Retina-Based Biomarkers in Epilepsy: Structural and Microvascular OCT Changes and Inflammatory Markers (sCD14, sCD163, CCL2, IL-1β) in Relation to Pathophysiology, Phenotype, Prognosis, and Drug-Resistant Epilepsy (DRE)
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 250
- 试验地点
- 1
- 主要终点
- Annualized percentage change in peripapillary retinal nerve fiber layer thickness measured by OCT
研究概览
简要总结
This prospective, longitudinal observational study investigates whether epilepsy involves a progressive neurodegenerative process. Retinal structural and microvascular changes assessed by optical coherence tomography (OCT) and optical coherence (OCTA) will be analyzed alongside inflammatory biomarkers (sCD14, sCD163, CCL2, IL-1β). The study aims to explore their association with epilepsy pathophysiology, clinical phenotype, prognosis, and drug-resistant epilepsy (DRE). Among participants with epilepsy, seizure severity and antiseizure medication-related adverse-effect burden will also be assessed longitudinally using the National Hospital Seizure Severity Scale (NHS3) and the Turkish version of Liverpool Adverse Events Profile (LAEP-TR).
详细描述
Epilepsy may be associated with neuroinflammatory and neurodegenerative mechanisms. The retina provides a non-invasive window for evaluating neuroaxonal and microvascular changes through OCT and OCTA. This study will investigate whether retinal structural, microvascular, and serum inflammatory biomarker measures are associated with epilepsy phenotype, disease severity, prognosis, and drug-resistant epilepsy. Participants will be enrolled into three cohorts: adults with epilepsy, adults using antiseizure medications for non-epileptic indications, and healthy controls. Clinical data will include demographic characteristics, epilepsy history, mean monthly seizure frequency derived from seizure diaries and clinical records, antiseizure medication use, neurological examination findings, electroencephalography (EEG) findings, and magnetic resonance imaging (MRI) findings. Among participants with epilepsy, clinical epilepsy activity will be characterized using two prespecified components: mean monthly seizure frequency and seizure severity assessed with the National Hospital Seizure Severity Scale (NHS3). These components will be analyzed separately and jointly in multivariable models rather than combined into a study-specific unvalidated total score. The NHS3 will be administered at baseline and at 18 months based on the participant's most severe habitual seizure during the preceding 6 months. Patient-reported adverse effects associated with antiseizure medication treatment will be assessed separately at the same visits using the Turkish version of Liverpool Adverse Events Profile (LAEP-TR). All participants will undergo ophthalmological assessment, including visual acuity, intraocular pressure measurement, and refraction assessment. OCT and OCTA imaging will be used to measure peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, inner nuclear layer thickness, macular volume, hyperreflective retinal foci, capillary density, and foveal avascular zone area.
Peripheral venous blood samples will be collected only from participants in the epilepsy group at baseline and at 18 months for serum biomarker analysis. Serum samples will be stored at -80°C. Serum soluble CD14, soluble CD163, C-C motif chemokine ligand 2, and interleukin-1 beta concentrations will be measured using commercial enzyme-linked immunosorbent assay kits according to the manufacturers' protocols. Serum biomarker outcomes and serum biomarker-based prediction analyses will therefore be restricted to participants with epilepsy.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age between 18 and 40 years
- •Ability to provide written informed consent
- •For the epilepsy group: diagnosis of epilepsy for at least 1 year
- •For the epilepsy group: treatment with at least one antiseizure medication for at least 1 year
- •For the disease-control group: diagnosis of migraine, analgesic-overuse headache, or neuralgia
- •For the disease-control group: current treatment with at least one antiseizure medication for a non-epileptic indication
- •For the disease-control group: no history of epilepsy or unprovoked seizures
- •For the healthy-control group: no history of epilepsy, major neurological disease, ophthalmological disease, or regular antiseizure medication use
排除标准
- •Age younger than 18 years or older than 40 years
- •Inability or unwillingness to provide written informed consent
- •History of ocular surgery, ocular trauma, glaucoma, retinal disease, optic neuropathy, or severe refractive error, defined as spherical equivalent greater than ±6.0 diopters
- •Media opacity or poor image quality preventing reliable OCT or OCTA assessment
- •Vigabatrin or Valproate use
- •Multiple sclerosis, Parkinson's disease, dementia, brain tumor, stroke, optic neuritis, or other major neurological disorders
- •Evidence of visual pathway lesions on MRI
- •Diabetes mellitus, uncontrolled hypertension, or other systemic vascular, metabolic diseases that may affect retinal or OCTA parameters
- •Chronic alcohol or psychoactive substance abuse
- •Inability to undergo OCT or OCTA examination because of cognitive, behavioral, or physical limitations
结局指标
主要结局
Annualized percentage change in peripapillary retinal nerve fiber layer thickness measured by OCT
时间窗: Baseline to 18 months after enrollment.
