Brain-derived neurotrophic factor Val66Met polymorphism in vagal nerve stimulation patients affected by drug-resistant epilepsy.

Purpose: Vagal nerve stimulation (VNS) is safe and effective in adults and children with epilepsy according to FDA. BDNF is implicated in many neurophysiological processes and exerts effects on hippocampal serotonergic pathways during both acute and chronic VNS stimulation. BDNF gene encodes a precursor peptide (proBDNF) and non-conservative single nucleotide polymorphism (SNP) has been identified in humans producing an aminoacid substitution (Val66Met). This SNP affects intracellular processing and secretion of BDNF, leading to impaired hippocampal function in humans. (Kowiański P, et al., Cell Mol Neurobiol. 2017; :1–15; Egan MF, et el., Cell. 2003; 112:257–69.) Thus, assuming that Val66Met polymorphism underlies an ineffective processing mechanism in DRE, we structured a pilot study to identify whether this SNP is present and correlates with low responder implanted epileptic patients. Method: After approval by the ethics committee, 25 patients (17 M, 8 F) aged between 14 and 58 yo (median age 44), with DRE, not eligible for surgical treatment, were selected. Genomic DNA was extracted from blood samples and then amplified by PCR + RFLP to detect BDNF Val66Met. The Mann-Whitney test was used to verify the different presence of polymorphism in responders versus non-responders. Results: Clinical response to VNS was assessed according to McHugh classification (.) before and 1 year after VNS: 11 patients (class I and II) were considered responders, 14 patients (class III or more) non-responders. There is a correlation between the presence of Val66Met Polymorphism and worse clinical response (p-value 0.0015**; Mean ± SEM of Class I-II: 0,1818 ± 0,122, n=11; Mean ± SEM of Class III-V: 0,7857 ± 0,1138, n=14). Conclusions: The correlation between the presence of Val66Met polymorphism and reduced response to VNS, if confirmed on a larger number of individuals, could be a useful marker in clinical practice to better tailor therapies proposed to individual patients. Moreover, this finding would also confirm in humans a reduced neuronal plasticity when the polymorphism is present