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Epileptic networks are intimately connected with the autonomic nervous system, as exemplified by a plethora of ictal (during a seizure) autonomic manifestations, including epigastric sensations, palpitations, goosebumps and syncope (fainting). Ictal autonomic changes might serve as diagnostic clues, provide targets for seizure detection and help us to understand the mechanisms that underlie sudden unexpected death in epilepsy (SUDEP). Autonomic alterations are generally more prominent in focal seizures originating from the temporal lobe, demonstrating the importance of limbic structures to the autonomic nervous system, and are particularly pronounced in focal-to-bilateral and generalized tonic–clonic seizures. The presence, type and severity of autonomic features are determined by the seizure onset zone, propagation pathways, lateralization and timing of the seizures, and the presence of interictal autonomic dysfunction. Evidence is mounting that not all autonomic manifestations are linked to SUDEP. In addition, experimental and clinical data emphasize the heterogeneity of SUDEP and its infrequent overlap with sudden cardiac death. Here, we review the spectrum and diagnostic value of the mostly benign and self-limiting autonomic manifestations of epilepsy. In particular, we focus on presentations that are likely to contribute to SUDEP and discuss how wearable devices might help to prevent SUDEP.The close connection between epileptic networks and the autonomic nervous system is illustrated by a range of autonomic manifestations during a seizure. This article reviews the spectrum and diagnostic value of these manifestations, focusing on presentations that could contribute to sudden unexpected death in epilepsy.

Orthostatic hypotension is an unusually large decrease in blood pressure on standing that increases the risk of adverse outcomes even when asymptomatic. Improvements in haemodynamic profiling with continuous blood pressure measurements have uncovered four major subtypes: initial orthostatic hypotension, delayed blood pressure recovery, classic orthostatic hypotension, and delayed orthostatic hypotension. Clinical presentations are varied and range from cognitive slowing with hypotensive unawareness or unexplained falls to classic presyncope and syncope. Establishing whether symptoms are due to orthostatic hypotension requires careful history taking, a thorough physical examination, and supine and upright blood pressure measurements. Management and prognosis vary according to the underlying cause, with the main distinction being whether orthostatic hypotension is neurogenic or non-neurogenic. Neurogenic orthostatic hypotension might be the earliest clinical manifestation of Parkinson's disease or related synucleinopathies, and often coincides with supine hypertension. The emerging variety of clinical presentations advocates a stepwise, individualised, and primarily non-pharmacological approach to the management of orthostatic hypotension. Such an approach could include the cessation of blood pressure lowering drugs, adoption of lifestyle measures (eg, counterpressure manoeuvres), and treatment with pharmacological agents in selected cases.

Sudden unexpected death in epilepsy most frequently occurs in people with chronic epilepsy, and seems to be a seizure-related event. In this article, Surges et al . review the incidence of sudden unexpected death in epilepsy and the risk factors associated with this condition, before exploring the pathological mechanisms related to chronic epilepsy that could lead to sudden death. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy, and most frequently occurs in people with chronic epilepsy. The main risk factors for SUDEP are associated with poorly controlled seizures, suggesting that most cases of SUDEP are seizure-related events. Dysregulation in cardiac and respiratory physiology, dysfunction in systemic and cerebral circulation physiology, and seizure-induced hormonal and metabolic changes might all contribute to SUDEP. Cardiac factors include bradyarrhythmias and asystole, as well as tachyarrhythmias and alterations to cardiac repolarization. Altered electrolytes and blood pH, as well as the release of catecholamines, modulate cardiac excitability and might facilitate arrhythmias. Respiratory symptoms are not uncommon during seizures and comprise central apnea or bradypnea, and, less frequently, obstruction of the airways and neurogenic pulmonary edema. Alterations to autonomic function, such as a reduction in heart rate variability or disturbed baroreflex sensitivity, can impair the body's capacity to cope with challenging situations of elevated stress, such as seizures. Here, we summarize data on the incidence of and risk factors for SUDEP, and consider the pathophysiological aspects of chronic epilepsy that might lead to sudden death. We suggest that SUDEP is caused by the fatal coexistence of several predisposing and triggering factors. Key Points Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of death directly related to epilepsy, and most often occurs in individuals with chronic epilepsy The most important risk factors for SUDEP are related to poorly controlled seizures, suggesting that SUDEP is a seizure-related event Cardiac arrhythmia, respiratory dysfunction, dysregulation of systemic or cerebral circulation, and seizure-induced hormonal and metabolic changes have all been suggested as potential pathomechanisms in SUDEP SUDEP is most probably triggered by the peri-ictal concurrence of a number of predisposing and precipitating factors

