Ezogabine impacts seizures and development in patients with KCNQ2 developmental and epileptic encephalopathy

Tipologia: BRIEF COMMUNICATION

2023-04-25

Abstract

Genetic variants in KCNQ2 are associated with a range of epilepsies, from self- limited (familial) neonatal-infantile epilepsy to developmental and epileptic encephalopathy (DEE). We retrospectively reviewed clinical data from eight patients with KCNQ2-related DEE who were treated with ezogabine. Treatment was initiated at a median age of 8 months (range 7 weeks to 2.5 years) and continued for a median of 2.6 years (range 7 months to 4.5 years). Five individuals had daily seizures at baseline and experienced at least 50% seizure reduction with treatment, sustained in four. One individual with two to four yearly seizures improved to rare events. Two individuals were seizure-free; treatment targeted cognition and development. Developmental improvements were reported in all eight patients. Weaning of ezogabine was associated with increased seizure frequency (N = 4), agitation and irritability (N = 2), poor sleep (N = 1), and developmental regression (N = 2). These data suggest that treatment with ezogabine is effective at reducing seizure burden and is associated with improved development. Minimal side effects were observed. Weaning was associated with increased seizures and behavioral disturbances in a subset. An approach targeting potassium channel dysfunction with ezogabine is warranted in patients with KCNQ2-related DEE.

Fonte: Epilepsia, Devon Knight, Sonal Mahida, Mckenna Kelly, Annapurna Poduri, Heather E. Olson

Early timing of anesthesia in status epilepticus is associated with complete recovery: A 7‐year retrospective two‐center study

Tipologia: RESEARCH ARTICLE

2023-04-25

Abstract

Objective

This study was undertaken to investigate the efficacy, tolerability, and outcome of different timing of anesthesia in adult patients with status epilepticus (SE).

Methods

Patients with anesthesia for SE from 2015 to 2021 at two Swiss academic medical centers were categorized as anesthetized as recommended third-line treatment, earlier (as first- or second-line treatment), and delayed (later as third-line treatment). Associations between timing of anesthesia and in-hospital outcomes were estimated by logistic regression.

Results

Of 762 patients, 246 received anesthesia; 21% were anesthetized as recommended, 55% earlier, and 24% delayed. Propofol was preferably used for earlier (86% vs. 55.5% for recommended/delayed anesthesia) and midazolam for later anesthesia (17.2% vs. 15.9% for earlier anesthesia). Earlier anesthesia was statistically significantly associated with fewer infections (17% vs. 32.7%), shorter median SE duration (.5 vs. 1.5 days), and more returns to premorbid neurologic function (52.9% vs. 35.5%). Multivariable analyses revealed decreasing odds for return to premorbid function with every additional nonanesthetic antiseizure medication given prior to anesthesia (odds ratio [OR] = .71, 95% confidence interval [CI] = .53–.94) independent of confounders. Subgroup analyses revealed decreased odds for return to premorbid function with increasing delay of anesthesia independent of the Status Epilepticus Severity Score (STESS; STESS = 1-2: OR = .45, 95% CI = .27–.74; STESS > 2: OR = .53, 95% CI = .34–.85), especially in patients without potentially fatal etiology (OR = .5, 95% CI = .35–.73) and in patients experiencing motor symptoms (OR = .67, 95% CI = .48–.93).

Significance

In this SE cohort, anesthetics were administered as recommended third-line therapy in only every fifth patient and earlier in every second. Increasing delay of anesthesia was associated with decreased odds for return to premorbid function, especially in patients with motor symptoms and no potentially fatal etiology.

