Effect of childhood epilepsy and antiepileptic drugs on visual evoked potential response and optical coherence tomography

Epilepsy is recently defined according to the International League against epilepsy based on the following: a) 2 unprovoked seizures with 24 h in between; b) one unprovoked or reflex seizure with possibility of recurrence > 60% than in general population in the upcoming10 years; and c) diagnosis of an epilepsy syndrome [1].

Epileptic seizures can arise from an excessively synchronous and sustained discharge of a group of neurons. The main feature of epilepsy syndromes is a persistent neuronal hyper excitability [2].

The childhood epilepsy syndromes are divided into three categories: (a) self-limited focal epilepsies (SeLFEs); (b) generalized epilepsy syndromes; and (c) developmental and/or epileptic encephalopathies (DEEs) [3].

Visual affection in epileptic children could be attributed to the disease itself or the use of anti-epileptic drugs, and these changes may involve visual field constriction, color vision affection, blurred vision and abnormal electro-physiological response [4].

As epilepsy has abnormal excessive activity of the central nervous system (CNS), it can also lead to morphological and functional loss in the brain. As the retina has anatomical, embryological and physiological similarities to the brain, imaging the retina can give feedback about the affection of neurodegenerative diseases on the brain [5].

The decision to start treatment in newly diagnosed epilepsy needs careful appraisal of the risk-to-benefit ratio and the patient’s and family’s preferences [6].

Microstructural differences in the brain cannot be adequately detected with MRI, but examination of the retina and optic nerves by optical coherence tomography (OCT) and visual evoked potential (VEP) provides a window or a mirror to the brain [7].

This biphasic study (case control and controlled clinical trial) aimed to investigate effect of idiopathic childhood epilepsy per se on (1) visual evoked potential and (2) optical coherence tomography and effect of selected two antiepileptic medications on them.

This prospective cohort study was conducted at neuro-pediatric clinic at neurology department from March 2021 till March 2023. This study enrolled 100 subjects who were divided into two groups; group 1 including 50 drug naive children newly diagnosed with epilepsy, that were investigated before antiepileptic medications then they were subdivided into two subgroups based on two antiepileptic medications (Na valproate and levetiracetam) that given based on body weight and followed up over 24 months and group 2 including 50 age- and sex-matched healthy controls.

All subjects were aged from 6 to 18 years with normal brain imaging and both sexes were involved. Children with any autoimmune diseases, intellectual disabilities, other neurological disorders, ophthalmological disorders (e.g., glaucoma and severe errors of refraction) and evidence of white matter disease in brain magnetic resonance imaging (MRI) were excluded from the study.

The diagnosis of epilepsy was based on either the occurrence of at least two unprovoked seizures with 24 h in between, one unprovoked or reflex seizure with inter-ictal epileptiform activity in electro-encephalogram (EEG) or diagnosis of an epilepsy syndrome [1]. The procedure was explained to both subjects and their caregivers and informed consent was signed before the study by the caregivers.

All subjects were exposed to pattern reversal visual evoked potential (VEP) (NIHON KHODEN) and record P-100 latency and amplitude from both eyes by maintaining looking at the screen (checkerboard), every eye was examined separately, for 200 s for each eye and the children were instructed to focus by each eye on the middle of the screen after conducting the positive and negative electrodes on the child’s scalp by paste (the recording electrodes were positioned on the occipital scalp at Oz and the reference electrode on Fz) and the ground electrode on a bony prominence at forehead done by the investigator to all the study sample.

The P100 latency, exceeding 118 ms or inter-ocular P100 latency difference greater than 10.1 ms, were considered abnormal.

Regarding statistical analysis, the collected data was revised, coded, tabulated and introduced to a PC using Statistical package for Social Science version 25 (SPSS 25). Mean, standard deviation (± SD) and range for parametric numerical data, while Median and Interquartile range (IQR) for non-parametric numerical data, while frequency and percentage of non-numerical data. For analytical statistics, Student T Test was used to assess the statistical significance of the difference between two study group means, ANOVA test was used to assess the statistical significance of the difference between more than two study group means, Chi-square test was used to examine the relationship between two qualitative variables, Fisher’s exact test was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells, Spearman’s method to assess the strength of association between quantitative and categorical variables. The correlation coefficient "rho" defines the strength and direction (positive or negative) of the linear relationship between two variables (r = 0–0.19 is regarded as very weak correlation, r = 0.6–0.79 as strong correlation and r = 0.8–1 as very strong correlation) and Paired t test was used to evaluate the statistical significance of the difference between two means measured twice for the same study group [p value: level of significance: -P > 0.05: Non-significant (NS) and − P < 0.05: Significant (S)].

