The role of the insula in heart rate variability

Des preuves cumulatives soutiennent le rôle de l'insula dans la régulation autonomique cardiaque et son dysfonctionnement pourrait être impliqué dans la physiopathologie de la mort subite et inexpliquée en épilepsie (MSIE –SUDEP en anglais). La variabilité de la fréquence cardiaque (VFC) est un outil simple et fiable pour évaluer la fonction autonomique; il est également considéré comme un prédicteur potentiel de la tachycardie ventriculaire et de la mort subite chez les patients après un infarctus du myocarde. Au cours des deux dernières décennies, la VFC a suscité beaucoup d'intérêt dans le monde de l'épilepsie. Toutefois, même si plusieurs études ont tenté d'évaluer les changements de VFC dans différentes formes d'épilepsie, les résultats ont été hétérogènes voire paradoxaux de sorte que son utilité en tant que marqueur de la MSIE est loin d’être concluant. Notons que la majorité des études ont porté sur l’épilepsie temporale. Aucune étude n’a étudié les changements de la fonction autonomique cardiaque dans l'épilepsie insulo-operculaire (EIO). Il est encore incertain si une chirurgie d’épilepsie insulaire peut accélérer la dysfonction autonomique inhérente. Dans cette étude, nous visons à étudier les changements de la VFC interictale chez les patients avec EIO. Nous avons en outre évalué l'effet de la chirurgie insulo-operculaire sur ces modifications de la VFC. Quatorze patients avec une EIO et un bon résultat post-chirurgie insulo-operculaire (Engel I-II) ont été recrutés pour cette étude. Quatorze patients appariés pour l'âge et le sexe atteints d'épilepsie du lobe temporal (ELT) et exempts de crise après une lobectomie temporale antérieure et 28 individus en bonne santé appariés selon l'âge et le sexe ont également été identifiés pour les besoins de l’étude. La VFC dans le domaine temporel RMSSD (root mean square of successive RR interval differences, pNN50 (percentage of successive RR intervals that differ by more than 50ms) et le domaine fréquentiel LF (low frequency) et HF (high frequency) ont été étudiés dans les périodes préopératoire et postopératoire (6-204 mois). La VFC avant la chirurgie des patients épileptiques fut calculée à partir des enregistrements EKG obtenus simultanément aux enregistrements vidéo-EEGs effectués dans le cadre de leur évaluation préchirurgicale. La VFC après la chirurgie fut calculée chez tous les patients et les sujets sains à partir d’un EKG de repos d'une durée d’une heure au laboratoire. Le score d’inventaire des risques de MSIE (le score SUDEP-7) a été calculé à partir des données cliniques obtenues dans le dossier médical de chaque patient. Les résultats n'ont montré aucune différence statistiquement significative dans toutes les mesures de VFC entre les groupes de patients avec EIO, de patients avec ELT avant la chirurgie et de sujets sains. Chez les patients avec EIO, le score SUDEP-7 variant de 1 à 6 (moyenne de 2,9; SD :1,2) était positivement corrélé avec le pNN50 (r = 0,671; p = 0,009 et Ln (RMSSD) (r = 0,591; p = 0,026). En postopératoire, les mesures de la VFC n'étaient pas statistiquement différentes des valeurs préopératoires ou de celles des témoins. Nous avons mené une analyse exploratoire dans laquelle nous avons stratifié les patients avec EIO en deux sous-groupes : un premier groupe (1a) dont les valeurs préopératoires de Ln (RMSSD) étaient inférieures à 3,52 (valeur moyenne de notre échantillon sain) et un second groupe (1b) dont les valeurs préopératoires étaient au-dessus. En préopératoire, dans le groupe 1a, toutes les valeurs du domaine temporel et fréquentiel (LnRMSSD, pNN50, LnLF et LnHF) étaient significativement inférieures à celles du groupe témoin (p <0,01), tandis que dans le groupe 1b, seules les valeurs du domaine temporel (LnRMSSD et pNN50) étaient significativement plus élevées que ceux du groupe témoin (p <0,01). Dans les deux groupes, les valeurs de la VFC avaient tendance à se normaliser après l'opération. En revanche, la lobectomie temporale antérieure des patients avec ELT n'a pas modifié les valeurs de HRV. Ces résultats préliminaires suggèrent que dans les EIO réfractaires, la VFC peut être soit diminuée au niveau du tonus sympathique et parasympathique, soit augmentée au niveau du tonus parasympathique. L'augmentation du tonus parasympathique est possiblement inquiétante puisqu’elle était corrélée positivement avec le score SUDEP-7. Une operculo-insulectomie n'a pas affecté négativement la VFC; au contraire, une chirurgie réussie semble entraîner une certaine ‘normalisation’ de l’HRV. Une confirmation avec un échantillon plus grand est nécessaire.Cumulative evidence supports the role of the insula in cardiac autonomic regulation whose dysfunction may be involved in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). Heart rate variability (HRV) is a simple and reliable tool to assess autonomic function; it is even considered a potential predictor of ventricular tachycardia and sudden death in patients after myocardial infarction. Over the last two decades, heart rate variability (HRV) has also received much interest in epilepsy research. Several studies have tried to assess HRV changes in different epilepsy types but the results have been heterogeneous and sometimes contradictory; its role as a marker of SUDEP remains uncertain. Of note, most studies involved TLE patients and TLE surgeries; none have looked at HRV changes in insulo-opercular epilepsy (IOE) and how insular resection can affect autonomic function. In this study, we aimed to investigate changes in interictal HRV in IOE. We further evaluated the effect of insulo-opercular surgery on these HRV changes. Fourteen IOE patients who had a good outcome (Engel I-II) after an insulo-opercular surgery were enrolled in this study. Fourteen age- and sex-matched patients with temporal lobe epilepsy (TLE) who were seizure-free after temporal lobectomy and 28 age- and sex-matched healthy individuals were also included. HRV measurements including time domain root mean square of successive RR interval differences (RMSSD) and percentage of successive RR intervals that differ by more than 50ms (pNN50) and frequency domain low-frequency (LF) and high-frequency (HF) parameters were carried out in pre- and post-operative periods (6-204 months). Presurgical HRV values for epileptic patients were calculated using EKG obtained simultaneously with video-EEG recordings during the presurgical evaluation. HRV of healthy individuals and post-surgical HRV from all operated epileptic patients were calculated from a 1-hour resting electrocardiogram at the laboratory. We also collected the patients’ presurgical data to calculate the SUDEP-7 risk inventory score. Findings showed no statistically significant differences in all HRV measurements between groups of IOE patients, TLE patients before the surgery, and healthy controls. In IOE patients, the SUDEP-7 score ranged from 1 to 6 (mean 2,9; SD: 1,6) and was positively correlated with pNN50 (r=0,671; p<0,009) and LnRMSSD (r=0,591; p<0,026). Postoperatively, HRV measurements were not statistically different from either preoperative values or those of controls. We conducted exploratory analyses where we stratified IOE patients into those whose preoperative LnRMSSD values were below (Group 1a) versus above (Group 1b) a cut-off threshold of 3,52 (mean value of our healthy sample). Preoperatively, in Group 1a, all time and frequency domain values (LnRMSSD, pNN50, LnLF, and LnHF) were significantly lower than those of controls (p<0,01) while in Group 1b, only time-domain values (LnRMSSD and pNN50) were significantly higher than those of control subjects (p<0,01). In both groups, HRV values tended to normalize postoperatively. In contrast, anterior temporal lobectomy for TLE patients did not alter HRV values. Our preliminary results suggest that in refractory IOE, HRV may be either decreased globally in sympathetic and parasympathetic tones or increased in parasympathetic tone. The increase in parasympathetic tone observed preoperatively may be of clinical concern as it was positively correlated with the SUDEP-7 score. The insulo-opercular resection did not affect the HRV; successful surgery might even have a good impact on HRV changes. Confirmation with a larger sample size is necessary

