ORCID Profile
0000-0002-7855-7066
Current Organisations
University of Melbourne
,
Austin Health
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Publisher: Wiley
Date: 27-09-2021
DOI: 10.1002/AJMG.A.62505
Abstract: Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as “all focal epilepsy” and “all genetic generalized epilepsy”. In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or “microphenotype” may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome‐wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau–Kleffner patients ( GRIN2A ) and pediatric status epilepticus patients ( MECP2, SCN1A, SCN2A, SCN8A ).
Publisher: Wiley
Date: 02-10-2015
Publisher: Wiley
Date: 08-07-2023
DOI: 10.1002/EPD2.20093
Abstract: The pharmacological treatment of epilepsy entails several critical decisions that need to be based on an in idual careful risk–benefit analysis. These include when to initiate treatment and with which antiseizure medication (ASM). With more than 25 ASMs on the market, physicians have opportunities to tailor the treatment to in idual patients´ needs. ASM selection is primarily based on the patient's type of epilepsy and spectrum of ASM efficacy, but several other factors must be considered. These include age, sex, comorbidities, and concomitant medications to mention the most important. In idual susceptibility to adverse drug effects, ease of use, costs, and personal preferences should also be taken into account. Once an ASM has been selected, the next step is to decide on an in idual target maintenance dose and a titration scheme to reach this dose. When the clinical circumstances permit, a slow titration is generally preferred since it is associated with improved tolerability. The maintenance dose is adjusted based on the clinical response aiming at the lowest effective dose. Therapeutic drug monitoring can be of value in efforts to establish the optimal dose. If the first monotherapy fails to control seizures without significant adverse effects, the next step will be to gradually switch to an alternative monotherapy, or sometimes to add another ASM. If an add‐on is considered, combining ASMs with different modes of action is usually recommended. Misdiagnosis of epilepsy, non‐adherence and suboptimal dosing are frequent causes of treatment failure and should be excluded before a patient is regarded as drug‐resistant. Other treatment modalities, including epilepsy surgery, neuromodulation, and dietary therapies, should be considered for truly drug‐resistant patients. After some years of seizure freedom, the question of ASM withdrawal often arises. Although successful in many, withdrawal is also associated with risks and the decision needs to be based on careful risk–benefit analysis.
Publisher: Elsevier BV
Date: 07-2021
Publisher: American Medical Association (AMA)
Date: 10-2022
DOI: 10.1001/JAMANEUROL.2022.2456
Abstract: Neurocritical care (NCC) aims to improve the outcomes of critically ill patients with brain injury, although the benefits of such subspecialized care are yet to be determined. To evaluate the association of NCC with patient-centered outcomes in adults with acute brain injury who were admitted to intensive care units (ICUs). The protocol was preregistered on PROSPERO ( CRD42020177190 ). Three electronic databases were searched (Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials) from inception through December 15, 2021, and by citation chaining. Studies were included for interventions of neurocritical care units (NCCUs), neurointensivists, or NCC consulting services compared with general care in populations of neurologically ill adults or adults with acute brain injury in ICUs. Data extraction was performed in keeping with PRISMA guidelines and risk of bias assessed through the ROBINS-I Cochrane tool by 2 independent reviewers. Data were pooled using a random-effects model. The primary outcome was all-cause mortality at longest follow-up until 6 months. Secondary outcomes were ICU length of stay (LOS), hospital LOS, and functional outcomes. Data were measured as risk ratio (RR) if dichotomous or standardized mean difference if continuous. Subgroup analyses were performed for disease and models of NCC delivery. After 5659 nonduplicated published records were screened, 26 nonrandomized observational studies fulfilled eligibility criteria. A meta-analysis of mortality outcomes for 55 792 patients demonstrated a 17% relative risk reduction (RR, 0.83 95% CI, 0.75-0.92 P = .001) in those receiving subspecialized care (n = 27 061) compared with general care (n = 27 694). Subgroup analyses did not identify subgroup differences. Eight studies including 4667 patients demonstrated a 17% relative risk reduction (RR, 0.83 95% CI, 0.70-0.97 P = .03) for an unfavorable functional outcome with subspecialized care compared with general care. There were no differences in LOS outcomes. Heterogeneity was substantial in all analyses. Subspecialized NCC is associated with improved survival and functional outcomes for critically ill adults with brain injury. However, confidence in the evidence is limited by substantial heterogeneity. Further investigations are necessary to determine the specific aspects of NCC that contribute to these improved outcomes and its cost-effectiveness.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2019
DOI: 10.1212/WNL.0000000000006776
Abstract: To examine the prevalence and risk factors of sleep-disordered breathing (SDB) in in iduals with epilepsy and psychogenic nonepileptic seizures (PNES). We conducted a cross-sectional study of consecutive patients admitted for inpatient video-EEG monitoring at The Royal Melbourne Hospital, Australia, between December 1, 2011, and July 31, 2017. Participants underwent routine clinical investigations during their monitoring period including polysomnography, neurocognitive testing, and screening instruments of daytime somnolence, sleep quality, and quality of life. Our study population consisted of 370 participants who received a diagnosis of epilepsy (n = 255), PNES (n = 93), or both disorders (n = 22). Moderate to severe SDB (defined by an apnea-hypopnea index ≥15) was observed in 26.5% (98/370) of in iduals, and did not differ across subgroups: epilepsy 26.3% (67/255), PNES 29.0% (27/93), or both disorders 18.2% (4/22 p = 0.610). Following adjustment for confounders, pathologic daytime sleepiness predicted moderate to severe SDB in epilepsy (odds ratio [OR] 10.35, 95% confidence interval [CI] 2.09–51.39 p = 0.004). In multivariable analysis, independent predictors for moderate to severe SDB in epilepsy were older age (OR 1.07, 95% CI 1.04–1.10 p 0.001) and higher body mass index (OR 1.06, 95% CI 1.01–1.11 p = 0.029), and in PNES older age (OR 1.10, 95% CI 1.03–1.16 p = 0.002). Polysomnography during inpatient video-EEG monitoring identified a substantial number of patients with undiagnosed SDB. This was remarkable in the subgroup with PNES, who were often female and obese. Identification of risk factors may improve management of SDB in these populations. The association with pathologic daytime sleepiness suggests that SDB may be an important contributor to these common and disabling symptoms in patients with epilepsy.
