Effect of Childhood Epilepsy and Antiepileptic Drugs on Visual Evoked Potential Response and Optical Coherence Tomography

doi:10.21203/rs.3.rs-4940625/v1

Background: Epileptic seizures arise from an excessively synchronous and sustained discharge of a group of neurons. The single feature of all epileptic syndromes is a persistent increase of neuronal excitability. Visual affection in epileptic children could be attributed to the disease itself or the use of anti-epileptic drugs, these changes may involve abnormal electro-physiological response. This biphasic study, conducted at the neuro-pediatric clinic at neurology department at Ain Shams University, 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. All subjects were exposed to visual evoked potential and only cooperative subjects exposed to ocular coherence tomography before and after anti-epileptic drugs and were followed up over 2 years.

Results: The study included 50 newly diagnosed epileptic children and 50 healthy controls, the mean P100 latency in the right eyes of the control group was 110.4 ± 3.76ms, while in the patients group was 114.94 ± 12.81ms that showed significant difference between the two groups with p-value (0.020). After 2 years of treatment by levetiracetam and valproate, the mean P100 latency of the right and left eyes in the valproate group was 112.34 ± 7.05 and 112.59 ± 5.2ms respectively and it was 114.85 ± 10.39ms and 116.14 ± 9.84ms respectively in the valproate group, which showed insignificant difference between the two groups. The mean average of retinal nerve fiber layer thickness between patients and controls were significant in both right and left eyes with p- value 0.002 and < 0.001 respectively. After 1 year of treatment by levetiracetam in the 1st group and valproate in the 2nd group, there was no significant difference between the 2 groups neither regarding retinal nerve fiber layer thickness nor ganglion cell complex in both eyes.

Conclusion: There was prolonged latency in the epileptic children before starting anti-epileptic drugs more than the control group; also there was thinning of the retinal nerve fiber layer thickness and average part of the ganglion cell complex thickness more in the epileptic children than in the healthy controls.

childhood epilepsy

anti-epileptic drugs

visual evoked potential

optical coherence tomography

Epilepsy is recently defined according to the International League against epilepsy based on the following, a) 2 unprovoked seizures with 24 hours in between; b) one unprovoked or reflex seizure with possibility of recurrence > 60% than in general population in the upcoming10 years; 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 increased neuronal 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, 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.

Study design and participants

This biphasic study (1st phase was case control and 2nd phase was controlled clinical trial) conducted at the neuro-pediatric clinic at neurology department from March 2021 till March 2023. This study enrolled 100 subjects who were divided into 2 groups; group 1 including 50 drug naive children newly diagnosed with epilepsy, that were investigated before antiepileptic medications then they were subdivided into 2 subgroups based on 2 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 old 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.

All patients were diagnosed as epilepsy according to clinical features and 2 hours electro-encephalogram (EEG) according to 10\20 system. 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 seconds 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 milliseconds or inter-ocular P100 latency difference greater than 10.1 milliseconds, were considered abnormal.

Only cooperative children (were 28 of cases and 28 of controls) were investigated by optical coherence tomography (OCT) under effect of atropine (mydriatic) to obtain (peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, cortical macular thickness (CMT)) from both eyes after detailed eye examination and computerized visual acuity in the presence of expert ophthalmologist at the ophthalmology department. These investigations had done at the start of the study (before receiving antiepileptic medications), after 12 months of treatment (regarding VEP and OCT) and at the end of the study (after 24 months regarding VEP).

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, 33 (66%) of them were males and 17 (34%) of them were females. The control group involved 50 age and sex matched healthy children, 27 (54%) of them were males and 23 (46%) of them were females. The mean age of patients and controls was 10.52 ± 3.47 and 10.56 ± 3.41 respectively. The mean age and sex between the 2 groups were non- significant. There was 28% of the cases had positive history of consanguineous parents while no one of the control group had history of consanguineous parents, this was significant between the two groups. There were 4 patients had past history of neonatal intensive care unit (NICU) admission while none of the control group had previous history of NICU admission. There were 36% of the patients group had delayed developmental milestones while none of the control group had delayed developmental milestones which showed significant difference between the two groups as summarized in Table 1.