This study included 50 newly diagnosed epileptic children. The control group involved 50 age and sex matched healthy children. There was significant difference between the patients' and control group regarding history of consanguineous parents and delayed developmental milestones, as summarized in Table 1.

Regarding VEP parameters between control group and Children with epilepsy before starting anti-epileptic drugs (AEDs), there was significant difference between the two groups in P-100 latencies in right and left eyes with p value (0.020 and 0.023), respectively, as listed in Table 2.

There are 29 patients of our study population had normal study regarding VEP, while 19 patients showed demyelinating affection of retino-cortical pathway and 2 of our study population had axonal affection of the retino-cortical pathway, as shown in Fig. 1.

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In this study, the patients group was divided into two groups according to AEDs, the first group containing 23 patients are treated by levetiracetam (LEV) and the second one containing 27 patients are treated by sodium valproate (VPA). The characteristics of participants in each group are illustrated in Table 3.

Four patients failed to follow up with us over 2 years. After 1 year of treatment by LEV and VPA, there was non-significant difference between the two treatment groups regarding both P100 latency and amplitude in both eyes, as illustrated in Table 4.

After 2 years of treatment by LEV and VPA, there was non-significant difference between the two treatment groups regarding P-100 latencies in right and left eyes with p value 0.365 and 0.120, respectively, as listed in Table 5. In comparing the two groups regarding changes in amplitude, there is about 31% of LEV group showed improvement in the amplitude, while only 7% of VPA group showed improvement of the amplitude which showed significant difference between the two groups, as illustrated in Table 5 and Fig. 2.

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There was significant difference in amplitude among LEV group after 1 and 2 years of treatment with more increase in amplitude towards improvement, as shown in Table 6 and Fig. 3. The same in the VPA group is shown in Table 7 and Fig. 4. There was non-significant difference between VEP study and developmental mile stones, NICU admission, type of seizures and duration of illness.

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There were only 28 patients of the patients group were cooperative for OCT study and 28 age and sex matched controls that were cooperative for OCT. There was significant difference between the control and patients' group regarding history of consanguineous parents and delayed developmental milestones, as summarized in Table 8.

The mean average retinal nerve fiber layer (RNFL) thickness of the right and left eyes in the control group and patients' group showed significant difference that was thinner in patients' group with p value = 0.002 and < 0.001, respectively. In addition, the mean RNFL thickness of the superior and inferior portions of the right and left eyes in the patients 'group was thinner than in control group that again showed significant difference, as shown in Fig. 5. Meanwhile, there was significant difference between the control group and patients group only regarding the mean average ganglion cell complex (GCC) thickness of the left eye which was thinner in the patients group, as shown in Table 9 and Fig. 6. Moreover, there was no significant difference between the two groups regarding other portions of GCC and cortical macular thickness (CMT).

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After 1 year, three patients failed to follow up with us in the study. No significant difference between the two treatment groups after 1 year of treatment neither regarding RNFL thickness nor GCC in both eyes, as illustrated in Table 10. Among patients in the LEV group, there was no significant difference in RNFL thickness and GCC thickness after 1 year of treatment by LEV, as shown in Figs. 7, 8, 9. While, there was significant difference after 1 year of treatment by VPA in the VPA group in the mean average and inferior portions of RNFL thickness of the left eye which became thinner after 1 year of treatment, yet there was no significant difference after 1 year of treatment by VPA in the other portions of RNFL and GCC (Table 11 and Fig. 10). No significant difference between OCT parameters (CMT, RNFL thickness and GCC) and duration of illness.