Fonte: Epilepsia, Pia De Stefano, Sira M. Baumann, Pascale Grzonka, Oana E. Sarbu, Gian Marco De Marchis, Sabina Hunziker, Stephan Rüegg, Andreas Kleinschmidt, Hervé Quintard, Stephan Marsch, Margitta Seeck, Raoul Sutter

Familial Adult Myoclonus Epilepsy: neuroimaging and neuropathological findings

Tipologia: SPECIAL ISSUE ARTICLE

2023-04-25

Abstract

Familial adult myoclonus epilepsy (FAME) is characterized by cortical myoclonus and often epileptic seizures, but the pathophysiology of this condition remains uncertain. Here, we review the neuroimaging and neuropathological findings in FAME. Imaging findings, including functional MRI, are in line with a cortical origin of involuntary tremulous movements (cortical myoclonic tremor) and indicate a complex pattern of cerebellar functional connectivity. Scarce neuropathological reports, mainly from single families, provide evidence of morphological changes in the Purkinje cells. Cerebellar changes seem to be part of the syndrome, in at least some FAME pedigrees. Cortical hyperexcitability in FAME, resulting in the cardinal clinical symptoms might be the result of decreased cortical inhibition via the cerebellothalamocortical loop. The pathological findings might share some similarities with other pentanucleotide repeat disorders. The relation with genetic findings in FAME needs to be elucidated.

Fonte: Epilepsia, Anne‐Fleur van Rootselaar, Sirio Cocozza, Eleonora Aronica, Pasquale Striano

Seizure onset patterns predict outcome after stereo‐electroencephalography‐guided laser amygdalohippocampotomy

Tipologia: RESEARCH ARTICLE

2023-04-25

Abstract

Objective

Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom.

Methods

This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category.

Results

Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015).

Significance

Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Fonte: Epilepsia, Andrew J. Michalak, Adam Greenblatt, Shasha Wu, Steven Tobochnik, Hina Dave, Ramya Raghupathi, Yasar T. Esengul, Antonio Guerra, James X. Tao, Naoum P. Issa, Garth R. Cosgrove, Bradley Lega, Peter Warnke, H. Isaac Chen, Timothy Lucas, Sameer A. Sheth, Garrett P. Banks, Churl‐Su Kwon, Neil Feldstein, Brett Youngerman, Guy McKhann, Kathryn A. Davis, Catherine A. Schevon

Actigraphic correlates of neuropsychiatric symptoms in adults with focal epilepsy

Tipologia: RESEARCH ARTICLE

2023-04-24

Abstract

Objectives

Disability in patients with epilepsy (PWEs) is multifactorial: beyond seizure frequency/severity, PWEs are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly affect quality of life. Here, we explored how variations in seizure severity and the burden of self-reported somatic/neuropsychiatric symptoms correlate with disruptions to 24 h activity patterns (rest-activity rhythms [RARs]), determined through wrist accelerometry/actigraphy.

Methods

Multiday wrist-actigraphy recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18–72), who contemporaneously responded to validated psychometric instruments to measure anxiety, depression, sleepiness, and somatic symptoms. We conducted a similar in silico psychometric-actigraphic correlation in a publicly available data set of 1747 Hispanic subjects (35% male, ages 18–65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying amplitude, steepness, acrophase, and robustness) and nonparametric measures to estimate RAR stability, fragmentation, and sleep.

Results

Compared with matched SOL subjects, RARs from PWE subjects featured a significantly lower amplitude, a wider rest phase, and significantly more total daily sleep. Within PWEs, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy, whereas high anxiety, depression, and somatic symptom scores were associated with lower RAR robustness and acrophase delay. We applied the SOL data set to train logistic regression models to dichotomously classify subjective anxiety, depression, and sleepiness symptoms using demographic and RAR parameters. When tested on PWEs, these models predicted prevalent anxiety and depression symptom burden (accuracy ~70%) but failed to predict subjective sleepiness.

Significance

Together these results demonstrate that RAR features may encode prevalent depression and anxiety symptoms in patients with focal epilepsy, potentially offering wearable-derived endpoints to adjunct clinical care and drug/device trials. With larger PWE-specific actigraphic-psychometric data sets, we may identify RAR signatures that may more precisely correlate with varying seizure frequency, the burden of anticonvulsant therapy, and prevalent mood/anxiety symptoms.