Publisher: Wiley
Date: 04-07-2023
DOI: 10.1002/EPD2.20090
Abstract: A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions. 1 This left the family with many questions unanswered in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1111/J.1528-1167.2012.03589.X
Abstract: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta-analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non-assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose-response relationships of identified AEs. Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12-18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness) six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting) nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE-related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug-resistant epilepsy compared with patients with other disorders. A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.
Publisher: Wiley
Date: 07-2015
DOI: 10.1111/EPI.13029
Publisher: Springer Science and Business Media LLC
Date: 03-05-2018
DOI: 10.1038/NRDP.2018.24
Abstract: Epilepsy affects all age groups and is one of the most common and most disabling neurological disorders. The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences. Although many patients have seizure control using a single medication, others require multiple medications, resective surgery, neuromodulation devices or dietary therapies. In addition, one-third of patients will continue to have uncontrolled seizures. Epilepsy can substantially impair quality of life owing to seizures, comorbid mood and psychiatric disorders, cognitive deficits and adverse effects of medications. In addition, seizures can be fatal owing to direct effects on autonomic and arousal functions or owing to indirect effects such as drowning and other accidents. Deciphering the pathophysiology of epilepsy has advanced the understanding of the cellular and molecular events initiated by pathogenetic insults that transform normal circuits into epileptic circuits (epileptogenesis) and the mechanisms that generate seizures (ictogenesis). The discovery of >500 genes associated with epilepsy has led to new animal models, more precise diagnoses and, in some cases, targeted therapies.
Publisher: Elsevier BV
Date: 11-2023
Publisher: Wiley
Date: 13-11-2022
DOI: 10.1002/EPI4.12662
Abstract: The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. This is the second in a two‐part series of omics papers, with the other including genomics, transcriptomics, and epigenomics. The aim of the CDEs was to improve the standardization of experimental designs across a range of epilepsy research‐related methods. We have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for proteomics, lipidomics, and metabolomics of s les from rodent models and people with epilepsy. We discuss the important elements that need to be considered for the proteomics, lipidomics, and metabolomics methodologies, providing a rationale for the parameters that should be documented.
Publisher: Wiley
Date: 06-09-2023
DOI: 10.1002/EPI4.12822
Abstract: Differentiating status epilepticus (SE) from prolonged psychogenic non‐epileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES. Retrospective two‐centre study investigating the sensitivity and specificity of acute (≤12 hours of event offset) peripheral cell counts, cell ratios (neutrophil‐lymphocyte ratio, neutrophil‐monocyte ratio, monocyte‐lymphocyte ratio, platelet‐lymphocyte ratio, systemic immune inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalised additive models to generate biomarker versus time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII or SIRI with lactate levels were developed and validated in separate cohorts. For the development cohort, 1262 seizure‐like events were reviewed and 79 SE and 44 pPNES events included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events included. In idually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with neutrophil count, SIRI and SII performing best with sensitivities of 0.65‐0.84, specificities of 0.64‐0.89, and ROC AUCs of 0.78‐0.79. Lactate levels peaked at 60 minutes, while cell counts and ratios peaked after 240 minutes. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75‐0.79, specificities between 0.93‐1.00, and ROC AUCs of 0.89‐0.91. Lactate levels peak early post‐SE, whereas cell counts and ratios do so later. The differing post‐event time profiles of lactate levels versus neutrophil count, SIRI and SII allows incorporation into three separate scores which can assist in differentiating SE from pPNES.
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2022
DOI: 10.1101/2022.08.22.22278046
Abstract: Prenatal exposure to certain antiseizure medications (ASMs) has been associated with increased risk of adverse neurodevelopmental outcomes in offspring. While the cognitive and intellectual outcomes of ASM-exposed offspring have been well-described, the long-term behavioural and functional sequalae in these children have received less attention. This systematic review aims to synthesise evidence on the relationship between prenatal ASM exposure and postnatal adverse neurodevelopmental outcomes, focusing on non-cognitive and intellectual domains of neurodevelopment including reduced social, emotional, behavioural, and adaptive functioning, as well as the frequency of neurodevelopmental and psychiatric disorders. This will have meaningful clinical implications for how we counsel women taking ASMs in pregnancy. Studies reporting predefined neurodevelopmental outcomes will be identified by electronic searches of MEDLINE, PsychINFO, EMBASE, as well as additional manual and grey literature searches. Eligible studies will report outcomes of offspring exposed to ASMs in utero either prospectively or retrospectively from 1990 to present, with screening performed in duplicate. We will use the Newcastle-Ottawa Scale to conduct methodological quality assessments of included observational studies. A narrative synthesis will be used to report on the review findings. Meta-analysis is not anticipated. Ethics clearance is not required for the current study. The systematic review will be prepared as a journal article and published in a peer-reviewed journal upon completion. PROSPERO CRD42021281919 Strengths and limitations of this study This protocol was developed and written according to the PRISMA-P guidelines Publication of this protocol ensures transparency and reproducibility of the methods of the systematic review, as well as reduces the likelihood of review duplication Restricting publications to English only may introduce bias whereby some relevant data is not included Meta-analysis is not likely to be possible due to heterogeneity in study methodology, reducing the strength of the conclusions that can be drawn Targeting psychosocial and behavioural outcomes allows for a more nuanced understanding of the long-term clinical consequences of prenatal ASM-exposure
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.YEBEH.2022.108960
Abstract: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 % from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p 1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.
