A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers

Desentrañando los misterios de la muerte súbita en epilepsia

INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is the most frequent cause of premature death in epileptic patients. Most SUDEP events occur at night and frequently go unnoticed; the exact pathophysiological mechanisms of this phenomenon therefore remain undetermined. Nevertheless, most cases of SUDEP are attributed to an infrequent yet extremely severe complication of epileptic seizures. DEVELOPMENT: We conducted a systematic literature search on PubMed. Our review article summarises scientific evidence on the classification, pathophysiological mechanisms, risk factors, biomarkers, and prevention of SUDEP. Likewise, we propose new lines of research and critically analyse findings that are relevant to clinical practice. CONCLUSIONS: Current knowledge suggests that SUDEP is a heterogeneous phenomenon caused by multiple factors. In most cases, however, SUDEP is thought to be due to postictal cardiorespiratory failure triggered by generalised tonic-clonic seizures and ultimately leading to cardiac arrest. The underlying pathophysiological mechanism involves multiple factors, ranging from genetic predisposition to environmental factors. Risk of SUDEP is higher in young adults with uncontrolled generalised tonic-clonic seizures. However, patients apparently at lower risk may also experience SUDEP. Current research focuses on identifying genetic and neuroimaging biomarkers that may help determine which patients are at high risk for SUDEP. Antiepileptic treatment is the only preventive measure proven effective to date. Night-time monitoring together with early resuscitation may reduce the risk of SUDEP

Did the COVID-19 pandemic silence the needs of people with epilepsy?

The COVID-19 pandemic shook European healthcare systems, with unavoidable gaps in the management of patients with chronic diseases. We describe the impact of the pandemic on epilepsy care in three tertiary epilepsy centres from Spain and Italy, the most affected European countries. The three epilepsy centres, members of the European EpiCARE network, manage more than 5,700 people with epilepsy. In Bologna and Barcelona, the hospitals housing the epilepsy centres were fully converted into COVID-19 units. We describe the reorganization of the clinics and report on the frequency of SARS-CoV-2 in people with epilepsy as well as the frequency of seizures in patients admitted to the COVID units. Finally, we elaborate on critical issues regarding the second phase of the pandemic. The activities related to epilepsy care were reduced to less than 10% and were deprioritized. Discharges were expedited and elective epilepsy surgeries, including vagal nerve stimulator implantations, cancelled. Hospitalizations and EEG examinations were limited to emergencies. The outpatient visits for new patients were postponed, and follow-up visits mostly managed by telehealth. Antiseizure medication weaning plans and changes in vagal nerve stimulator settings were halted. Among the 5,700 people with epilepsy managed in our centres, only 14 tested positive for SARS-CoV-2, without obvious impact on their epilepsy. None of the 2,122 patients admitted to COVID units experienced seizures among the early symptoms. Epilepsy care was negatively impacted by the pandemic, irrespective of COVID-19 epidemiology or conversion of the hospital into a COVID-19 centre. The pandemic did not silence the needs of people with epilepsy, and this must be considered in the planning of the second phase

A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement No. 616268 F-TRACT, the European Union’s Horizon 2020 Framework Programme for Research and Innovation under Specific Grant Agreement No. 785907 and 945539 (Human Brain Project SGA2 and SGA3) and from the French ‘Investissements d’avenir’ programme under grant numbers ANR-11-INBS-0006 and ANR-10-IAIHU-06. P.H. was supported by Swiss National Science Foundation grant #CRSII5_170873

Evaluation of the density spectral array in the Wada test: report of six cases

Wada test is an invasive procedure used in the preoperative evaluation for epilepsy surgery to determine language lateralization, postoperative risk of amnesia syndrome, and to assess the risk of memory deficits. It involves injection of amobarbital into internal carotid artery of the affected hemisphere followed by the healthy hemisphere to shut down brain function. We performed an observational study evaluating the density spectral array (DSA) of the bilateral bispectral index VISTA™ Monitoring System (BVMS) in 6 patients with drug-resistant epilepsy undergoing Wada test. DSA revealed the presence of bifrontal alpha waves in absence of loss of consciousness in all patients

Degenerate time-dependent network dynamics anticipate seizures in human epileptic brain