Epilepsy is one of the most common serious brain conditions, affecting over 70 million people worldwide. Its incidence has a bimodal distribution with the highest risk in infants and older age groups. Progress in genomic technology is exposing the complex genetic architecture of the common types of epilepsy, and is driving a paradigm shift. Epilepsy is a symptom complex with multiple risk factors and a strong genetic predisposition rather than a condition with a single expression and cause. These advances have resulted in the new classification of epileptic seizures and epilepsies. A detailed clinical history and a reliable eyewitness account of a seizure are the cornerstones of the diagnosis. Ancillary investigations can help to determine cause and prognosis. Advances in brain imaging are helping to identify the structural and functional causes and consequences of the epilepsies. Comorbidities are increasingly recognised as important aetiological and prognostic markers. Antiseizure medication might suppress seizures in up to two-thirds of all individuals but do not alter long-term prognosis. Epilepsy surgery is the most effective way to achieve long-term seizure freedom in selected individuals with drug-resistant focal epilepsy, but it is probably not used enough. With improved understanding of the gradual development of epilepsy, epigenetic determinants, and pharmacogenomics comes the hope for better, disease-modifying, or even curative, pharmacological and non-pharmacological treatment strategies. Other developments are clinical implementation of seizure detection devices and new neuromodulation techniques, including responsive neural stimulation.

People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1-8.0.], p=0.034). The risk for SCA in epilepsy was particularly increased in young and females. Epilepsy in the general population seems to be associated with an increased risk for SCA.

Based on this activity, Lamictal could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia. [...]avoid the use of Lamictal in patients who have cardiac conduction disorders (eg, second‐ or third‐degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (eg, myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Lamictal did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, it could slow ventricular conduction and increase the risk of arrhythmia in patients with structural heart disease or myocardial ischemia. While in vitro data indicate lamotrigine has class IB antiarrhythmic sodium channel blocking properties, there is no change in ventricular conduction (QRS duration) in healthy individuals 5 and individuals with epilepsy without heart disease. 2 A modest increase in the AV conduction interval (PR prolongation) may occur, especially at high doses. 6 Significantly, unlike class IA antiarrhythmic drugs, lamotrigine does not prolong repolarization (no change in QT) in healthy people at thorough QT testing. 5 At high doses of lamotrigine, there is a mild QT shortening observed, 5 which is a class IB property. [...]based on the absence of QRS or QT changes, and only mild PR prolongation even at high doses, there is not an apparent arrhythmia risk of lamotrigine therapy in healthy people without heart disease. 5,6 It should also be noted that the class IB antiarrhythmic drugs lidocaine and mexiletine have a long record of use in people with ischemic heart disease. If used in people at risk, a repeat EKG should be considered at the target dose, mainly when the target dose (or the serum lamotrigine level) is near or above the upper limit of the therapeutic range, and always in the presence of concomitant use of other sodium channel blockers or substances known to impair atrioventricular and/or intraventricular cardiac conduction. Because concomitant use of such drugs put people at increased risk of impaired cardiac conduction when adding lamotrigine, an initial EKG should also be performed.

Background In persons with Parkinson’s Disease (PD) or certain forms of atypical parkinsonism, orthostatic hypotension is common and disabling, yet often underrecognized and undertreated. About half of affected individuals also exhibit supine hypertension. This common co-occurrence of both orthostatic hypotension and supine hypertension complicates pharmacological treatments as the treatment of the one can aggravate the other. Whole-body head-up tilt sleeping (HUTS) is the only known intervention that may improve both. Evidence on its effectiveness and tolerability is, however, lacking, and little is known about the implementability. Methods In this double-blind multicenter randomized controlled trial (phase II) we will test the efficacy and tolerability of HUTS at different angles in 50 people with PD or parkinsonism who have both symptomatic orthostatic hypotension and supine hypertension. All participants start with one week of horizontal sleeping and subsequently sleep at three different angles, each maintained for two weeks. The exact intervention will vary between the randomly allocated groups. Specifically, the intervention group will consecutively sleep at 6°, 12° and 18°, while the delayed treatment group starts with a placebo angle (1°), followed by 6° and 12°. We will evaluate tolerability using questionnaires and compliance to the study protocol. The primary endpoint is the change in average overnight blood pressure measured by a 24-hour ambulatory blood pressure recording. Secondary outcomes include orthostatic blood pressure, orthostatic tolerance, supine blood pressure, nocturia and various other motor and non-motor tests and questionnaires. Discussion We hypothesize that HUTS can simultaneously alleviate orthostatic hypotension and supine hypertension, and that higher angles of HUTS are more effective but less tolerable. The Heads-Up trial will help to clarify the effectiveness, tolerability, and feasibility of this intervention at home and can guide at-home implementation. Trial registration ClinicalTrials.gov NCT05551377; Date of registration: September 22, 2022.