Publisher: Hindawi Limited
Date: 07-03-2022
DOI: 10.1111/ANE.13609
Publisher: Wiley
Date: 12-01-2015
Publisher: Elsevier BV
Date: 10-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2020
DOI: 10.1097/WNP.0000000000000624
Abstract: In comatose patients, distinguishing between nonconvulsive status epilepticus and diffuse structural or metabolic encephalopathies is often challenging. Both conditions can generate periodic discharges on EEG with similar morphology and periodicity. We investigated the occurrence of high-frequency oscillations—potential biomarkers of epileptogenesis—on scalp EEG of comatose patients with periodic discharges in the EEG. Fifteen patients were included. Patients were ided into three groups, according to underlying etiology: Group 1, seizure related group 2, structural group 3, nonstructural. EEG recordings were compared with respect to the presence and rates of gamma (30–80 Hz) and ripples (80–250 Hz). Patients were 23 to 106 years old (median, 68 years) 60% were female. 206 channels were eligible for analysis (median, 15 channels atient). Overall, 43% of channels showed gamma, and 24% had ripples. Group 2 showed the highest proportion of channels with gamma (47%), followed by group 1 (38%) and group 3 (36%). Mean gamma rates were higher in group 2 (4.65 gamma/min/channel) than in group 1 (1.52) and group 3 (1.44) ( P 0.001). Group 2 showed the highest proportion of channels with ripples (29.2%), followed by group 1 (15%) and group 3 (24.2%). Mean ripple rates were higher in group 2 (5.09 ripple/min/channel) than in group 1 (0.96) and group 3 (0.83) ( P 0.001). Fast oscillations, including high-frequency oscillations, can be detected in scalp EEG of patients with altered consciousness. High rates of fast activity may suggest an underlying structural brain lesion. Future studies are needed to determine whether fast oscillations in the setting of acute/subacute brain lesions are a biomarker of subsequent development of human epilepsy.
Publisher: Wiley
Date: 16-02-2023
DOI: 10.1002/EPI4.12704
Abstract: Electroencephalogram (EEG) datasets from epilepsy patients have been used to develop seizure detection and prediction algorithms using machine learning (ML) techniques with the aim of implementing the learned model in a device. However, the format and structure of publicly available datasets are different from each other, and there is a lack of guidelines on the use of these datasets. This impacts the generatability, generalizability, and reproducibility of the results and findings produced by the studies. In this narrative review, we compiled and compared the different characteristics of the publicly available EEG datasets that are commonly used to develop seizure detection and prediction algorithms. We investigated the advantages and limitations of the characteristics of the EEG datasets. Based on our study, we identified 17 characteristics that make the EEG datasets unique from each other. We also briefly looked into how certain characteristics of the publicly available datasets affect the performance and outcome of a study, as well as the influences it has on the choice of ML techniques and preprocessing steps required to develop seizure detection and prediction algorithms. In conclusion, this study provides a guideline on the choice of publicly available EEG datasets to both clinicians and scientists working to develop a reproducible, generalizable, and effective seizure detection and prediction algorithm.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2021
DOI: 10.1212/WNL.0000000000012946
Abstract: We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. This international, multicenter, retrospective, nested case–control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, interquartile range [IQR] 32.6–52.6) than epilepsy controls (55.5, IQR 40.7–68.9 p = 0.015, critical value = 0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast −11.01, 95% confidence interval [CI] −20.29 to 1.73 p = 0.020, critical value = 0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI 0.95–0.995 p = 0.017, critical value = 0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP p = 0.002, critical value = 0.025). The survival model with normalized LFP was associated with SUDEP ( c statistic 0.66, 95% CI 0.55–0.77), which nonsignificantly increased with the addition of normalized HFP ( c statistic 0.70, 95% CI 0.59–0.81 p = 0.209). Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify in idual SUDEP risk. This study provides Class III evidence that in patients with epilepsy, some measures of HRV are associated with SUDEP.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/EPI.12075
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.YEBEH.2022.108848
Abstract: To utilize data from the Australian Register of Antiepileptic Drugs in Pregnancy (APR) to determine the hazard of fetal malformation in the subsequent pregnancy or pregnancies in women with epilepsy following a pregnancy associated with a fetal malformation, and to identify factors relevant to the hazard. There was a 7.4% initial pregnancy fetal malformation rate. The subsequent pregnancy malformation rate was 4.2% if there was no initial pregnancy malformation, but 21.2% if there was an initial pregnancy malformation (O.R. = 6.1448, 95% C.I. 2.3396, 16.1386). For pregnancies where antiseizure medication (ASM) therapy was unchanged between pregnancies (N = 196), the initial pregnancy malformation rate was 10.2%, but 30.0% in the subsequent pregnancy if there was a malformation in the initial pregnancy, and 2.35% if there was none (O.R. = 17.7857, 95% C.I. 4.4847, 70.5361). A cohort comprising 24% of the women with fetal malformations in their initial pregnancies seemed to be intrinsically vulnerable to fetal malformation during successive pregnancies: when their seizure disorder type had been recorded all had genetic generalized epilepsies, compared with a 45.8% generalized epilepsy rate in women with initial but not subsequent pregnancy malformations (P = 0.0121). If fetal malformation had occurred in an initial ASM-treated pregnancy there was a significantly increased hazard of fetal malformation in the subsequent pregnancy, particularly if the woman involved had a genetic generalized epilepsy.
