Brain Plasticity induced by Vagal Nerve Stimulation in Patients affected by Drug-resistant Epilepsy: effects on Brain Network and Neurotrophins

Chronic Vagal Nerve Stimulation (VNS) is an approved neuromodulation therapy that is effective in the treatment of drug-resistant epilepsy (DRE). Despite the high number of devices implanted and subjects treated (over 100,000), the exact mechanism of action is still debated in the literature: widespread effects on neurotransmitter expression, blood flow, brain network and EEG, neuroinflammation, and neurotrophins (e.g. BDNF and NGF) have been proposed as key to understanding the efficacy of VNS on seizure frequency, psychiatric symptoms, memory, and quality of life of DRE subjects. Neuroplasticity is the ability of the human brain to reorganize its functions in response to any experience. Several pathways are activated to lead to short- and long-term changes and a central role is played by neurotrophins, including BDNF. The action of the latter is negatively affected by the presence of the Val66Met polymorphism. The analysis of the human brain according to a network perspective allows studying its functional connections and their modifications, for example by the use of EEG. The study of EEG aperiodic components allows to analyze the basic brain activity, specific to the individual. The mechanisms of brain plasticity represent the neurophysiological substrate that leads to modifications in the brain network. Based on these premises, this study aims to analyze the effects of VNS on brain plasticity of DRE subjects, through the study of high-density EEG brain network and the BDNF expression. Furthermore, it aims to infer how the clinical outcome of VNS therapy is affected by the presence of the Val66Met polymorphism. In order to do so, we investigated (1) the change in functional connectivity and aperiodic EEG components after one year of VNS chronic therapy, and its correlation with clinical response, (2) the clinical response to VNS in subjects with and without BDNF Val66Met polymorphism, and (3) the expression of serum BDNF during VNS titration and its correlation with the presence of the polymorphism. The results showed that: (1) VNS therapy modifies the brain network differently in responder and non-responder subjects, and changes in aperiodic components correlate with the clinical response; (2) clinical response to VNS is worse in subjects carrying the Val66Met polymorphism; and (3) serum BDNF expression is variable across subjects during VNS titration. Thus, this study paves the way to the analysis of the effect of VNS on the brain background rhythm through aperiodic components and to the identification of a predictive factor of clinical response in the BDNF Val66Met polymorphism. Future directions will be aimed to the sample size enlargement and to the analysis of clinical outcomes more suitable to evaluate all the beneficial effects of VNS, to understand even better the mechanism of action of this neuromodulation technique

Study of functional cortical connectivity in patients affected by drug resistant epilepsy treated with vagal nerve stimulation.

Objectives To explore functional brain connectivity [namely Phase Lag Index (PLI), Clustering Coefficient (Cw) and Characteristic path length (Lw)] in patients affected by drug-resistant epilepsy (DRE) treated with vagal nerve stimulation (VNS) by means of high density EEG. Materials Seven patients (3 females, 4 males, 27-63 y) waiting for VNS implantation, with drug-resistant epilepsy, non-eligible for epilepsy surgery, good compliance to electroencephalographic (EEG) recordings and no psychiatric comorbidity were selected for this study. Method Patients underwent VNS surgery; scalp signals were recorded using a 64 channel EEG system and was performed before and 1 year (12-14 months) after the VNS surgery. Signals were acquired during a 40 min eyes-closed resting state, at a distance from seizures or post-ictal state. For each subject ten artifact-free epochs using average reference were selected for analysis, analyzed separately in four bands (alfa: 8-12 Hz; beta: 12-30 Hz; theta: 3-8 Hz; delta: 0,5-3 Hz) and exported. Phase Lag Index (PLI), Clustering Coefficient (Cw) and Characteristic path length (Lw) were derived using Brain-wave software. Cw and Lw value computed for every patient in every frequency band before and after VNS substitution were compared using Student's t-test. Each EEG was compared to the same patient’s recording performed before VNS surgery. Results Every band shows an upward trend for clustering coefficient and a downward trend for characteristic path length after the substitution with the exception of theta band which shows an opposite trend. Ratio between Cw or Lw value after and before VNS surgery wasn’t statistically significant for any of the rhythms examined (p value 0,0721 - 0,9287). Discussion The peculiar trend observed in theta band is a marker of reduced synchronization. Previous studies demonstrated that VNS induce gamma band desynchronization in temporal lobe drug-resistant epilepsy. Theta band is related to encoding of new information and episodic memory; hippocampal theta band closely correlates with Long-Term Potentiation process and neuronal plasticity. Therefore, the peculiar trend of theta band could be related (if confirmed by larger studies) to hippocampal neuronal plasticity. Conclusions This preliminary study paves the way for various hypotheses on the effects of VNS on neuronal plasticity. It will be necessary to expand the study to a larger number of patients before first VNS implant in order to value functional connectivity before and after VNS