Table 1

Comparison between cases and controls regarding Characteristics of the participants:
		Controls (n = 50)	Cases (n = 50)	Test of Significance
		Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value	Significance
Age		10.56 ± 3.47	10.52 ± 3.41	t = 0.0582	0.9537	NS
Gender	Male	27 (54%)	33 (66%)	X² = 1.50	0.221	NS
	Female	23 (46%)	17 (34%)
	Positive	27 (54%)	24 (48%)
Consanguinity	Negative	50 (100%)	36 (72%)	X² = 16.3	< 0.001	S
Consanguinity	Positive	0 (0%)	14 (28%)	X² = 16.3	< 0.001	S
NICU	Negative	50 (100%)	46 (92%)	FE	0.117	NS
NICU	Positive	0 (0%)	4 (8%)	FE	0.117	NS
Developmental milestones	Normal	50 (100%)	32 (64%)	X² = 21.9	< 0.001	S
	Delayed	0 (0%)	18 (36%)
	Metabolic	0 (0%)	2 (4%)
Student t-test of significance (t), Fisher’s Exact test of significance (FE), Chi-Square test of significance (X²), SD: standard deviation, NS: non-significant, S: significant, FH: family history, NICU: neonatal intensive care unit

As regard VEP parameters between control group and patients before starting anti-epileptic drugs ( AEDs), the mean P100 latency in the right and left eyes of the control group was 110.4 ± 3.76ms and 111.25 ± 3.92ms respectively, while in the patients group was 114.94 ± 12.81ms and115.37 ± 11.88ms respectively that showed significant difference between the two groups with p-value (0.020 and 0.023) respectively. Meanwhile, the mean amplitude of the right and left eyes in the control group was 10.29 ± 5.96 µv and 11.17 ± 5.59µv respectively, while in the patients group it was 9.3 ± 6.71µv and 9.15 ± 6.78µv respectively that showed non-significance between the two group regarding amplitude as in Table 2.

Table 2

Comparison between cases and controls regarding VEP baseline measurements:
	Controls	Cases	Student t-test of significance (t)
	Mean ± SD	Mean ± SD	Value	p-Value	Significance
P100 latency-RT Baseline	110.4 ± 3.76 ms	114.94 ± 12.81 ms	-2.402	0.020	S
P100 latency-LT Baseline	111.25 ± 3.92 ms	115.37 ± 11.88 ms	-2.329	0.023	S
AMP-RT Baseline	10.29 ± 5.96 µv	9.3 ± 6.71 µv	0.783	0.436	NS
AMP-LT Baseline	11.17 ± 5.59 µv	9.15 ± 6.78 µv	1.624	0.108	NS
Abbreviations: SD: standard deviation, S: significant, NS: non- significant, RT: right eye, LT: left eye, AMP: amplitude

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

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) (one with centro-temporal epilepsy, 6 with Panayiotopoulus, 3 with childhood occipital visual epilepsy,7 generalized tonic and clonic epilepsy,2 with juvenile myoclonic epilepsy, 3 with juvenile absence epilepsy and 1 with childhood absence epilepsy), 30.4% of them manifesting epilepsy for more than one year and the second one containing 27 patients are treated by sodium valproate (VPA) (7 of them had Panayiotopoulus, 6 of them with childhood occipital visual epilepsy, 10 of them had generalized tonic and clonic seizures and 4 with juvenile absence epilepsy), 22% of them manifesting epilepsy for more than one year. As regard EEG findings, 3 of our patients had normal EEG, 5 patients in each group had generalized epileptiform activity, and 5 patients in each group had frontal activity. (Table 3) There was no significant difference between the two groups regarding mean P100 latency and amplitude bilaterally.