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/ALZ.12549
Abstract: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total‐tau (t‐tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt‐Jakob registry (Creutzfeldt‐Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t‐tau in most real‐life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-05-2022
DOI: 10.1212/WNL.0000000000200173
Abstract: Epilepsy is associated with an increased risk of cardiovascular disease and premature mortality, including sudden unexpected death in epilepsy (SUDEP). Serious cardiac arrythmias might go undetected in routine epilepsy and cardiac investigations. This prospective cohort study aimed to detect cardiac arrhythmias in patients with chronic drug-resistant epilepsy (≥5 years duration) using subcutaneous cardiac monitors for a minimum follow-up duration of 12 months. Participants with known cardiovascular disease or those with abnormal 12-lead ECGs were excluded. The device was programmed to automatically record episodes of tachycardia ≥140 beats per minute (bpm), bradycardia ≤40 bpm for ≥3 seconds, or asystole ≥3 seconds. Thirty-one patients underwent subcutaneous cardiac monitoring for a median recording duration of 2.2 years (range 0.5–4.2). During this time, 28 patients (90.3%) had episodes of sustained (≥30 seconds) sinus tachycardia, 8/31 (25.8%) had sinus bradycardia, and 3 (9.7%) had asystole. Three patients (9.7%) had serious cardiac arrhythmias requiring additional cardiac interventions. Among them, 2 patients had prolonged sinus arrest and ventricular asystole ( seconds), leading to pacemaker insertion in one, and another patient with epileptic encephalopathy had multiple episodes of recurrent nonsustained polymorphic ventricular tachycardia and bundle branch conduction abnormalities. The time to first detection of a clinically significant cardiac arrhythmia ranged between 1.2 and 26.9 months following cardiac monitor insertion. Implantable cardiac monitors detected a high incidence of clinically significant cardiac arrhythmias in patients with chronic drug-resistant epilepsy, which may contribute to the incidence of premature mortality, including SUDEP.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.YEBEH.2022.108602
Abstract: To investigate possible factors that influenced whether pregnancy in women with epilepsy resulted in the desirable outcome of a live-born non-malformed infant and a mother whose pregnancy had been seizure free. The desirable outcome, as defined, occurred in 46.3% of unselected pregnancies in the database of the Australian Register of Antiepileptic Drugs in Pregnancy (APR). The only factor investigated that had a statistically significant (P < 0.05) effect, increasing the chance of such a desirable outcome, was freedom from seizures in the pre-pregnancy year. However, anti-seizure medication (ASM) doses, particularly valproate doses, had been reduced prior to 15.6% of the pregnancies, and this may have concealed factors that otherwise may have adversely affected the desirable outcome rate. Analysis of data for monotherapy with the more commonly used ASMs appears to suggest that employing levetiracetam at the outset of antiseizure therapy may offer a better chance of a desirable outcome to future pregnancies than monotherapy with other ASMs, but this finding is not confirmed statistically. In pregnancies where valproate use has already been minimized, seizure control throughout the pre-pregnancy year was associated with the best chance of a desirable outcome, as defined above. In most Australian women starting therapy for epilepsy initiating treatment with levetiracetam monotherapy may offer the best chance of such a desirable outcome to a future pregnancy, yet to be confirmed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2021
DOI: 10.1212/CPJ.0000000000001114
Abstract: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02–1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.