Fonte: Epilepsia, Mark A. Abboud, Jessica L. Kamen, John S. Bass, Lu Lin, Jay R. Gavvala, Sindhu Rao, Stephen F. Smagula, Vaishnav Krishnan

Changes in local and network brain activity after stereotactic thermocoagulation in patients with drug‐resistant epilepsy

Tipologia: RESEARCH ARTICLE

2023-04-24

Abstract

Objective

Stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RF-TC) aims to reduce seizure frequency by modifying epileptogenic networks through local thermocoagulative lesions. Although RF-TC is hypothesized to functionally modify brain networks, reports of changes in functional connectivity (FC) following the procedure are missing. We evaluated, by means of SEEG recordings, whether variation in brain activity after RF-TC is related to clinical outcome.

Methods

Interictal SEEG recordings from 33 patients with drug-resistant epilepsy (DRE) were analyzed. Therapeutic response was defined as a >50% reduction in seizure frequency for at least 1 month following RF-TC. Local (power spectral density [PSD]) and FC changes were evaluated in 3-min segments recorded shortly before (baseline), shortly after, and 15 min after RF-TC. The PSD and FC strength values after thermocoagulation were compared with baseline as well as between the responder and nonresponder groups.

Results

In responders, we found a significant reduction in PSD after RF-TC in channels that were thermocoagulated for all frequency bands (p = .007 for broad, delta and theta, p <.001 for alpha and beta bands). However, we did not observe such PSD decrease in nonresponders. At the network level, nonresponders displayed a significant FC increase in all frequency bands except theta (broad, delta, beta band: p <.001; alpha band: p <.01), although responders showed a significant FC decrease in delta (p <.001) and alpha bands (p <.05). Nonresponders showed stronger FC changes with respect to responders exclusively in TC channels (broad, alpha, theta, beta: p >.05; delta: p = .001).

Significance

Thermocoagulation induces both local and network-related (FC) changes in electrical brain activity of patients with DRE lasting for at least 15 min. This study demonstrates that the observed short-term modifications in brain network and local activity significantly differ between responders and nonresponders and opens new perspectives for studying the longer-lasting FC changes after RF-TC.

Fonte: Epilepsia, Sara Simula, Elodie Garnier, Margherita Contento, Francesca Pizzo, Julia Makhalova, Stanislas Lagarde, Christian‐George Bénar, Fabrice Bartolomei

Intracerebroventricular administration for delivery of antiseizure therapeutics: Challenges and opportunities

Tipologia: CRITICAL REVIEW

2023-04-22

SUMMARY

Intracerebroventricular (ICV) administration is being increasingly explored as a means for delivering antiseizure and antiepileptic therapies to epileptic brain tissue. This route bypasses the BBB, thus enabling the delivery of therapeutics that are restricted from the brain, while reducing the risk of systemic adverse reactions. Nevertheless, projections from studies in patients with other diseases suggest that efficacy of some ICV-delivered therapeutics may be limited when the epileptogenic tissue or network circuits are localized more than a few millimeters away from the ventricles. In this article, we present the characteristics of the CSF as a drug administration site, the brain barriers, and their relevance to treating focal and generalized epilepsies. We refer to ICV delivery of advanced therapies for treating neurodevelopmental disorders with epilepsy. We describe properties of therapeutic compounds, from small molecules to RNA-based therapeutics, proteins, and viral vectors, which can make them either fitting or poor candidates for ICV administration in epilepsy. We additionally provide an overview of preclinical studies and clinical trials involving the ICV route of delivery. Finally, we compare ICV delivery with other routes of administration that bypass the cerebral circulation. This review aims to provide information that can help investigators select candidate patients and therapeutics for ICV therapies, and to highlight advantages and challenges inherent to this approach.

Fonte: Epilepsia, Firas Fahoum, Sara Eyal

Domain‐specific relationships of subjective and objective cognition in epilepsy

Tipologia: RESEARCH ARTICLE

2023-04-21

Abstract

Objective

Many people with epilepsy report subjective cognitive impairment (SCI), i.e., problems with memory, attention or executive functions, reducing quality of life. Nevertheless, overlap with objective cognitive impairment (OCI) is often weak. One reason may be a domain-specific mismatch between subjective reports and objective tests. We aimed to evaluate relations between SCI and OCI of corresponding domains and to assess whether these differ between persons that over- or underestimate their performance.