The Role of Nondrug Treatment Methods in the Management of Epilepsy

The review is devoted to the issue of nondrug epilepsy treatment in the adult population in Russia and abroad. The conducted literature review allowed us to reveal the basic nondrug epilepsy treatment options. However, not all of these options have a sufficient evidence base, and some of them are not always safe. Particularly, methods with low level of evidence include acupuncture and aromatherapy. Further studies are needed to explore the methods aimed to eliminate the epileptic system dominant through the development of a new, more powerful dominant. One of the methods, which can influence the pathogenesis of epilepsy, is physical activity for patients with epilepsy, since epileptiform activity on the EEG is reported to disappear during exercises. The positive results of the application of art therapy (music therapy) are also described in the modern literature. Tеmpo-rhythm correction methods hold a specific place in neurorehabilitation. There are considerable amount of studies concerning the application of tempo-rhythmic methods in neurology and psychiatry. It can be concluded that these methods are relevant worldwide and can be used in diagnostics and correction of neurological and psychiatric diseases (such as schizophrenia, Parkinson’s disease, epilepsy)

ALTERATIONS IN GABAERGIC NTS NEURON FUNCTION IN ASSOCIATION WITH TLE AND SUDEP

Epilepsy is a neurological disorder that is characterized by aberrant electrical activity in the brain resulting in at least two unprovoked seizures over a period longer than 24 hours. Approximately 60% of individuals with epilepsy are diagnosed with temporal lobe epilepsy (TLE) and about one third of those individuals do not respond well to anti-seizure medications. This places those individuals at high risk for sudden unexpected death in epilepsy (SUDEP). SUDEP is defined as when an individual with epilepsy, who is otherwise healthy, dies suddenly and unexpectedly for unknown reasons. SUDEP is one of the leading causes of death in individuals with acquired epilepsies (i.e. not due to genetic mutations), such as TLE. Previous studies utilizing genetic models of epilepsy have suggested that circuitry within the vagal complex of the brainstem may play a role in SUDEP risk. Gamma-aminobutyric acid (GABA) neurons of the nucleus tractus solitarius (NTS) within the vagal complex receive, filter, and modulate cardiorespiratory information from the vagus nerve. GABAergic NTS neurons then project to cardiac vagal motor neurons, eventually effecting parasympathetic output to the periphery. In this study, a mouse model of TLE was used to assess the effect of epileptogenesis on GABAergic NTS neuron function and determine if functional alterations in these neurons impact SUDEP risk. It was discovered that mice with TLE (i.e. TLE mice) have significantly increased mortality rates compared to control animals, suggesting that SUDEP occurs in this model. Using whole cell electrophysiology synaptic and intrinsic properties of GABAergic NTS neurons were investigated in TLE and control mice. Results suggest that during epileptogenesis, GABAergic NTS neurons become hyperexcitable, potentially due to a reduction in A-type potassium channel current and increased excitatory synaptic input. Increases in hyperexcitability have been shown to be associated with an increased risk of spreading depolarization and action potential inactivation leading to neuronal quiescence. This may lead to a decreased inhibition of parasympathetic tone, causing cardiorespiratory collapse and SUDEP in TLE

Sudden unexpected death in epilepsy, incidence, circumstances and risk factors

Although Sudden Unexpected Death in Epilepsy (SUDEP) has attracted increasing attention from the scientific community during the last 20 years, important gaps in knowledge still exist that hamper the development of methods aiming at prevention of this, the most devastating consequence of epilepsy. We are still missing large population-based studies on the incidence of SUDEP. Our understanding of the circumstances surrounding SUDEP is incomplete which is a major limitation when it comes to development of potential SUDEP-preventing devices. Finally, our understanding of risk factors for SUDEP is limited to a few established risk factors. The purpose of this study was to examine the incidence, circumstances and risk factors for SUDEP in Sweden. The project is based on a study population (n=78 524) which comprises all persons living in Sweden at 1. July 2006, who at some point during 1998-2005 where registered with the diagnosis