Peripapillary RNFL thickness will be assessed with Heidelberg OCT at baseline and 18 months using the optic nerve head-centered circular scan protocol. Eye-tracking and follow-up registration will ensure reproducibility. Automated segmentation will be reviewed for centration and accuracy; global and quadrant values (superior, inferior, nasal, temporal) will be recorded. Images will be checked for quality and artifacts; scans failing criteria or with uncorrectable errors will be repeated or excluded. For participants with two eligible eyes, mean thickness will be analyzed; if one eye is eligible, that measurement will be used. Annualized percentage change will be calculated as: \[((18-month pRNFL thickness - baseline pRNFL thickness) / baseline pRNFL thickness) × 100\] / 1.5 years. Unit of measure: Percent change per year
Annualized percentage change in ganglion cell-inner plexiform layer thickness measured by OCT
时间窗: Baseline to 18 months after enrollment
Ganglion cell-inner plexiform layer (GC-IPL) thickness will be measured with Heidelberg OCT at baseline and 18 months using a fovea-centered 6 × 6 mm macular scan. Identical parameters and eye-tracking functions will ensure reproducibility. Automated segmentation will be reviewed for centration, accuracy, and artifacts; errors will be corrected when possible. GC-IPL thickness will be calculated as the sum of ganglion cell and inner plexiform layers. Scans failing quality criteria or with uncorrectable artifacts will be repeated or excluded. For two eligible eyes, mean thickness will be analyzed; if one eye is eligible, that measurement will be used. Annualized percentage change will be calculated as: {\[(18-month GC-IPL thickness - baseline GC-IPL thickness) / baseline GC-IPL thickness\] × 100} / 1.5 years. Unit of measure: Percent change per year
Difference in annualized percentage change in peripapillary retinal nerve fiber layer thickness between drug-resistant and non-drug-resistant epilepsy groups
时间窗: Baseline to 18 months after enrollment.
Annualized percentage change in peripapillary retinal nerve fiber layer thickness measured by optical coherence tomography will be compared between participants with drug-resistant epilepsy and participants without drug-resistant epilepsy. This analysis will be performed only among participants with epilepsy. Drug-resistant epilepsy will be defined as failure of adequate trials of two tolerated, appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom. Unit of measure: Percent change per year
Difference in annualized percentage change in ganglion cell-inner plexiform layer thickness between drug-resistant and non-drug-resistant epilepsy groups
时间窗: Baseline to 18 months after enrollment.
Annualized percentage change in ganglion cell-inner plexiform layer thickness measured by macular optical coherence tomography will be compared between participants with drug-resistant epilepsy and participants without drug-resistant epilepsy. This analysis will be performed only among participants with epilepsy. Drug-resistant epilepsy will be defined as failure of adequate trials of two tolerated, appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom. Unit of measure: Percent change per year
次要结局
- Change in hyperreflective foci count measured on optical coherence tomography(Baseline to 18 months after enrollment.)
- Difference in hyperreflective retinal foci count between drug-resistant and non-drug-resistant epilepsy groups(Baseline to 18 months after enrollment.)
- Change in superficial macular vessel density measured by optical coherence tomography angiography(Baseline to 18 months after enrollment.)
- Change in deep macular vessel density measured by optical coherence tomography angiography(Baseline to 18 months after enrollment.)
- Change in peripapillary capillary vessel density measured by optical coherence tomography angiography(Baseline to 18 months after enrollment.)
- Change in foveal avascular zone area measured by optical coherence tomography angiography(Baseline to 18 months after enrollment.)
- Change from baseline in serum interleukin-1 beta concentration measured by enzyme-linked immunosorbent assay in participants with epilepsy(Baseline to 18 months after enrollment.)
- Change from baseline in serum C-C motif chemokine ligand 2 concentration measured by enzyme-linked immunosorbent assay in participants with epilepsy(Baseline to 18 months after enrollment.)
- Change from baseline in serum soluble CD14 concentration measured by enzyme-linked immunosorbent assay in participants with epilepsy(Baseline to 18 months after enrollment.)
- Change from baseline in serum soluble CD163 concentration measured by enzyme-linked immunosorbent assay in participants with epilepsy(Baseline to 18 months after enrollment.)
- Association of mean monthly seizure frequency and baseline National Hospital Seizure Severity Scale score with annualized percentage change in peripapillary retinal nerve fiber layer thickness(Baseline to 18 months after enrollment.)
- Association of mean monthly seizure frequency and baseline National Hospital Seizure Severity Scale score with annualized percentage change in ganglion cell-inner plexiform layer thickness(Baseline to 18 months after enrollment.)
- Correlation between number of antiseizure medications and ganglion cell-inner plexiform layer thickness measured by optical coherence tomography(Baseline to 18 months after enrollment.)
- Difference in peripapillary retinal nerve fiber layer thickness across epilepsy syndrome groups(Baseline to 18 months after enrollment.)
- Difference in ganglion cell-inner plexiform layer thickness across epilepsy syndrome groups(Baseline to 18 months after enrollment.)
- Predictive performance of a predefined retinal-inflammatory biomarker model for drug-resistant epilepsy status(Baseline to 18 months after enrollment.)
- Change from baseline in National Hospital Seizure Severity Scale score among participants with epilepsy(Baseline to 18 months after enrollment)
- Change from baseline in Turkish version of Liverpool Adverse Events Profile total score among participants with epilepsy(Baseline to 18 months after enrollment)
研究者
Kemal Tutkavul
Professor
Saglik Bilimleri Universitesi