Table 3

Comparing the two treatment groups regarding Characteristics of the participants:
		Levetiracetam (n = 23)	Valproate (n = 27)	Test of Significance
		Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value	Significance
Age		10.13 ± 3.58	10.56 ± 2.95	t= -0.460	0.648	NS
Gender	Male	14 (60.87%)	19 (70.37%)	X² = 0.5	0.480	NS
	Female	9 (39.13%)	8 (29.63%)
	Positive	9 (39.13%)	15 (55.56%)
Consanguinity	Negative	17 (73.91%)	19 (70.37%)	X² = 0.077	0.781	NS
	Positive	6 (26.09%)	8 (29.63%)
	Positive	2 (8.7%)	4 (14.81%)
NICU	Negative	22 (95.65%)	24 (88.89%)	FE	0.614	NS
	Positive	1 (4.35%)	3 (11.11%)
	Delayed	8 (34.78%)	10 (37.04%)
	Metabolic	1 (4.35%)	1 (3.7%)
	Head Trauma	1 (4.35%)	2 (7.41%)
Duration of illness	< 1	16 (69.57%)	21 (77.78%)	X² = 0.435	0.509	NS
Duration of illness	> 1	7 (30.43%)	6 (22.22%)	X² = 0.435	0.509	NS
Type of epilepsy syndrome	Centro-temporal	1 (4.35%)	0 (0%)	FE	0.496	NS
	Panayiotopoulus	6 (26.08%)	7 (33.70%)
	Childhood occipital visual epilepsy	3 (13.05%)	6 (14.45%)
	Generalized tonic clonic alone	7 (30.43%)	10 (37.04%)
	Childhood absence epilepsy	1 (4.35%)	0 (0%)
	Juvenile absence epilepsy	3 (13.04%)	4 (14.81%)
	Juvenile myoclonic epilepsy	2 (8.7%)	0 (0%)
	Complex partial	9 (39.13%)	13 (48.15%)
	Generalized tonic clonic seizures	7 (30.43%)	10 (37.04%)
	Absence	1 (4.35%)	0 (0%)
	Atonic	0 (0%)	0 (0%)
	Tonic	0 (0%)	0 (0%)
	Myoclonic	2 (8.7%)	0 (0%)
	Mixed	3 (13.04%)	4 (14.81%)
EEG	Normal	3 (13.04%)	0 (0%)	FE	0.539	NS
	Generalized epileptiform activity	5 (21.74%)	5 (18.52%)
	Occipital	1 (4.35%)	0 (0%)
	Frontal	5 (21.74%)	5 (18.52%)
	Temporal	4 (17.39%)	7 (25.93%)
	Parietal	1 (4.35%)	2 (7.41%)
	Central	0 (0%)	1 (3.7%)
	Multifocal	4 (17.39%)	7 (25.93%)
Student t-test of significance (t), Fisher’s Exact test of significance (FE), Chi-Square test of significance (X2), SD: standard deviation, NS: non-significant, S: significant, FH: family history, NICU: neonatal intensive care unit, EEG: electro-encephalogram

There were 4 patients failed to follow up with us over 2 years. After 1 year of treatment by LEV and VPA, the mean p100 latency of the right and left eyes in the LEV was 112.64 ± 7.02ms and 112.81 ± 5.39ms respectively. While it was 114.96 ± 10.13ms and 116.11 ± 9.59ms respectively in the VPA group after 1 year of treatment, this showed non-significant difference between the two groups. As regard the amplitude, the mean amplitude of the right and left eyes in the LEV group was 14.91 ± 8.33µv and 13.81 ± 7.51µv respectively, and in the VPA group 13.93 ± 8.04µv and 13.13 ± 7.9µv respectively, that again showed non-significant difference between the two groups as illustrated in Table 4.

