT was documented with valproate- and phenytoin-treated children in study group.

Our study showed average BMI was not significantly higher among children receiving AED compared with that of controls (P = 0.77). In a study on epileptic children done by El-Farahaty et al.,[16] BMI measured was significantly higher among cases receiving valproate (23.8 ± 3.8 kg/m2) and levetiracetam (23.7 ± 2.4 kg/m2) compared to controls (21.4 ± 3.7 kg/m2, P = 0.003). Verrotti et al.[17] in their study of 114 valproate-treated children, obesity and subsequent metabolic syndrome were shown in 46 and 20 children over a period of 24 months. Increase in BMI documented was significant during that period (30.2 ± 1.1, P ≤ 0.001).[17]

The results for CIMT in our study are consistent with a study by Erdemir et al.[13] In their study of 44 epileptic children on valproate monotherapy for more than 12 months, CIMT was increased among children receiving valproate (0.48 ± 0.06) compared to controls (0.43 ± 0.06) with statistical significance (P = 0.001).[13]

In this study, it was found that lipid levels for TC, TG, LDL, and Apo A1 were significantly altered. Atherogenicity for individual AED as studied by El-Farahaty et al.,[16] showed that epileptic children receiving valproate monotherapy had abnormal and significant TC, LDL, HDL, TC/HDL, and LDL/HDL with P value of < 0.001.[15] Tomoum et al.,[18] in their study including 22 children on either carbamazepine or valproate monotherapy, observed that Apo A1 levels were significantly decreased among the cases (114.7 ± 16.2 mg/dL) compared with the control group (138.8 ± 10.4 mg/dL, t = 5.05).

Attilakos et al.[19] conducted a study in 39 children who were receiving levetiracetam therapy. Serum lipid levels were assessed before and after levetiracetam treatment. A favorable effect of the drug was noted as TG and TG/HDL ratio were significantly reduced at 6 and 12 months of levetiracetam treatment (P = 0.026 and P = 0.001 and P = 0.024, P = 0.003), respectively. Ratio of LDL/HDL too showed significant reduction at 12 months of treatment (P = 0.025). No significant alterations were noted in other parameters. They concluded that levetiracetam has less progression toward atherosclerotic process in epileptic children.[19] Likewise lipid profile did not show significant change in levetiracetam-treated group even in this study. Few Indian studies too showed a similar result of increase in metabolic parameters and lipid profile after valproate and phenytoin therapy.[820]

Sankhyan et al.[21] carried out a study on epileptic children including a subgroup of 30 children on phenytoin monotherapy for more than 18 months. They assessed CIMT and lipid values along with sugars and brachial flow–mediated dilatation. The results were similar to this study showing high HDL levels (54.6 ± 9.4 vs. 45.8 ± 7.7 mg/dL, P < 0.001) and higher average CIMT (0.374 ± 0.04 vs. 0.348 ± 0.05 mm, P = 0.035) compared to controls.[21] El-Farahaty et al.[16] also showed CIMT in individual AED group, and they established that the means of CIMT (in mm) were higher for valproate (0.64 ± 0.1 mm) and levetiracetam (0.563 ± 0.04 mm) groups with P value of <0.001.[15]

In addition, correlation between serum lipid profile and CIMT was done in our study, which has not been published so far. We state statistically significant correlation between individual lipid parameter and CIMT.

We conclude, children on long-term monotherapy with valproate, phenytoin, and levetiracetam have significantly abnormal CIMT. This might be associated with atherosclerotic changes, and these children may require close follow-up to prevent cardiovascular and cerebrovascular risks. Though advocated as a relatively safe drug, levetiracetam too needs close follow-up. Healthy lifestyle practices and dietary controls can be praised for avoiding overweight and subsequent vascular issues. Nonavailability of data before initiation of AEDs and a smaller percentage of patients in levetiracetam group were the limitations of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.