Publisher: Wiley
Date: 14-12-2020
DOI: 10.1111/EPI.16788
Abstract: Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.YEBEH.2009.03.016
Abstract: Epilepsy is a chronic disorder with complex effects on social, vocational, physical, and psychological well-being. Patient-oriented research has demonstrated that recurrent seizures have a strong adverse effect on health-related quality of life, but also that seizure rate in persons with pharmacoresistant epilepsy has only a modest correlation with quality of life. Although treatment side effects have received limited attention in epilepsy research, available evidence indicates that adverse medication effects may explain more variance in quality of life than any other clinical variable in persons with pharmacoresistant epilepsy. Furthermore, systematic screening for adverse effects has been shown to be associated with significant reduction in subjective toxicity and improvement in quality of life. There has been only limited research on the relative contribution of specific adverse effects to impaired health-related quality of life. The relative importance of reduction of medication burden after resective epilepsy surgery or vagal nerve stimulation has similarly received sparse attention. Existing deficiencies in the available published research present challenges and opportunities to perform further investigations to define and improve best clinical practices in epilepsy care.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2023
DOI: 10.1212/WNL.0000000000201655
Abstract: The Raoul Wallenberg Australian Pregnancy Register (APR) was established to collect, analyze, and publish data on the risks to babies exposed to antiseizure medications (ASMs) and to facilitate quality improvements in management care over time. It is one of the seveal prospective observational pregnancy registers of ASMs that has been established around the world. Although the APR and other registries have contributed to knowledge gain that has been applied to decrease adverse pregnancy outcomes, their cost-effectiveness remains unknown. Here, we aimed to evaluate the economic impacts of the APR from both societal and health care system perspectives. Using decision analytic modeling, we estimated the effectiveness (prevention of adverse pregnancy outcomes) and costs (costs of adverse pregnancy outcomes and the register itself) of the APR over a 20-year time horizon (2000–2019). The comparator was set as the adverse pregnancy outcomes collected by the APR between 1998 and 2002 (i.e., no APR derived improvements in care). In the scenario analysis, we conservatively assumed a 2.5% and 5% contribution of the APR to the savings in health care and societal costs. Adverse pregnancy outcomes included stillbirth, birth defects, and induced abortion. All cost data were derived from published sources. Health and economic outcomes were extrapolated to the total target Australian epilepsy population. The primary outcomes of interest were the return of investment (ROI) for the APR and incremental cost-effectiveness ratio (ICER) for cost per adverse outcome avoided. Over the 20-year time horizon, the ROI from the APR from a societal perspective was Australian dollars (AUD) 2,250 (i.e., every dollar spent on the program resulted in a return of AUD2,250). Over this time, it was estimated that 9,609 adverse pregnancy outcomes were avoided, and health care and societal costs were reduced by AUD 191 million and AUD 9.0 billion, respectively. Hence, from a health economic point of view, the APR was dominant, providing cost saving ICERs from both perspectives. Following its inception 20+ years ago, the APR has represented excellent value for investment for Australia, being also health-saving and cost saving from a societal and a health care perspective. With the growing number of marketed ASMs, the APR is expected to continue to have a major impact in the foreseeable future.
Publisher: Wiley
Date: 05-02-2021
DOI: 10.1111/EPI.16827
Publisher: Elsevier BV
Date: 08-2023
Publisher: SAGE Publications
Date: 2021
Abstract: To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features. We retrospectively analysed adult patients at the Royal Melbourne Hospital electronically identified to have ICD codes for MS and seizures and/or epilepsy between 1996 to 2019, utilising paper and electronic-based records. Of the 2,125 MS patients identified, 16 (0.75%) experienced epileptic seizures during a mean follow-up period of 12.9 years. Median age of MS diagnosis (SD) was 38 (9.3) years. Four patients had relapsing remitting MS (25%), 10 secondary progressive MS (63.5%), and 2 primary progressive MS (12.5%). More than two-thirds of patients had seizure onset following the diagnosis of MS, and the majority of these had advanced disease (approximate EDSS ) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures. The estimated prevalence of seizures in our cohort was lower than in previous studies (0.75 vs 2–4%). In most cases, seizures occurred after the diagnosis of MS in the context of advanced disease. Further studies are required to determine if MS disease modifying treatments reduce the risk of seizures in this cohort.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-11-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-08-2018
DOI: 10.1212/WNL.0000000000006158
Abstract: To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial. We hypothesized that a seizure-free outcome could be expected in patients in whom the surgical planning included the majority of HFO-generating brain tissue while a poor seizure outcome could be expected in patients in whom only a few such areas were planned to be resected. Fifty-two patients were included from 3 tertiary epilepsy centers during a 1-year period. Ripples (80–250 Hz) and fast ripples (250–500 Hz) were automatically detected during slow-wave sleep with chronic intracranial EEG in 2 centers and acute intraoperative electrocorticography in 1 patient. There was a correlation between the removal of HFO-generating regions and seizure-free outcome at the group level for all patients. No correlation was found, however, for the center-specific analysis, and an in idual prognostication of seizure outcome was true in only 36 patients (67%). Moreover, some patients became seizure-free without removal of the majority of HFO-generating tissue. The investigation of influencing factors, including comparisons of visual and automatic analysis, using a threshold analysis for areas with high HFO activity, and excluding contacts bordering the resection, did not result in improved prognostication. On an in idual patient level, a prediction of outcome was not possible in all patients. This may be due to the analysis techniques used. Alternatively, HFOs may be less specific for epileptic tissue than earlier studies have indicated.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 09-2012