code for epilepsy (ICD G 40) in the Swedish National Patient Register (SNPR). To identify cases of SUDEP, the study population was linked to the National Cause-of- Death Register. During the follow-up time from July 1, 2006 to December 31, 2011, we identified 9605 deaths. All death certificates in the study population between 1 July 2006 and 31 December 2011 with epilepsy mentioned on death certificate and all deaths during 2008 (n=3166) were reviewed. Based on the information in the death certificates, obvious non-SUDEP deaths were excluded from further analysis. For all others we analyzed patient medical records, autopsy and police reports and information was extracted using a standardized protocol. From the study population, five epilepsy controls per SUDEP case, of the same sex, who were alive at the case´s time of death, were randomly selected by the National Board of Health and Welfare. During 2008, 1890 individuals from the study population died. Of these, 99 met Annegers‘ SUDEP criteria (49 definite, 19 probable, and 31 possible) (paper I). Definite and probable SUDEP accounted for 3.6% of all deaths in the study population during 2008, and 5.2% when possible was included. In the age group 0-15 years, the relative contribution of SUDEP (definite, probable and possible) to overall deaths was 36.0%. SUDEP incidence was 1.20/1000 person-years (definite/ probable) and 1.74/1000 if possible SUDEP was included. Epilepsy was mentioned in any position of the death certificate in 63.6% of the 99 SUDEP cases. Of the 329 SUDEP deaths identified from July 1, 2006 to December 31, 2011 (167 definite, 89 probable, 73 possible), more than half (58%) occurred at night and 91% died at home, whereof 65% were found deceased in bed (paper II). Death was witnessed in 17% of all SUDEP cases and when a seizure was witnessed in conjunction with SUDEP (n=49) all were generalized tonic-clonic seizures (GTCS). Where a body position was documented (43%), more than two thirds (70%) were found prone. Dying at night made it more likely (80%) to be found prone than other times (55%) (p<0.001). Among adult SUDEP cases, 75% were living alone, and only 14% of all SUDEP cases shared a bedroom. In papers III and IV, 255 SUDEP cases (167 definite, 88 probable) were compared to their matched 1148 controls. Those with a history of GTCS had a tenfold increased SUDEP risk and the risk was increased to 32-fold with 4-10 GTCS during the last year of observation. When a history of nocturnal GTCS was present, a nine-fold SUDEP risk was observed and a 15-fold risk was seen if nocturnal GTCS were present during the last year of observation. No increased risk of SUDEP was seen in those experiencing exclusively non-GTCS during the preceding year. There was a fivefold increased risk of SUDEP among those living alone, while the risk was reduced to twofold when sharing household but not bedroom. Individuals experiencing ≥1 GTCS and not sharing a bedroom with someone had 67-fold increased risk of SUDEP compared to individuals not having GTCS, who shared their bedroom with someone, with attributable proportion due to interaction estimated at 0.69 (95% confidence interval, CI 0.53-0.85). Polytherapy, especially taking three or more AEDs was associated with a 69% reduced SUDEP risk after adjusting for GTCS frequency and other covariates. Levetiracetam as monotherapy was associated with a significantly lower SUDEP risk when compared to no AED treatment (odds ratio, OR 0.10, 95% CI 0.03-0.61). Lamotrigine, valproic acid and levetiracetam were associated with a significantly reduced risk when used as part of a polytherapy. Use of statins was associated with a reduced risk of SUDEP (OR 0.34, 95% CI 0.11-0.99). Our results show that SUDEP is an important contributor to mortality in epilepsy patients, and accounts for one third of deaths in children with epilepsy and one fifth of deaths among young adults with epilepsy. Since the majority died at home in bed, at night with indications of a previous GTCS, SUDEP can be considered an event related to night time and unobserved GTCS. We found no excess risk of SUDEP among individuals experiencing non-GTCS only, which has important clinical implications. GTCS and lack of supervision were the main risk factors. Moreover, our results suggest that up to 69% of SUDEP cases could be prevented in individuals with GTCS who live alone, if they were made free from GTCS or did not sleep alone. Polytherapy was associated with a substantially reduced SUDEP risk indicating that physicians should to consider AED polytherapy more pro-actively for patients with poorly controlled GTCS