Methods

In this prospective, cross-sectional sample of 104 adult in-patients with epilepsy, we performed multiple regression analyses predicting SCI in the domains attention, memory and executive functions. We tested relationships with measures of psychomotor speed, short-term memory, verbal learning, verbal delayed recall, and word fluency while controlling for age, sex, seizure frequency, structural lesions, mono- vs. polytherapy and adverse events of antiseizure medication (ASM), depressive and anxiety symptoms, level of education, and employment status. Furthermore, we tested whether these relationships differed between realistic raters and over- and underestimators.

Results

We found domain-specific relations for attention and executive functions for the full sample, explaining a small proportion of variance of SCI (General dominance index [GDI] 0.03 and 0.004), whereas ASM adverse events and psychological variables were more important predictors. When dividing the sample according to the concordance of SCI and OCI, we found high frequencies of both over- (23-46%) and underestimation (31-35%) depending on the domain. The explanatory power of OCI for SCI was stronger within the subgroups compared to the full sample, suggesting non-linear relationships and different underlying mechanisms for realistic raters, underestimators and overestimators.

Significance

Domain-specific SCI and OCI are related, and both should be assessed with standardized instruments. These relationships differ between over- and underestimators as well as realistic raters. Based on the concordance of self-ratings and objective measures, tailored counseling and treatment should be offered.

Fonte: Epilepsia, Louisa Hohmann, Justus Berger, Shirley‐Uloma Kastell, Martin Holtkamp

SUDEP counseling: Where do we stand?

Tipologia: CRITICAL REVIEW

2023-04-21

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in children and adults living with epilepsy. Several recent clinical practice guidelines have recommended that all individuals living with epilepsy and their caregivers be informed about SUDEP as a part of routine epilepsy counseling. Furthermore, several studies over the last two decades have explored the state of SUDEP counseling. Patients with epilepsy and their families want to be informed about the risk of SUDEP at or near the time of diagnosis, and preferably in person. Despite guideline recommendations, many pediatric and adult neurologists do not routinely inform individuals with epilepsy and their families about SUDEP. Some neurologists discuss SUDEP with only a subset of patients with epilepsy, such as those with risk factors like frequent generalized or focal to bilateral tonic–clonic seizures, nocturnal seizures, noncompliance, or medically refractory epilepsy. Proponents of routine SUDEP counseling argue that patients with epilepsy and their families have a “right to know” and that counseling may positively impact epilepsy self-management (i.e., behavioral modification and risk reduction). Some neurologists still believe that SUDEP counseling may cause unnecessary stress and anxiety for patients and their families (although this is erroneous) and that they also have a “right not to know.” This narrative review explores the current gaps in SUDEP counseling, patients' and caregivers' perspectives of SUDEP counseling, and SUDEP prevention.

Fonte: Epilepsia, Robyn Whitney, Kevin C. Jones, Suvasini Sharma, Rajesh RamachandranNair

Seizure occurrence is linked to multiday cycles in diverse physiological signals

Tipologia: RESEARCH ARTICLE

2023-04-20

Abstract

Objective

The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing.

Methods

In this cohort study, 14 subjects underwent chronic ambulatory monitoring with a multimodal wrist-worn sensor (recording heart rate, accelerometry, electrodermal activity, and temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities and electrographic seizures). Wavelet and filter–Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology.

Results

Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable electroencephalographic seizure detections (mean = 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal.

Significance

Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time-varying approaches to epilepsy care.

Fonte: Epilepsia, Nicholas M. Gregg, Tal Pal Attia, Mona Nasseri, Boney Joseph, Philippa Karoly, Jie Cui, Rachel E. Stirling, Pedro F. Viana, Thomas J. Richner, Ewan S. Nurse, Andreas Schulze‐Bonhage, Mark J. Cook, Gregory A. Worrell, Mark P. Richardson, Dean R. Freestone, Benjamin H. Brinkmann