Epilessia focale con crisi ipermotorie in sonno e terapia chirurgica:case report

INTRODUZIONE. La concordanza tra clinica, studi neurofisiologici e imaging è fondamentale per l’indicazione al trattamento chirurgico dell’epilessia, tuttavia l’assenza di un focolaio all’EEG e alla RM non esclude la possibilità di un trattamento chirurgico. CASO CLINICO. Presentiamo il caso di un paziente di 22 anni affetto da epilessia focale con crisi ipermotorie in sonno esordita all’età di 9 anni con crisi prevalentemente notturne caratterizzate da sensazione dolorosa crampiforme con estensione e irrigidimento del braccio sinistro, automatismi agli arti inferiori e agitazione psicomotoria. La videopolisonnografia notturna evidenziava numerosi episodi critici in sonno REM e NREM di circa 20 secondi senza anomalie EEG intercritiche né immediatamente precedenti l’inizio delle crisi. Nonostante l’assenza di chiare alterazioni focali allo studio RM, considerata la clinica indicativa per una focalità insulare e la farmacoresistenza, il paziente è stato avviato ad un centro di chirurgia dell’epilessia dove è stato eseguito monitoraggio video-stereo-EEG che evidenziava un focus epilettogeno insulo-opercolare destro, per cui il paziente è stato trattato con termocoagulazione e avviato al trattamento chirurgico. Dopo la termocoagulazione il paziente per circa 10 giorni non ha presentato nessun episodio critico ma, in seguito, è andato incontro ad una progressiva, graduale ripresa delle crisi sino alla frequenza pre-impianto. È stato quindi sottoposto ad intervento di cortectomia insulo-perisilviana destra con scomparsa delle crisi. DISCUSSIONE. L’epilessia focale con crisi ipermotorie in sonno (Sleep-related Hypermotor Epilepsy: SHE) è caratterizzata da crisi di breve durata, prevalentemente in sonno, pattern motorio stereotipato e semeiologia ipermotoria. Il focolaio epilettogeno può essere localizzato nel lobo frontale, nel lobo temporale o in regione insulo-opercolare. Circa il 30% di questi pazienti risultano resistenti alla terapia farmacologica con ridotta qualità del sonno e aumentato rischio di Sudden Unexpected Death in Epilepsy (SUDEP). CONCLUSIONI. La chirurgia dell’epilessia fornisce risultati eccellenti nel trattamento della SHE farmacoresistente, sia nel controllo delle crisi che nelle alterazioni del sonno correlate all’epilessia

Estimated EEG functional connectivity and aperiodic component induced by vagal nerve stimulation in patients with drug-resistant epilepsy