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This study included 50 drug naïve epileptic children in comparison with 50 healthy controls regarding VEP parameters (p-100 and amplitude) and OCT parameters (denoting RNFL thickness, GCC thickness and CMT) in only the cooperative children who were 28 of the 50, then the patients’ group was divided into two groups according to treatment, 23 of them in the LEV group and 27 of them in the VPA group and were followed up over 2 years to compare differences between the two groups regarding the previous parameters. In this study, the mean age of children in the patients’ group was 10.52 with SD 3.47 years, while in a study by Verrotti and his colleague in 2000,​ the mean age of patients were 13.7 6 with SD 7.9 years. 33 of our patients were male and 17 patients were females, while in Verrotti and colleagues study, 30 epileptic patients were males and 28 were females [8]. In this study, 22 patients suffered from complex partial seizures, 17 patients suffered from generalized tonic and clonic seizures (GTCs), 2 patients suffered from myoclonic seizures, 1 patient had absence seizure, 1 had focal seizure and 7 patients had mixed types of seizures, while in another study conducted in Turkey, by Genç and his colleagues in 2005, 26 patients suffered from complex partial, 41 patients suffered from GTCs, 17 patients complained of myoclonus and 17 patients suffered from absence seizures [9].

In this study, 21 patients had abnormal VEP, 2 of them had axonal affection of cortico-retinal pathway and the others had demyelinating affection at baseline and before starting the AEDs. In contrast to Verrotti and his colleagues study, all patients conducted to that study were of normal VEP before starting the AEDs [8]. The mean P-100 latency in both right and left eye were longer in the patients’ group in comparison with the control group before starting the AEDs, while there was no significant difference between the two groups regarding the amplitude in the two eyes in this study, that is similar to a study conducted by Genç and his colleagues in 2005 and another study by Demirbilek and colleagues in 2000 that found that P100 latency values were significantly longer than those of the control group [9, 10]. This could be explained by disturbance in the gabamenergic neurotransmitter system, that is one of the hypothesis of pathogenesis of epilepsy that neural circuitry plays an important role in mediation of the responses of cells in the visual cortex and retina and helps in remodeling the receptive fields of the cells in layers of the occipital cortex. These cells are among the principle generators of VEP [4], yet it found disagreement with Verrotti and his colleagues study that found non-significant differences in latencies and amplitudes between the control and the patients' group [8].

In this study, there was non-significant difference between the LEV treatment group and VPA treatment group after 1 year of treatment regarding latency and amplitude, this found agreement with a study conducted in India by Behgal and co-workers, in 2019 that found that epileptic children treated with either of VPA or LEV does not result in electrophysiological dysfunction of visual sensory pathway [11]. Moreover, there are no further studies had compared between the two medications regarding their effect on VEP but there are further studies had investigated the effect of each drug without comparison.

Surprisingly, this study demonstrated that there was no significant difference of the mean p-100 latency among each of LEV group and VPA group after 2 years of treatment, while there is significant difference among each group regarding amplitude which became more increased over 2 years of treatment, this could be explained by the normal maturation of amplitude in the pediatric age group with aging process till adolescence as mentioned in a previous study by Wadhera and Dudhmal in 2015 [12], but in comparing the two groups regarding changes in amplitude, there is about 31% of LEV group showed improvement in the amplitude while only 7% of VPA group showed improvement of the amplitude which showed significant difference between the two groups with p value (0.048), so there was favorable effect of LEV than VPA on the improvement of amplitude, yet there was no deterioration of amplitude in the VPA group than the LEV group, that was partially agreed (regarding the mean latency) in a study conducted in Germany by Jai Behgal and colleagues which found non-significant difference regarding p-100 latencies and amplitude between the patients who received different AEDs before and after treatment [11]. That may be explained by a possible mode of action of the AEDs at subcortical level or a non-primary cortical site [13]. This was disagreed with Verrotti and his colleague study and Jai Behgal and his colleague study which found that there was a significant difference regarding latencies in patients receiving valproate before and after treatment [8, 11]. Again, in a study done in Iran by Farabi Y and his colleague in 2019 found that there was significant difference in p-100 latency in patients receiving valproate yet, this study was not a comparative one before and after treatment, so this difference may be attributed to the disease itself [14].