Anatomical and physiological investigation of pathways mediating the effects of electrical stimulation of the external auricle of the ear on autonomic nervous system activity in rats

The Auricular Branch of the Vagus Nerve (ABVN) is a sensory nerve that innervates select areas of the external auricular dermatome. Electrical stimulation of the auricular region innervated by the ABVN influences the autonomic nervous system, observed by changes in control of the heart in humans and animals. However, the pathways and mechanisms for these effects are unknown. This thesis investigated in rats the pathways mediating the effects of electrical stimulation of the external auricle, comparing an ABVN innervated site of the external ear (the tragus) to an area not reported to receive ABVN innervation, the earlobe. Injection of the neuronal tracer cholera toxin B chain (CTB) into the right tragus (n=4) and right earlobe (n=4) revealed a large degree of similarity in sensory afferent termination sites. Afferent terminals were predominantly labelled ipsilateral to the injection site, with the densest labelling within laminae III-IV of the dorsal horn of the upper cervical spinal cord. In the medulla oblongata, CTB labelled afferents were observed in the paratrigeminal nucleus, cuneate nucleus, and to a minor extent in the nucleus tractus solitarius. Efforts were made to identify the targets of labelled afferents using immunofluorescence for choline acetyltransferase, calbindin, parvalbumin, glutamate decarboxylase 67 and neurokinin receptor 1 expressing cells, but inputs to each cell type were rare. Physiological recordings of the responses to ear stimulation were made in an anaesthetic free Working Heart Brainstem Preparation (WHBP) of the rat. Autonomic profiles of WHBP rats were first examined. Recordings made from rats at night time, revealed more robust sympathetic activity in comparison to day time rats, thus subsequent experiments were conducted in rats at night time. Electrical stimulation (100 Hz, 2.5 mA) was delivered for 5 minutes into the auricular stimulation sites in the WHBP. Direct recording from the sympathetic chain revealed a central sympathoinhibition from both tragus and earlobe stimulation. Sectioning of upper cervical afferent nerve roots silenced the sympathoinhibitory effects of tragus stimulation. Considering the predominance of afferent labelling in the cervical spinal cord dorsal horn and that cervical afferent nerve section reduced the sympathoinhibition evoked by tragus stimulation, this suggests that the autonomic effects of auricular stimulation are conveyed through somatosensory afferents rather than the ABVN

Coexistence of Vagus Nerve Stimulation and Epicardial Implantable Cardioverter-Defibrillator System, Possible Interference: A Case Report and Systematic Review of the Literature

Vagus nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsies in adults [1] and children [2]. Although VNS is generally well tolerated, rare cases of severe bradycardia..