Table 4

Comparing the two treatment groups regarding VEP after 1 year:
	Levetiracetam (n = 19)	Valproate (n = 27)	Test of Significance
	Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value	Significance
P100 latency-RT 1	112.64 ± 7.02 ms	114.96 ± 10.13 ms	t= -0.863	0.393	NS
P100 latency-LT 1	112.81 ± 5.39 ms	116.11 ± 9.59 ms	t= -1.490	0.144	NS
AMP-RT1	14.91 ± 8.33 µv	13.93 ± 8.04 µv	t = 0.401	0.690	NS
AMP-LT1	13.81 ± 7.51 µv	13.13 ± 7.9 µv	t = 0.294	0.770	NS
Student t-test of significance (t)
Fisher’s Exact test of significance (FE)
Abbreviations: SD: standard deviation, NS: non-significant, RT1: right eye after one year, LT1: left eye after one year, AMP: amplitude, study 1: study results after 1 year

After 2 years of treatment by LEV and VPA, the mean P100 latency of the right and left eyes in the LEV group was 112.34 ± 7.05 and 112.59 ± 5.2ms respectively and it was 114.85 ± 10.39ms and 116.14 ± 9.84ms respectively in the VPA group, which showed insignificant difference between the two groups. As regard amplitude, the mean amplitude of the right and left eyes in the LEV group was 15.14 ± 8.25µv and 14.14 ± 7.46µv respectively and was 13.85 ± 8.06µv and 13.02 ± 7.86µv respectively in the VPA group that again showed non-significant difference as 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 with p- value (0.048) as illustrated in Table 5 and Fig. 2.

Table 5

Comparing the two treatment groups regarding VEP after 2 years:
		Levetiracetam (n = 19)	Valproate (n = 27)	Test of Significance
		Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value	Significance
P100 latency-RT2		112.34 ± 7.05 ms	114.85 ± 10.39 ms	t= -0.915	0.365	NS
P100 latency-LT2		112.59 ± 5.2 ms	116.14 ± 9.84 ms	t= -1.588	0.120	NS
AMP-RT2		15.14 ± 8.25 µv	13.85 ± 8.06 µv	t = 0.530	0.599	NS
AMP-LT2		14.14 ± 7.46 µv	13.02 ± 7.86 µv	t = 0.486	0.630	NS
P100 latency-RT2 changes	No Change	14 (73.68%)	22 (81.48%)	FE	0.165	NS
	Delayed yet normal	0 (0%)	1 (3.7%)
	Improved	5 (26.32%)	2 (7.41%)
	Delayed and abnormal	0 (0%)	2 (7.41%)
P100 latency-LT2 changes	No Change	15 (78.95%)	22 (81.48%)	FE	0.100	NS
	Delayed yet normal	0 (0%)	1 (3.7%)
	Improved	4 (21.05%)	1 (3.7%)
	Delayed and abnormal	0 (0%)	3 (11.11%)
AMP-RT2 changes	No Change	13 (68.42%)	23 (85.19%)	FE	0.048	S
	Delayed yet normal	0 (0%)	2 (7.41%)
	Improved	6 (31.58%)	2 (7.41%)
	Delayed and abnormal	0 (0%)	0 (0%)
AMP-LT2 changes	No Change	13 (68.42%)	23 (85.19%)	FE	0.048	S
	Delayed yet normal	0 (0%)	2 (7.41%)
	Improved	6 (31.58%)	2 (7.41%)
	Delayed and abnormal	0 (0%)	0 (0%)
	Abnormal demyelinating	4 (21.05%)	10 (37.04%)
	Abnormal axonal	0 (0%)	1 (3.7%)
Student t-test of significance (t)
Fisher’s Exact test of significance (FE)
Abbreviations: SD: standard deviation, NS: non-significant, S: significant, RT2: right eye after two years, LT2: left eye after two years, AMP: amplitude

There was non-significant difference regarding P100 latency among LEV group after 1 and 2 years of treatment yet there was significant difference regarding amplitude among LEV group after the first and second year of treatment with more increase in amplitude towards improvement with P-value < 0.001 as in Table 6 and Fig. 3. There was non-significant difference regarding P100 latency among valproate group after 1 and 2 years of treatment yet there was significant difference regarding amplitude among valproate group after the first and second year of treatment with more increase in amplitude towards improvement with P-value < 0.001 as 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.