As regard OCT, in this study, we found that there was significant difference between patients and control group regarding RNFL thickness of both eyes in all parts and in average part of GCC of the left eye between the two groups, which were thinner in the patients group, while there was no significant difference between the two groups as regard CMT, that found agreement with a study by AZA Tak and his colleagues in 2019, study in India conducted by Mustafa Duran and his colleagues in 2023 and a study conducted by Simona Balestrini and his colleagues in 2016,which found that there was a statistical difference between patients and control group regarding RNFL and GCC thickness which was thinner in patients group regardless duration of illness and treatment, yet there was no significant difference as regard CMT [15‐17]. Another agreement with this study was in a study by Neslihan Bayraktar Bilen and his colleagues in 2021 in Ankara that found that Superior and superotemporal quadrant GCC, average, and superior quadrant RNFL thickness measurements were significantly lower in epilepsy group compared to healthy control subjects and in a study conducted by Jesús González de la Aleja and colleagues in 2019 which found significant thinning of the average RNFL in the patients' group than the control group [5, 7].

Although this study was agreed with findings of the previous study, yet those studies did not measure OCT parameters in drug naïve epileptic children, so they did not study the effect of epilepsy alone on CMT, GCC thickness and RNFL thickness. This difference between epileptic patients and control group is explained by the neuro-degenerative process of epilepsy that may be associated with taupathies and the retina is considered an extension to CNS so, changes in the CNS is similar to the retina that is considered a window to the brain [5]. In this study, we did not find significant correlation between the duration of illness and the RNFL, CMT or GCC thickness, which was agreed with AZA Tak and his colleagues’ study, who found that there was non-significant correlation between the duration of illness and OCT parameters [15], this may be attributed to the relative smaller sample size.

In this study, there was non-significant difference between the LEV group and VPA group after 1 year of treatment regarding CMT, GCC and RNFL thickness after their follow-up, which was partially agreed with a study conducted by Tong Jong Haw Matthew and colleagues in 2019 that found no significant difference between patients receiving valproate and carbamazepine regarding OCT parameters [18].

In comparing the effect of LEV alone on OCT in epileptic patients after 12 months duration of treatment in this study, there was no significant difference before and after 12 months of treatment with LEV regarding GCC and RNFL thickness, which was agreed with a study conducted in 2019 that found that LEV monotherapy causes non-significant change in function or morphology in ocular tissues in childhood epilepsy [19]. This was explained by the action of LEV as a histone deacetylase inhibitor, suggesting that this drug exhibits both anti-inflammatory and anti-oxidative effects [20], but this was disagreed by a study done by Dicle Hazirolan and colleagues in 2020 that found affection in CMT and GCC thickness in patients receiving levetiracetam in comparison with healthy control but this may be due to epilepsy effect [21], while in comparing the effect of valproate alone on OCT in epileptic patients after 12 month duration of treatment in this study, we found significant difference regarding the inferior quadrant of RNFL thickness in the left eye that became thinner after 1 year of treatment, this found an agreement with a study conducted in 2015 that found the average and superior RNFL thicknesses were thinner in patients receiving VPA compared with control group [22]. This was explained by valproate gabamenergic effect, which may be toxic to the retina by increasing gamma amino butyric acid (GABA) levels [17], yet this was disagreed by a study conducted by Lucio Lobefalo and colleagues in 2006 that found no modification of RNFL and macular thickness parameters is found after 1 year of treatment with valproate [23].

Studying only 2 AEDs, smaller number of children who can co-operatively perform the OCT and limited age group (who can perform the pattern VEP study) were limitations to this study, so flash VEP can be used in further study (but it is less accurate than pattern VEP) and also involving much more AEDs is recommended in further study.

There was prolonged latency in the epileptic children before starting AEDs more than the control group; also there was thinning of the RNFL thickness and average part of the GCC thickness more in the epileptic children than in the healthy controls. This means that there was a disruption of the neural circuit by the epilepsy due to disruption of gabamenergic neurotransmitter system which plays an important role in mediating responses of cells in the visual cortex and retina and assists in shaping the receptive fields of the pyramidal cells in the superficial layers of the occipital cortex. That favors that epilepsy can be classified as a neuro-degenerative disorder. On following up the patients after 24 months of treatment by levetiracetam versus valproate, there was non-significant difference between the two medications regarding VEP and OCT. Yet, we found that patients on valproate therapy showing thinning of the inferior part of RNFL thickness of the left eye only after 12 months of treatment, this was not found in the levetiracetam group. This could be attributed to the toxic gabamenergic effect of valproate on the retina.