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.EPLEPSYRES.2016.09.009
Abstract: High-frequency oscillations (80-500Hz HFOs) have been shown to be a specific biomarker of the seizure-onset zone. The relationship of HFOs with seizures having different intracranial electroencephalography (iEEG) morphological onsets, however, has shown significant relationships in experimental animals but has not been studied in humans. We investigated how interictal and ictal HFOs relate to different seizure-onset morphological patterns. We analyzed the most representative seizure type of 37 patients with drug-resistant focal epilepsy who underwent iEEG for diagnostic evaluation. According to the morphology, 211 seizure-onset zone channels were classified in six patterns (low-voltage fast activity sharp activity at ≤13Hz low-frequency high- litude periodic spikes burst of high- litude polyspikes spike-and-wave activity and delta brush). Interictal and ictal HFOs were compared between the six seizure-onset patterns. Interictal ripple and fast ripple rates differed significantly across seizure-onset patterns (p<0.001). Significant differences were also found for ictal HFOs density across the different seizure-onset patterns (p<0.001). Sharp activity at ≤13Hz was associated with the lowest interictal HFO rate suggesting either that the mechanism that generates this type of EEG morphology do not generate HFOs or possibly that this pattern is more likely to be generated in a region of seizure spread. Regarding the difference in HFO density between pre-ictal baseline and seizure-onset section across the six patterns, burst of high- litude polyspikes and delta brushes had the highest densities of both ripples and fast ripples (p<0.001). We demonstrated that distinct seizure-onset patterns correlate specific interictal and ictal HFO profiles confirming that seizures with different morphological patterns likely have different mechanisms of generation. This study emphazises that, in clinical practice, seizure-onset patterns should be distinguished and specified when analyzing HFOs, particularly if they are used in presurgical evaluation to better localize the seizure-onset zone.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2023
Publisher: Hindawi Limited
Date: 19-08-2022
DOI: 10.1111/ANE.13688
Abstract: To investigate control of epileptic seizures during pairs of successive pregnancies in antiseizure medication (ASM)-treated women with epilepsy. Analysis of seizure freedom rates during 436 pairs of successive pregnancies in Australian women with epilepsy, in nearly all instances long-standing epilepsy. There was a higher rate of seizure-free second pregnancies compared with first paired pregnancies (63.1% vs. 51.4% Relative Risk (R.R.) = 1.2277 95% CI 1.0930, 1.3789) and of seizure-free pre-pregnancy years before second as compared with first paired pregnancies in the same women (63.6% vs. 52.4% R.R. = 1.2616 95% CI 1.1337, 1.4040). In 108 women whose ASM therapy was unaltered throughout both of their pregnancies, the seizure-freedom rate was higher in the second of the paired pregnancies (82.4% vs. 69.4% R.R. = 1.1867, 95% CI 1.0189, 1.3821). Altered ASM therapy after the first of a pair of successive pregnancies did not fully account for the better overall seizure control in the corresponding second pregnancies. Some additional factor may have been in operation, possibly a greater preparedness to undertake a further pregnancy if seizures were already fully controlled.
Publisher: Wiley
Date: 09-09-2022
DOI: 10.1002/EPI4.12640
Abstract: The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. The aim of the CDEs is to improve the standardization of experimental designs across a range of epilepsy research‐related methods. Here, we have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for genomics, transcriptomics, and epigenomics in rodent models of epilepsy, with a specific focus on adult rats and mice. We discuss the important elements that need to be considered for genomics, transcriptomics, and epigenomics methodologies, providing a rationale for the parameters that should be collected. This is the first in a two‐part series of omics papers with the second installment to cover proteomics, lipidomics, and metabolomics in adult rodents.
Publisher: Wiley
Date: 22-06-2023
DOI: 10.1002/EPD2.20026
Abstract: The self‐limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal‐ or infantile‐onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called “self‐limited”. A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self‐limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2012
DOI: 10.1007/S00228-012-1213-X
Abstract: In a recent meta-analysis of 38 double-blind randomized controlled trials (RCTs) comparing pregabalin (PGB) to placebo, we found 20 adverse events (AEs) to be significantly associated with PGB treatment. In the present study, we evaluated whether the incidence of these 20 AEs differs across distinct disorders in which PGB was investigated. Among the 38 previously identified RCTs of PGB, we selected only those including a PGB 600 mg/day arm and subsequently classified them into four distinct groups according to the disorder in which PGB was investigated: (1) drug-resistant partial epilepsy, (2) psychiatric disorders, (3) fibromyalgia, and (4) neuropathic pain. We used risk differences (RDs) to quantify the placebo-corrected proportion of subjects discontinuing PGB due to intolerable AEs and to determine the placebo-corrected incidence of each of the 20 PGB AEs across the four disorders. Twenty-two RCTs were included in this study. Neither the proportion of subjects discontinuing PGB due to intolerable AEs nor the incidence of PGB AEs (with the exception of ataxia) differed significantly across the four disorders. Ataxia was more common in drug-resistant partial epilepsy compared to fibromyalgia. When limiting analyses to subjects on placebo, most vestibulo-cerebellar AEs (ataxia, diplopia, and blurred vision) were found to be more common in drug-resistant partial epilepsy compared to all other disorders. Diplopia and blurred vision were more common in epilepsy than in neuropathic pain and ataxia had a higher incidence in epilepsy than in anxiety disorder and fibromyalgia. Among other CNS AEs, somnolence was more common in epilepsy compared to neuropathic pain and in anxiety disorders alone compared to neuropathic pain and fibromyalgia. Asthenia was also more common in epilepsy than in neuropathic pain and fibromyalgia. Although drug-resistant partial epilepsy is associated with a higher probability of developing vestibulo-cerebellar AEs, the risk for PGB toxicity does not differ across distinct disorders.
