Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology.

OBJECTIVE: Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS: We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS: The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE: This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.

Long-term outcomes of reoperations in epilepsy surgery.

OBJECTIVE: To analyze longitudinal seizure outcomes following epilepsy surgery, including reoperations, in patients with intractable focal epilepsy. METHODS: Clinicoradiological characteristics of patients who underwent epilepsy surgery from 1995 to 2016 with follow-up of ≥1 year were reviewed. In patients undergoing reoperations, the latest resection was considered the index surgery. The primary outcome was complete seizure freedom (Engel I) at last follow-up. Potentially significant outcome variables were first identified using univariate analyses and then fit in multivariate Cox proportional hazards models. RESULTS: Of 898 patients fulfilling study criteria, 110 had reoperations; 92 had one resection prior to the index surgery and 18 patients had two or more prior resective surgeries. Two years after the index surgery, 69% of patients with no prior surgeries had an Engel score of I, as opposed to only 42% of those with one prior surgery, and 33% of those with two or more prior resections (P < .001). Among surgical outcome predictors, the number of prior epilepsy surgeries, female sex, lesional initial magnetic resonance imaging, no prior history of generalization, and pathology correlated with better seizure outcomes on univariate analysis. However, only sex (P = .011), history of generalization (P = .016), and number of prior surgeries (P = .002) remained statistically significant in the multivariate model. SIGNIFICANCE: Although long-term seizure control is possible in patients with failed prior epilepsy surgery, the chances of success diminish with every subsequent resection. Outcome is additionally determined by inherent biological markers (sex and secondary generalization tendency), rather than traditional outcome predictors, supporting a hypothesis of "surgical refractoriness."

Localization yield and seizure outcome in patients undergoing bilateral SEEG exploration.

OBJECTIVE: We aimed to determine the rates and predictors of resection and seizure freedom after bilateral stereo-electroencephalography (SEEG) implantation. METHODS: We reviewed 184 patients who underwent bilateral SEEG implantation (2009-2015). Noninvasive and invasive evaluation findings were collected. Outcomes of interest included subsequent resection and seizure freedom. Statistical analyses employed multivariable logistic regression and proportional hazard modeling. Preoperative and postoperative seizure frequency, severity, and quality of life scales were also compared. RESULTS: Following bilateral SEEG implantation, 106 of 184 patients (58%) underwent resection. Single seizure type (P = 0.007), a family history of epilepsy (P = 0.003), 10 or more seizures per month (P = 0.004), lower number of electrodes (P = 0.02), or sentinel electrode placement (P = 0.04) was predictive of undergoing a resection, as were lack of nonlocalized (P < 0.0001) or bilateral (P < 0.0001) ictal-onset zones on SEEG. Twenty-six of 81 patients (32% with follow-up greater than 1 year) remained seizure-free. Predictors of seizure freedom were single seizure type (P = 0.01), short epilepsy duration (P = 0.008), use of 2 or fewer antiepileptic drugs (AEDs) at the time of surgery (P = 0.0006), primary localization hypothesis involving the frontal lobe (P = 0.002), sentinel electrode placement only (P = 0.02), and lack of overlap between ictal-onset zone and eloquent cortex (P = 0.04), along with epilepsy substrate histopathology (P = 0.007). Complete resection of a suspected focal cortical dysplasia showed a trend to increased likelihood of seizure freedom (P = 0.09). The 44 of 55 patients (80%) who underwent resection and experienced seizure recurrence had >50% seizure reduction, as opposed to 26 of 45 patients (58%) who continued medical therapy alone (P = 0.003). Seventy-two percent of patients had a clinically meaningful quality of life improvement (>10% decrease in the Quality of Life in Epilepsy [QOLIE-10] score) at 1 year. SIGNIFICANCE: A strong preimplantation hypothesis of a suspected unifocal epilepsy increases the odds of resection and seizure freedom. We discuss a tailored approach, taking into account localization hypothesis and suspected epilepsy etiology in guiding implantation and subsequent surgical strategy.