In this observational cross-sectional study, we included 48 consecutive patients with focal epilepsy admitted to the Moscow Research and Clinical Center for Neuropsychiatry between October 2020 and August 2021 (Epilepsy group). The inclusion criteria were as follows: individuals aged 18 years or older, with a diagnosis of focal epilepsy, confirmed through consensus of at least two experienced epileptologists, in accordance with the International League against Epilepsy (ILAE) classification of epilepsy (13). The exclusion criteria were as follows: smoking; severe psychiatric comorbidities (schizophrenia, psychosis, intellectual disability, or dementia), other than major depressive disorder (MDD); a history of psychogenic non-epileptic seizures; diabetes mellitus; severe somatic, neurological, or ophthalmic disorders (including high myopia >6.0 diopters and previous ocular surgery); and active COVID-19 (ICD U 07.1, U 07.2), based upon a positive COVID-19 polymerase chain reaction (PCR) test.

A total of 24 (50%) of the 48 patients in our cohort had structural focal epilepsy (due to traumatic brain injury, stroke, malformations of cortical development, etc.), while the etiology of the remaining cases of focal epilepsy was unknown. The duration of epilepsy was 14.7 ± 11.9 years, and the age of epilepsy onset was 22.4 ± 16.0 years. Only 14 (29%) of the 48 PWE were seizure-free. Twelve PWE had one to two seizures per year, 10 PWE had less than one seizure per month, and 12 PWE had more than one seizure monthly. Twenty (42%) PWE were drug-resistant.

PWE were not treatment-naïve and had mostly received ASMs from the following groups for ≥14 days before screening: modulators of voltage-gated sodium channels (carbamazepine, lacosamide, lamotrigine, and oxcarbazepine), modifiers of the presynaptic release machinery (pregabalin, gabapentin, levetiracetam, brivaracetam, and ethosuximide), and valproates (valproic acid and sodium valproate) (14).

The diagnosis of comorbid MDD [current depressive episode, (cDE)] was made by a psychiatrist experienced in mood disorders, based on the ICD-10 criteria.

Forty-six age- and sex-matched healthy volunteers formed the control group.

This study adhered to the tenets of the Declaration of Helsinki and received approval from the local ethics committee. Informed consent was obtained from all subjects before participation.

OCTA was performed with the OCT HS-100 (Canon Inc., Tokyo, Japan) using Angio eXpert, OCTA version 2.0 (Tokyo, Japan). The OCT HS-100 is a spectral-domain OCT with a scanning rate of 70.000 A-scans/s and a central wavelength of 855 nm. Its declared axial resolution in tissue is 3 μm, and lateral resolution is 20 μm. Structural OCT was also performed to exclude concomitant ophthalmic disorders.

In all subjects, only the right eye was examined without pupil dilation (the choice between the right and left eyes was made randomly). Scans with signal strength ≥7 were included. To measure quantitative OCTA parameters, two protocols were used. The “OCTA (6 × 6 mm) (Macula)” protocol measures the superficial and deep capillary plexuses in the macular area. This area is divided according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scheme into a central (1 mm diameter) and four parafoveal zones, forming an inner ring (annulus) with an inner diameter of 1 mm and an outer diameter of 3 mm. In the central zone, the foveal avascular zone (FAZ) is measured semi-automatically. The “OCTA (4 × 4 mm) (Disc)” protocol measures the peripapillary radial capillary plexus, which is divided into four peripapillary zones, forming an annulus with a size of 1–3 mm.

All OCTA protocols provide two types of measurements—area density and skeleton density. Area density is “the percentage of white pixels in the region (%).” Skeleton density is defined as follows: “This function transforms the lines of a binary image created from an OCTA image into thin lines and indicates the value obtained by dividing the sum of the length of the thin lines in the region by the area (mm⁻¹)” [OCT HS-100 Operation Manual. Canon Inc., 2019, p.130]. Area density reflects the area of active (perfused) vessels forming the vascular (mostly capillary) bed in a given region. Unlike area density, skeleton density does not depend on the vessels’ size (diameter) and reflects only the number and total length of the vessels. It should be noted that OCTA terminology is not standardized. In other OCTA devices, area density is also referred to as perfusion density, vessel density, or vessel area density. Skeleton density is also referred to as vessel density or skeleton area density, or it may not be measured at all.