Publisher: Oxford University Press (OUP)
Date: 30-10-2013
DOI: 10.1093/BRAIN/AWT299
Abstract: Because seizures originate from different pathological substrates, the question arises of whether distinct or similar mechanisms underlie seizure generation across different pathologies. Better defining intracranial electroencephalographic morphological patterns at seizure-onset could improve the understanding of such mechanisms. To this end, we investigated intracranial electroencephalographic seizure-onset patterns associated with different epileptogenic lesions, and defined high-frequency oscillation correlates of each pattern. We analysed representative seizure types from 33 consecutive patients with drug-resistant focal epilepsy and a structural magnetic resonance imaging lesion (11 mesial temporal sclerosis, nine focal cortical dysplasia, six cortical atrophy, three periventricular nodular heterotopia, three polymicrogyria, and one tuberous sclerosis complex) who underwent depth-electrode electroencephalographic recordings (500 Hz filter, 2000 Hz s ling rate). Patients were included only if seizures arose from contacts located in lesional eri-lesional tissue, and if clinical manifestations followed the electrographic onset. Seizure-onset patterns were defined independently by two reviewers blinded to clinical information, and consensus was reached after discussion. For each seizure, pre-ictal and ictal sections were selected for high-frequency oscillation analysis. Seven seizure-onset patterns were identified across the 53 seizures s led: low-voltage fast activity (43%) low-frequency high- litude periodic spikes (21%) sharp activity at ≤13 Hz (15%) spike-and-wave activity (9%) burst of high- litude polyspikes (6%) burst suppression (4%) and delta brush (4%). Each pattern occurred across several pathologies, except for periodic spikes, only observed with mesial temporal sclerosis, and delta brush, exclusive to focal cortical dysplasia. However, mesial temporal sclerosis was not always associated with periodic spikes nor focal cortical dysplasia with delta brush. Compared to other patterns, low-voltage fast activity was associated with a larger seizure-onset zone (P = 0.04). Four patterns, sharp activity at ≤13 Hz, low-voltage fast activity, spike-and-wave activity and periodic spikes, were also found in regions of seizure spread, with periodic spikes only emerging from mesial temporal sclerosis. Each of the seven patterns was accompanied by a significant increase in high-frequency oscillations upon seizure-onset. Overall, our data indicate that: (i) biologically-distinct epileptogenic lesions share intracranial electroencephalographic seizure-onset patterns, suggesting that different pathological substrates can affect similarly networks or mechanisms underlying seizure generation (ii) certain pathologies are associated with intracranial electroencephalographic signatures at seizure-onset, e.g. periodic spikes which may reflect mechanisms specific to mesial temporal sclerosis (iii) some seizure-onset patterns, including periodic spikes, can also be found in regions of spread, which cautions against relying on the morphology of the initial discharge to define the epileptogenic zone and (iv) high-frequency oscillations increase at seizure-onset, independently of the pattern.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.YEBEH.2022.108740
Abstract: To analyze the records of the pregnancies of 2283 Australian women with epilepsy in the Australian Register of Antiepileptic Drugs in Pregnancy database to identify neurological factors relevant to the Cesarean sections carried out in these pregnancies. The Cesarean section rate in Australian women overall increased by an average of 0.59% annually over 20 years, from 26.0% to its calculated 2020 value of 37.3%. For the operations in women with epilepsy, the corresponding figures were 0.71% annually, and 34.4% and 48.7%. The average annual rate of increase for pre-labor operations was 0.89% to a 2020 value of 39.1%, the annual rate for operations during labor showing no statistically significant change. Multivariate regression analysis identified a number of characteristics of women with epilepsy that were statistically significantly associated with an increased likelihood of Cesarean section, but of these only seizures continuing to occur in the third trimester and having chronic illness, in particular migraine, were neurological ones. In 70 migraine-affected women, the Cesarean section rate was 51.4%, compared with 39% in the remaining pregnancies (P < 0.05). Having seizures in the final trimester of pregnancy and having chronic neurological illness, especially migraine, favored Cesarean section being carried out in Australian women with epilepsy, but did not adequately account for the increasing rates of occurrence of the operation over the past 20 years.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-02-2011
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.02.001
Abstract: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis. We performed WES, followed by targeted analysis of 64 epilepsy genes, on 40 consecutive children and adults enrolled prospectively from routine clinical practice who had MRI-negative focal epilepsy and a family history of febrile seizures or any type of epilepsy in at least one first- or second-degree relative. Exclusion criteria were previous genetic testing, severe intellectual disability and benign focal epilepsies of childhood. 5/40 (12.5%) patients had a pathogenic or likely pathogenic variant, detected in SCN1A, DEPDC5, PCDH19, GABRG2 or NPRL2. Identifying a pathogenic SCN1A variant in a patient with drug-resistant epilepsy prompted to halt presurgical investigations due to concern of unfavorable post-surgical outcome. It also led in the same patient to discontinue long-standing carbamazepine therapy (a potentially aggravating drug in epilepsies due to SCN1A mutations), resulting in complete seizure control. Patients with pathogenic or likely pathogenic variants had a younger median age of seizure onset (range) compared to those without [18 months (8 months-18 years) vs 18 years (18 months-70 years), p=0.02]. Our data demonstrate that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies in whom a genetic etiology is suspected. It can also influence clinical decision-making, including antiepileptic drug selection and consideration of epilepsy surgery, hence supporting its incorporation in the routine clinical care of this patient group.
Publisher: World Scientific Pub Co Pte Ltd
Date: 2023
DOI: 10.1142/S0129065723500016
Abstract: Deep learning for automated interictal epileptiform discharge (IED) detection has been topical with many published papers in recent years. All existing works viewed EEG signals as time-series and developed specific models for IED classification however, general time-series classification (TSC) methods were not considered. Moreover, none of these methods were evaluated on any public datasets, making direct comparisons challenging. This paper explored two state-of-the-art convolutional-based TSC algorithms, InceptionTime and Minirocket, on IED detection. We fine-tuned and cross-evaluated them on a public (Temple University Events — TUEV) and two private datasets and provided ready metrics for benchmarking future work. We observed that the optimal parameters correlated with the clinical duration of an IED and achieved the best area under precision-recall curve (AUPRC) of 0.98 and F1 of 0.80 on the private datasets, respectively. The AUPRC and F1 on the TUEV dataset were 0.99 and 0.97, respectively. While algorithms trained on the private sets maintained their performance when tested on the TUEV data, those trained on TUEV could not generalize well to the private data. These results emerge from differences in the class distributions across datasets and indicate a need for public datasets with a better ersity of IED waveforms, background activities and artifacts to facilitate standardization and benchmarking of algorithms.