To systematically summarize the evidence of head-up tilt sleeping (HUTS) on orthostatic tolerance, we conducted a systematic, predefined search in PubMed, OVID Embase, Cochrane and Web of Science. We included studies assessing the effect of HUTS on orthostatic tolerance and other cardiovascular measures and rated the quality with the American Academy of Neurology risk of bias tool. We included 10 studies (n = 185) in four groups: orthostatic hypotension (OH; 6 studies, n = 103), vasovagal syncope (1 study, n = 12), nocturnal angina pectoris (1 study, n = 10) and healthy subjects (2 studies, n = 58). HUTS duration varied (1 day–4 months) with variable inclinations (5°–15°). In two of six OH studies, HUTS significantly improved standing systolic blood pressure. Orthostatic tolerance was consistently enhanced in OH studies with higher angles (≥12°), in 2 out of 3 with smaller angles (5°) but also in one studying horizontal sleeping. In vasovagal syncope, HUTS significantly augmented resilience to extreme orthostatic stress. One study was rated as a class II risk of bias, one of Class II/III and eight of Class IV. The evidence favouring HUTS to improve orthostatic tolerance is weak due to variable interventions, populations, small samples and a high risk of bias. Despite this, we found some physiological signs suggesting a beneficial effect.

Objective Antiseizure medications (ASMs), which may influence cortical excitability, are the mainstay of epilepsy treatment. Transcranial magnetic stimulation (TMS) helps evaluate cortical excitability. We assessed changes in TMS responses using serial TMS measurements in people treated with an adjunctive noncompetitive AMPA‐receptor antagonist. Methods We included adults with refractory, active epilepsy (≥ 1 seizure/month), advised to start adjunctive treatment with the noncompetitive AMPA‐receptor antagonist perampanel as outpatients. After informed consent, we performed TMS measurement at three points: baseline before starting perampanel, at around 2 months after starting (4 mg/day), and at a final/effective dose around 6 months. Dependent on seizure reduction (> 50%), participants were dichotomized into responders (Rs) and nonresponders (NRs). We compared changes in motor cortex excitability through the rMT using a linear mixed‐effects model. We evaluated TMS‐evoked potentials (TEPs) to single pulse and paired pulse using within‐subject Monte Carlo–based permutation analysis. Results We included 18 adults, of whom 17 (6 R, 11 NR, 1 lost to follow‐up) had baseline and second‐month measurements, and nine (4 R, 5 NR) had all three. In responders, motor cortex excitability, quantified by rMT, significantly increased with increasing dose. Conversely, no significant changes were seen in the NR subgroup. TEPs for the single pulse and paired pulse showed no significant clusters for any peaks between measurement and group comparisons. Interpretation The TEPs showed no significant changes between measurements and/or groups. Motor cortex excitability quantified by rMT is a potential biomarker to track or predict treatment outcomes in people starting adjunctive perampanel for epilepsy.

Abstract Introduction: Orthostatic hypotension is common in people with Parkinson’s disease (PD) due to autonomic dysfunction and medication use and can have a significant negative impact on quality of life. Pharmacological treatment is often complicated due to complex blood pressure regulation problems. This case report presents a patient whose symptoms of orthostatic intolerance were successfully treated with the non-pharmacological method of head-up tilt sleeping (HUTS). Case Presentation: A 69-year-old man with PD and prominent autonomic failure received recommendation from the neurologist to use HUTS to battle orthostatic intolerance, of which complaints were worst in the early morning. The patient noted a marked improvement of the orthostatic intolerance after a period in which he slowly step-by-step inclined the bed to an angle just over 10°. When ceasing HUTS for a brief period, complaints of orthostatic intolerance immediately returned and the patient returned to tilted sleeping right away. After a follow-up of 3 months, the patient did not report orthostatic intolerance during a standing test. Conclusion: This case illuminates that, despite difficulties intrinsic to this method, whole-body HUTS can ameliorate orthostatic intolerance and improve the daily life of people with advanced movement disorders.