Table 6

Comparing VEP in different times among Levetiracetam group:
Levetiracetam (n = 19)	Baseline	1	2	Repeated measures ANOVA test of significance (f)
Levetiracetam (n = 19)	Mean ± SD	Mean ± SD	Mean ± SD	Value	p-Value	Significance
P100 latency RT	113.6 ± 6.84 ms	112.64 ± 7.02 ms	112.34 ± 7.05	0.355	0.703	NS
P100 latency LT	114.2 ± 6.75 ms	112.81 ± 5.39 ms	112.59 ± 5.2	1.338	0.275	NS
AMP-RT	9.81 ± 6.73 µv	14.91 ± 8.33 µv	15.14 ± 8.25	24.503	< 0.001	S
AMP-LT	9.13 ± 6.52 µv	13.81 ± 7.51 µv	14.14 ± 7.46	22.465	< 0.001	S
Abbreviations: SD: standard deviation, NS: non-significant, S: significant, RT: right eye, LT: left eye, AMP: amplitude

Table 7

Comparing VEP in different times among Valproate group:
Valproate (n = 27)	Baseline	1	2	Repeated measures ANOVA test of significance (f)
Valproate (n = 27)	Mean ± SD	Mean ± SD	Mean ± SD	Value	p-Value	Significance
P100 latency RT	114.4 ± 11.54 ms	114.96 ± 10.13 ms	114.85 ± 10.39 ms	0.039	0.962	NS
P100 latency LT	116.05 ± 14.1 ms	116.11 ± 9.59 ms	116.14 ± 9.84 ms	0.002	0.998	NS
AMP-RT	9.52 ± 6.98 µv	13.93 ± 8.04 µv	13.85 ± 8.06 µv	22.643	< 0.001	S
AMP-LT	9.2 ± 7.28 µv	13.13 ± 7.9 µv	13.02 ± 7.86 µv	13.671	< 0.001	S
Abbreviations: SD: standard deviation, NS: non-significant, S: significant, RT: right eye, LT: left eye, AMP: amplitude

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, 16 of them were males and 12 of them were females. The mean age of controls was 12.25 ± 3.47 and 11.29 ± 2.71 in the cases group which showed non-significant difference between the control and cases group. There was 25% of the patients group showing delayed developmental milestones while none of the control had delayed developmental milestones that showed significant difference between the two groups with p-value 0.010. About 21% of the cases group had positive history of consanguineous parents while none of the controls had history of consanguineous parents, which showed significant difference between patients and controls with p-value 0.023 as summarized in Table 8.

Table 8

Comparing Cases and controls regarding Characteristics of the participants:
		Controls (n = 28)	Cases (n = 28)	Test of Significance
		Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value	Significance
Age		12.25 ± 3.47	11.29 ± 2.71	t = 1.159	0.251	NS
Gender	Male	16 (57.14%)	16 (57.14%)	X²= 0	1.000	NS
	Female	12 (42.86%)	12 (42.86%)
	Positive	19 (67.86%)	12 (42.86%)
Consanguinity	Negative	28 (100%)	22 (78.57%)	FE	0.023	S
	Positive	0 (0%)	6 (21.43%)
	Positive	0 (0%)	1 (3.57%)
	Positive	0 (0%)	1 (3.57%)
Developmental milestones	Normal	28 (100%)	21 (75%)	FE	0.010	S
	Delayed	0 (0%)	7 (25%)
	Metabolic	0 (0%)	2 (7.14%)
Student t-test of significance (t), Fisher’s Exact test of significance (FE), Chi-Square test of significance (X2)
SD: standard deviation, NS: non-significant, S: significant, FH: family history

The mean average retinal nerve fiber layer (RNFL) thickness of the right eye in the control group was 115.86 ± 12.78µm, while it was 106.43 ± 8.14µm in the patients group which is of significant difference with p-value = 0.002, as well as in the left eye (p-value < 0.001). Also, the mean RNFL thickness of the superior portion of the right eye in the control group was 120.11 ± 14.1µm, while it was thinner in the patients group (108.36 ± 7.22µm) that again of significant difference between the two groups with p-value < 0.001 as well as in the left eye with p-value < 0.001. Also, the mean RNFL thickness of the inferior portion of the right eye in the control group was 111.61 ± 13.09µm, while it was thinner in the patients group (104.64 ± 11.76µm) that is again of significant difference between the two groups with p-value 0.041 as well as the left eye with p-value 0.008 as in Fig. 5. Meanwhile, there was significant difference between the control group (102.22 ± 6.13µm) and patients group (98.46 ± 6.81 µm) only regarding the mean average ganglion cell complex (GCC) thickness of the left eye which was thinner in the patients group with p-value 0.36 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).

Table 9

Comparing Cases and controls regarding baseline OCT measurements:
		Controls	Cases	Student t-test of significance (t)
		Mean ± SD	Mean ± SD	Value	p-Value	Significance
CMT	RT	248.64 ± 21.53 µm	239.82 ± 16.03 µm	1.739	0.088	NS
CMT	LT	247.14 ± 20.3 µm	243.61 ± 17.64 µm	0.696	0.490	NS
RNFL	Average RT	115.86 ± 12.78 µm	106.43 ± 8.14 µm	3.293	0.002	S
	Average LT	116.86 ± 12.78 µm	106.25 ± 8.47 µm	3.660	< 0.001	S
	Sup-RT	120.11 ± 14.1 µm	108.36 ± 7.22 µm	3.926	< 0.001	S
	Sup-LT	119.89 ± 14.23 µm	108.71 ± 8.35 µm	3.585	< 0.001	S
	Inf-RT	111.61 ± 13.09 µm	104.64 ± 11.76 µm	2.094	0.041	S
	Inf-LT	111.93 ± 11.3 µm	103.89 ± 10.62 µm	2.742	0.008	S
GCC	Average RT	100.25 ± 6.79 µm	101.71 ± 6.67 µm	-0.814	0.419	NS
	Average LT	102.22 ± 6.13 µm	98.46 ± 6.81 µm	2.149	0.036	S
	Sup-RT	100.04 ± 6.15 µm	101.11 ± 8.37 µm	-0.546	0.587	NS
	Sup-LT	101.32 ± 6.19 µm	98.75 ± 6.8 µm	1.480	0.145	NS
	Inf-RT	100.75 ± 8.13 µm	102.36 ± 5.81 µm	-0.851	0.398	NS
	Inf-LT	101.14 ± 5.01 µm	98.07 ± 8.4 µm	1.662	0.102	NS
SD: standard deviation, NS: non-significant, S: significant, CMT: central macular thickness, RNFL: retinal nerve fibre layer, GCC: ganglion cell complex, SUP: superior, INF: inferior, RT: right eye, LT: left eye

After one year, there were 3 patients failed to follow up with us in the study. There was no significant difference between the 2 groups of 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 regarding RNFL thickness and GCC thickness after one year of treatment by LEV as shown in Fig. 7,8&9.While, there was significant difference after one year of treatment by VPA in the VPA group as regard the mean average and inferior portions of RNFL thickness of the left eye which became thinner after one year of treatment with p-value 0.038 and 0.030 respectively, yet there was no significant difference after one year of treatment by VPA as regarding other portions of RNFL and GCC. (Table 11 and Fig. 10). There was non-significant difference between OCT parameters (CMT, RNFL thickness and GCC) and duration of illness.