To simplify the comparison of area and skeleton density across different groups of patients, this study calculated the average densities in four parafoveal or four peripapillary zones (quadrants).

Statistical analysis was performed using the R software package, version 4.1.2 (The R Foundation for Statistical Computing, http://www.R-project.org, accessed 11 March 2022) and Jamovi software, version 2.3.28 (Jamovi project, https://www.jamovi.org, accessed 06 August 2024). The normality of distributions was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Normally distributed variables are presented as mean (M) ± standard deviation (SD), whereas non-normally distributed variables are presented as median (Me) and interquartile range (IQR). A comparison of continuous variables in two groups was performed using Student’s t-test for independent samples, Welch’s t-test, or Mann–Whitney U-test, as appropriate. Categorical variables were compared using Fisher’s exact test. Multivariate linear regression analysis was performed to assess the association between OCTA parameters and demographic parameters, epilepsy duration, seizure frequency, ASM influence, etc. p < 0.05 was considered statistically significant.

A psychiatric evaluation found MDD (cDE) in 25 out of 48 PWE. A comparison of groups of patients with focal epilepsy and concomitant MDD (group MDD (+), n = 25) and with focal epilepsy without MDD (group MDD (−), n = 23) did not show differences in age and sex (Table 1) and did not reveal any differences in OCTA parameters (averages of four quadrants) (Table 2). This corresponds to the results obtained in our previous study (15) and allowed further analysis without taking into account the presence of concomitant MDD.

To study the influence of focal epilepsy on OCTA parameters the comparison was performed between the epilepsy and control groups. Age and sex did not differ in these groups (Table 3). No differences were found in the averaged four quadrants area and skeleton densities (Table 4) and in all other OCTA parameters (Table 5).

Taking into account that more than 60% of PWE received antiseizure medications (ASM) in two to three groups, an analysis of the influence of ASMs and other factors on OCTA in PWE was performed using multivariate linear regression. Demographic parameters (age, sex, education, etc.) and epilepsy features (seizure frequency, epilepsy duration, etc.) did not show any significant impact on OCTA. The ASMs of two groups (valproates and modifiers of the presynaptic release machinery) showed a significant negative effect on the area and skeleton densities of both superficial and deep capillary plexuses in the macular region. In contrast, only the skeleton density of the deep capillary plexus showed a positive association with the use of modulators of voltage-gated sodium channels (Table 6). No similar effects were found for the peripapillary radial capillary plexus.

The associations reported in Table 6 are illustrated in Figure 1 and Table 7, which provide a direct comparison of OCTA parameters in patients who received versus those who did not receive a particular group of ASMs, as presented in Table 6. It should be noted that there were no age differences between the compared groups, while groups of patients who received and did not receive modulators of voltage-gated sodium channels differed significantly in terms of sex. However, multiple regression revealed a very weak influence of sex and age on the OCTA parameters studied.

Figure 1 and Table 7 show that the capillary retinal vascular bed is significantly decreased in patients receiving valproates or modifiers of the presynaptic release machinery while the skeleton density of the deep capillary plexus in patients on modulators of voltage-gated sodium channels is significantly increased.

The comparison groups of patients who received and did not receive a particular group of ASMs are relatively small, and some patients received ASMs from two or more groups. The reported effects of ASMs on OCTA need to be confirmed in larger groups of patients receiving ASM monotherapy.

The relationship between the capillary vascular bed of the retina and the brain, as suggested by existing literature, was not explored in this study. This topic requires a separate investigation using special methods to assess the condition of small cerebral vessels and cerebral blood flow.