Epileptic seizures are known to follow specific changes in brain dynamics. While some algorithms can nowadays robustly detect these changes, a clear understanding of the mechanism by which these alterations occur and generate seizures is still lacking. Here, we provide crossvalidated evidence that such changes are initiated by an alteration of physiological network state dynamics. Specifically, our analysis of long intracranial electroencephalography (iEEG) recordings from a group of 10 patients identifies a critical phase of a few hours in which time-dependent network states become less variable ("degenerate"), and this phase is followed by a global functional connectivity reduction before seizure onset. This critical phase is characterized by an abnormal occurrence of highly correlated network instances and is shown to be particularly associated with the activity of the resected regions in patients with validated postsurgical outcome. Our approach characterizes preseizure network dynamics as a cascade of 2 sequential events providing new insights into seizure prediction and control

Detection of recurrent activation patterns across focal seizures: Application to seizure onset zone identification

OBJECTIVE: We introduce a method that quantifies the consistent involvement of intracranially monitored regions in recurrent focal seizures. METHODS: We evaluated the consistency of two ictal spectral activation patterns (mean power change and power change onset time) in intracranial recordings across focal seizures from seven patients with clinically marked seizure onset zone (SOZ). We examined SOZ discrimination using both patterns in different frequency bands and periods of interest. RESULTS: Activation patterns were proved to be consistent across more than 80% of recurrent ictal epochs. In all patients, whole-seizure mean activations were significantly higher for SOZ than non-SOZ regions (P<0.05) while activation onset times were significantly lower for SOZ than for non-SOZ regions (P<0.001) in six patients. Alpha-beta bands (8-20Hz) achieved the highest patient-average effect size on the whole-seizure period while gamma band (20-70Hz) achieved the highest discrimination values between SOZ and non-SOZ sites near seizure onset (0-5s). CONCLUSIONS: Consistent spectral activation patterns in focal epilepsies discriminate the SOZ with high effect sizes upon appropriate selection of frequency bands and activation periods. SIGNIFICANCE: The present method may be used to improve epileptogenic identification as well as pinpoint additional regions that are functionally altered during ictal events.The research was supported by the European Union’s Horizon2020 research and innovation program under Grant AgreementNo. 720270. M.V. was supported by the Catalan Research projectAL08814 - AGAUR - 2014SGR856. G.D. was supported by the Euro-pean Research Council Advanced Grant DYSTRUCTURE (Grant295129) and by the Spanish Research Project AEI/FEDER-PSI2016–75688-P. A.T.C. was supported by the European ResearchCouncil Advanced Grant DYSTRUCTURE (Grant 295129) and by theSpanish Research Project AEI/FEDER-PSI2016–75688-P

Mood disturbances, anxiety, and impact on quality of life in patients admitted to epilepsy monitoring units

Introduction: the overall combined prevalence of anxiety and depression in patients with epilepsy has been estimated at 20.2 and 22.9%, respectively, and is considered more severe in drug-refractory epilepsy. Patients admitted to epilepsy monitoring units constitute a particular group. Also, patients with psychogenic non-epileptic seizures can reach more than 20% of all admissions. This study aims to characterize these symptoms in a large cohort of patients admitted for evaluation in a tertiary epilepsy center. Materials and Methods: the study was conducted among 493 consecutive patients (age: 38.78 ± 12.7, 57% females) admitted for long-term video EEG from January 2013 to February 2021. Demographic, clinical, and mood disorder patients' data were collected. Anxiety and depression symptoms were assessed through the Hospital Anxiety Depression Scale (HADS-A and HADS-D), the State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI-II). Quality of life was determined using the QOLIE-10. Patients were divided into three groups: patients with epilepsy (n = 395), psychogenic non-epileptic seizures (PNES) (n = 56), and combined (n = 33). A univariate and multivariate regression analysis was performed for variables associated with quality of life. Results: of 493 patients, 45.0% had structural etiology, and considering epilepsy classification, 43.6% were of temporal lobe origin. In addition, 32.45% of patients had a previous psychiatric history, 49.9% of patients had depressive symptoms in BDI, and 30.9% according to HADS-D; 56.42 and 52.63% of patients presented pathological anxiety scores in STAI-T and STAI-S, respectively; and 44.78% according to HADS-A. PNES and combined groups revealed a higher incidence of pathologic BDI scores (64.29 and 78.79%, p 13 (females = 56.6%, males = 41.0%; p = 0.0006). QOLIE-10 showed that 71% of the patients had their quality of life affected with significantly higher scores in the combined group than in the epilepsy and PNES groups (p = 0.0015). Conclusions: subjective anxiety, depression, and reduced quality of life are highly prevalent in patients with refractory epilepsy. These symptoms are more evident when PNES are associated with epilepsy and more severe among female patients. Most of the cases were not previously diagnosed. These factors should be considered in everyday clinical practice, and specific approaches might be adapted depending on the patient's profile