Table 10

Compare the two treatment groups regarding OCT measurements after 1 year:
		Levetiracetam (n = 11)	Valproate (n = 14)	Student t-test of significance (t)
		Mean ± SD	Mean ± SD	Value	p-Value	Significance
RNFL	avr RT1	107.36 ± 6.58 µm	105.5 ± 8.37 µm	0.605	0.551	NS
	avr-LT 1	109 ± 6.57 µm	104.14 ± 6.67 µm	1.819	0.082	NS
	sup-RT 1	109 ± 4.84 µm	108.36 ± 7.58 µm	0.244	0.809	NS
	sup-LT 1	112.27 ± 7.07 µm	106.93 ± 7.31 µm	1.840	0.079	NS
	inf-RT 1	104.91 ± 7.48 µm	102.93 ± 12.84 µm	0.454	0.654	NS
	inf-LT 1	106.64 ± 7.62 µm	101.5 ± 7.98 µm	1.629	0.117	NS
GCC	avr-RT 1	101.18 ± 5.71 µm	99.86 ± 6.29 µm	0.544	0.592	NS
	avr-LT 1	100.27 ± 6.07 µm	99.29 ± 6.71 µm	0.381	0.707	NS
	sup-RT1	98.82 ± 6.59 µm	99.21 ± 6.53 µm	-0.150	0.882	NS
	sup-LT 1	100.27 ± 6.05 µm	99.36 ± 6.12 µm	0.373	0.713	NS
	Inf-RT 1	103.27 ± 5.5 µm	100.93 ± 6.16 µm	0.990	0.333	NS
	Inf-LT 1	99.82 ± 8.54 µm	99.79 ± 7.81 µm	0.010	0.992	NS
SD: standard deviation, NS: non-significant, avr: average, LT1: left eye after 1 year, RT1: right eye after 1 year, sup: superior quadrant, inf: inferior quadrant, RNFL: retinal nerve fibre layer, GCC: ganglion cell complex

Table 11

Comparing OCT measurements in different times among Valproate group:
Valproate (n = 14)		Baseline	1 year	Paired t-test of Significance
Valproate (n = 14)		Mean ± SD	Mean ± SD	Value	p-Value	Significance
RNFL	avr-RT	107.71 ± 8.8 µm	105.5 ± 8.37 µm	1.182	0.258	NS
	avr-LT	106.57 ± 9.09 µm	104.14 ± 6.67 µm	2.308	0.038	S
	sup-RT	108.93 ± 6.37 µm	108.36 ± 7.58 µm	0.437	0.669	NS
	sup-LT	107.93 ± 7.95 µm	106.93 ± 7.31 µm	0.959	0.355	NS
	inf-RT	106.79 ± 14.61 µm	102.93 ± 12.84 µm	1.409	0.182	NS
	inf-LT	105.36 ± 12.84 µm	101.5 ± 7.98 µm	2.438	0.030	S
GCC	avr-RT	101.07 ± 5.98 µm	99.86 ± 6.29 µm	1.723	0.109	NS
	avr-LT	99.57 ± 6.35 µm	99.29 ± 6.71 µm	0.376	0.713	NS
	sup-RT	100.07 ± 6.01 µm	99.21 ± 6.53 µm	1.147	0.272	NS
	sup-LT	99.5 ± 6.42 µm	99.36 ± 6.12 µm	0.186	0.856	NS
	inf-RT	102.07 ± 6.12 µm	100.93 ± 6.16 µm	1.665	0.120	NS
	inf-LT	99.93 ± 6.73 µm	99.79 ± 7.81 µm	0.155	0.879	NS
SD: standard deviation, NS: non-significant, avr: average, LT: left eye, RT: right eye, sup: superior quadrant, inf: inferior quadrant, RNFL: retinal nerve fibre layer, GCC: ganglion cell complex

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 2 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 et al. 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 our 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 et al., 2000 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 to the control group before starting the AEDs, while there was no significant difference between the 2 groups regarding the amplitude in the 2 eyes in our 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 et al., study, Martinović and his colleagues study and YÜKSEL and colleagues study that all found non-significant differences in latencies and amplitudes between the control and the patients' group. (8, 11, 12)