Background: Vagal nerve stimulation (VNS) improves seizure frequency and quality of life in patients with drug-resistant epilepsy (DRE), although the exact mechanism is not fully understood. Previous studies have evaluated the effect of VNS on functional connectivity using the phase lag index (PLI), but none has analyzed its effect on EEG aperiodic parameters (offset and exponent), which are highly conserved and related to physiological functions. Objective: This study aimed to evaluate the effect of VNS on PLI and aperiodic parameters and infer whether these changes correlate with clinical responses in subjects with DRE. Materials and methods: PLI, exponent, and offset were derived for each epoch (and each frequency band for PLI), on scalp-derived 64-channel EEG traces of 10 subjects with DRE, recorded before and 1 year after VNS. PLI, exponent, and offset were compared before and after VNS for each patient on a global basis, individual scalp regions, and channels and separately in responders and non-responders. A correlation analysis was performed between global changes in PLI and aperiodic parameters and clinical response. Results: PLI (global and regional) decreased after VNS for gamma and delta bands and increased for an alpha band in responders, but it was not modified in non-responders. Aperiodic parameters after VNS showed an opposite trend in responders vs. non-responders: both were reduced in responders after VNS, but they were increased in non-responders. Changes in aperiodic parameters correlated with the clinical response. Conclusion: This study explored the action of VNS therapy from a new perspective and identified EEG aperiodic parameters as a new and promising method to analyze the efficacy of neuromodulation

Neuropsychological and Behavioral Profile in Sleep-Related Hypermotor Epilepsy (SHE) and Disorders of Arousal (DOA): A Multimodal Analysis

Study Objectives: Disorder of arousal (DOA) and sleep-related hypermotor epilepsy (SHE) are complex, often bizarre, involuntary sleep behaviors, whose differential diagnosis may be challenging because they share some clinical features, such as sleep fragmentation. Mounting evidence highlights the critical role of sleep in cognitive functions. Controversial findings are raised about the cognitive profile in SHE; however, no studies have investigated the cognitive profile in DOA. This study aimed to assess whether sleep instability affects cognitive functions in patients with SHE or DOA. Methods: This study analyzed 11 patients with DOA, 11 patients with SHE, and 22 healthy controls (HC). They underwent full-night video polysomnography (vPSG) and comprehensive neuropsychological and behavioral evaluation. Differences in the variables of interest among the SHE group, DOA group, and their respective control groups were evaluated. The auto-contractive map (auto-CM) system was used to evaluate the strength of association across the collected data. Results: The SHE group had reduced sleep efficiency and increased wake after sleep onset (WASO); both the SHE and DOA groups showed increased % of N2 and REM sleep compared to the HC group. Neuropsychological and behavioral evaluations showed a different cognitive profile in the SHE group with respect to the HC group. The auto-CM showed that Pittsburgh Sleep Quality Index (PSQI), Beck depression inventory (BDI), MWCST_PE, Epworth sleepiness scale (ESS), WASO, N1, and % REM were strictly correlated with SHE, whereas the SE and arousal index (AI) were strictly related to DOA. Conclusions: Patients with SHE and DOA present different cognitive and psychiatric profiles, with subtle and selective cognitive impairments only in those with SHE, supporting the discriminative power of cognitive and psychiatric assessment in these two conditions

Ocular pneumoplethysmography can help in the diagnosis of giant-cell arteritis.

We compared the results of ocular pneumoplethysmography in nine patients who had a temporal artery biopsy (TAB) diagnostic of giant-cell arteritis with results of ocular pneumoplethysmography in nine patients with normal TAB results and 112 patients with anterior ischemic optic neuropathy or central retinal artery occlusion assumed to be nonarteritic. The mean +/- SD ocular pulse amplitude with ocular pneumoplethysmography was 3.9 +/- 1.8 mm in the group with abnormal TAB results and 10.6 +/- 4.0 mm in the group with normal TAB results. Every patient with abnormal TAB results had an average calculated ocular blood flow less than 0.60 mL/min, while only one patient with normal TAB results fell in this range. The average calculated ocular blood flow had a sensitivity of 100% and a specificity of 93.4% in the diagnosis of giant-cell arteritis, with a diagnostic accuracy of 93.9%. These results rival the diagnostic accuracy of the erythrocyte sedimentation rate and TAB results

An Italian consensus on the management of Lennox-Gastaut syndrome

Purpose: Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS. Methods: The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score >= 7. Results: Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved. Conclusions: Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy