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

Abstract

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.

Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link

“…For instance, Wang et al [224] showed that interictal elevated serum IL-6, IFNγ, IL-17a, IFNλ3, and CSF IL-6, IL-17a, IFNλ3 levels were associated with seizure severity in PWE. In contrast, Alvim et al [225] found reduced cytokine (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFNγ) levels in plasma, while neurotrophic factor (BDNF, NT3, and NGF) levels were elevated in PWE compared to healthy controls. Moreover, Zhong et al [226] reported elevated CRP levels in peripheral blood from PWE compared to healthy controls.…”

Neuronal and Astrocytic Tetraploidy Is Increased in Drug-Resistant Epilepsy

“…Moreover, an association between tetraploid neurons and tetraploid astrocytes was detected. This fact may be potentially explained if epilepsy could stimulate overexpression of factors that induce cell cycle re-entry (such as neurotrophins) [12,19,47] and tetraploidy in both cell populations. Similarly to recent treatments proposed for Alzheimer [48], we hypothesize that the modulation of tetraploidy could be a potential treatment for DRE.…”

Blood biomarkers in epilepsy

“…43,44 One study did not find altered levels in children with acute encephalopathy and/or prolonged febrile seizures (PFS), 45 while another study even observed a decrease in serum IL-2 and IL-4 in epilepsies of different etiologies. 46 High levels of plasma IL-6 have been reported in studies on febrile seizures, 42,43,47 while serum IL-6 was also observed at elevated levels in several epilepsy studies, particularly in TLE. 39,43,48,49 Increased serum IL-8 and IL-10 levels have been demonstrated in neonatal and febrile seizures.…”

“…Significant upregulation of serum TNF‐α has been demonstrated in patients with epilepsy, but so has unchanged TNF‐α levels 43,54,56,57 . Soluble TNF receptor 2 (sTNFr2), an isoform of the TNF‐α receptors, had good discriminative capacity with regard to separating patients from controls in one study, compared with TNF‐α and sTNFr1 46 …”