In our study, there was non- significant difference between the LEV treatment group and VPA treatment group after one 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. (13) 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, our study demonstrated that there was no significant difference of the mean p-100 latency among LEV group and VPA group after 2 years of treatment, while there is significant difference among that group regarding amplitude which became more increased after 2 years of treatment, 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 Lücking and his colleague in 1970 and Harding and his colleague study which found non- significant difference regarding p-100 latencies and amplitude between the patients who received different AEDs before and after treatment. (14, 15) That may be explained by a possible mode of action of the AEDs at subcortical level or a non-primary cortical site. (15) This was disagreed with YÜKSEL et al., in 1995 which found that the P-100 latencies were more delayed after 12 months of VPA therapy but this difference did not reach statistical significance, yet amplitude showed no consistent changes after 12 months of valproate therapy. (12). Another disagreement was in 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, 13) 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 wasn’t a comparative one before and after treatment, so this difference may be attributed to the disease itself. (16)

As regard OCT, in our 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 2 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 (17, 18, 19). Another agreement with our 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 our study was agreed with findings of the previous study, yet those studies didn’t measure OCT parameters in drug naïve epileptic children, so they didn’t 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 didn’t found 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. (17), 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 one 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. (20)

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. (21).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. (22), 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 to healthy control but this may be due to epilepsy effect. (23), while in comparing the effect of valproate alone on OCT in epileptic patients after 12 months 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. (24).This was explained by valproate gabamenergic effect, which may be toxic to the retina by increasing gamma amino butyric acid (GABA) levels. (19), 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. (25)

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 wasn’t found in the levetiracetam group. This could be attributed to the toxic gabamenergic effect of valproate on the retina.

SeLFEs self-limited focal epilepsies

DEEs developmental and/or epileptic encephalopathies

CNS central nervous system

OCT optical coherence tomography

VEP visual evoked potential

MRI magnetic resonance imaging

EEG electro-encephalogram

RNFL retinal nerve fiber layer

GCC ganglion cell complex

CMT cortical macular thickness

SPSS25 Statistical package for Social Science version 25

SD Standard deviation

IQR Interquartile range

NS Non-significant

S significant

NICU neonatal intensive care unit

AEDs anti-epileptic drugs

LEV levetiracetam

VPA sodium valproate

GTCs generalized tonic and clonic seizures

GABA gamma amino butyric acid

Ethics approval and consent to participate

The study conformed to the standards of the ethical Review Committee, Ain Shams University (FAMASU MD 97\2021). We obtained approval from research ethics committee no. FWA 000017585. Before the study was inaugurated, a written informed consent was signed from the leading guardian of the study participants after adequately explaining the study aims and outcomes. The anonymity of the subjects was ensured, no identifying information was obtained, and the results were stored in a secure place with access only to the main author of the study.

Consent for publication

Not applicable

Availability of data and materials

The dataset created and analyzed during the current study will be available from the corresponding author on the editor's request.

Competing interests

The authors declared that they have no competing interests.

Funding

The research was total funded by the researchers.

Author contributions

All authors had made a substantial contribution to the design of work, data collection and interpretation, writing the manuscript, revising it and approving the final version.

AA: Data collection and research project execution.

MA: contribution to the concept and design, drafting the manuscript.

AM: Conception of the work, manuscript revision

AM: acquisition of data and analysis of data,

AA: analysis and interpretation of data

AM: Conception of the work, Approved the version to be published

MA: Conception and design, revised the manuscript critically for important intellectual content

All authors have agreed to conditions noted on the Authorship Agreement Form and have read and approved the final version submitted.

Acknowledgement

Not applicable

Authors' information

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No competing interests reported.

Effect of Childhood Epilepsy and Antiepileptic Drugs on Visual Evoked Potential Response and Optical Coherence Tomography

Status:

Version 1

Abstract

Figures

Background

Methods

Study design and participants

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1