Publisher: Wiley
Date: 27-10-2021
DOI: 10.1111/EPI.17104
Abstract: We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)–resistant vs ASM‐responsive outcome for patients with idiopathic generalized epilepsy (IGE). This was a case‐control study of ASM‐resistant cases and ASM‐responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM‐resistant IGE. We identified 118 ASM‐resistant cases and 114 ASM‐responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM‐resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32–10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure‐type combinations (absence, myoclonic, and generalized tonic‐clonic seizures [OR 7.06, 95% CI 2.55–20.96] absence and generalized tonic‐clonic seizures [OR 4.45, 95% CI 1.84–11.34]), as well as EEG markers of increased generalized spike‐wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12–11.36 for frequent and OR 7.21, 95% CI 1.50–54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs OR 5.49, 95% CI 1.27–38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver‐operating characteristic curve, was 0.80. Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure‐type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 06-01-2015
DOI: 10.1038/NRNEUROL.2014.255
Abstract: In 2014, novel, large-scale collaborative efforts and frameworks resulted in major advances in the epilepsy field, from publication of a new definition of epilepsy to important discoveries regarding aetiology, pathophysiology and management. These collaborative works provide a platform from which further advances are anticipated, and a model for future research.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.NEUROIMAGE.2014.02.032
Abstract: Growing evidence indicates that fast oscillations (>80 Hz) can be recorded interictally in the scalp EEG of patients with epilepsy, and that they may point to the seizure-onset zone. However, mechanisms underpinning the emergence of scalp fast oscillations, and whether they differ from those of interictal epileptic discharges (IEDs), are yet to be understood. The visibility of cortical electric activity on scalp EEG recordings is dependent on two factors: the characteristics of the cortical generator and the background level. We studied this issue using scalp EEG recordings and detailed simulations, with a finite element model including 8 million elements and 8 different tissues. We observed an almost linear relationship between the litude of scalp electric potential and the extent of the generator on the cortex. However, this relationship is subject to substantial variability, with variations in factors greater than 3 occurring simply by changing the location on the cortex of generators of fixed extent. In addition, we showed that the background power in scalp EEG recordings decreases at higher frequency bands, being inversely proportional to a power of 2.5 of the frequency. In the specific case of fast oscillations, they can be detected within the lower noise level of the ripple band (80-200 Hz) even though their median litude on scalp EEG recordings is more than 10 times smaller than IEDs and consistent with cortical generators of approximately 1 cm(2). In conclusion, the physics governing the propagation of electrical activity from the brain to the scalp are consistent with the hypothesis that scalp fast oscillations and intracranial high-frequency oscillations (HFOs, 80-500 Hz) are expressions of common generators. Given the potential role of HFOs as biomarkers in epilepsy, the possibility to obtain some of the associated information from scalp EEG is of high clinical significance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-01-2022
DOI: 10.1212/WNL.0000000000013066
Abstract: Focal cortical dysplasia (FCD) has been associated with poorer postsurgical seizure outcomes compared to other pathologies. FCD surgical series have been assembled on the basis of a histologic diagnosis, including patients with abnormal and normal preoperative MRI. However, in clinical workflow, patient selection for surgery is based on preoperative findings, including MRI. We performed a systematic review and meta-analysis of the literature to determine the rate and predictors of favorable seizure outcome after surgery for MRI-detected FCD. We devised our study protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered the protocol with PROSPERO. We searched MEDLINE, EMBASE, and Web of Science for studies of patients followed up for ≥12 months after resective surgery for drug-resistant epilepsy with MRI-detected FCD. Random-effects meta-analysis was used to calculate the proportion of patients attaining a favorable outcome, defined as Engel class I, International League Against Epilepsy class 1 to 2, or seizure-free status. Meta-regression was performed to investigate sources of heterogeneity. Our search identified 3,745 references. Of these, 35 studies (total of 1,353 patients) were included. Most studies (89%) followed up patients for ≥24 months after surgery. The overall postsurgical favorable outcome rate was 70% (95% confidence interval [CI] 64–75). There was high interstudy heterogeneity. Favorable outcome was associated with complete resection of the FCD lesion (risk ratio [RR] 2.42 [95% confidence interval (CI) 1.55–3.76], p 0.001) and location of the FCD lesion in the temporal lobe (RR 1.38 [95% CI 1.07–1.79], p = 0.013) but not lesion extent, intracranial EEG use, or FCD histologic type. The number of FCD histologic types included in the same study accounted for 7.6% of the observed heterogeneity. Seventy percent of patients with drug-resistant epilepsy and MRI features of FCD attain a favorable seizure outcome after resective surgery. Our findings can be incorporated into routine preoperative counseling and reinforce the importance of completely resecting the MRI-detected FCD when safe and feasible.
Publisher: Wiley
Date: 21-10-2018
DOI: 10.1111/EPI.14587
Abstract: Our objective was to critically evaluate the literature surrounding heart rate variability (HRV) in people with epilepsy and to make recommendations as to how future research could be directed to facilitate and accelerate integration into clinical practice. We reviewed relevant HRV publications including those involving human subjects with seizures. HRV has been studied in patients with epilepsy for more than 30 years and, overall, patients with epilepsy display altered interictal HRV, suggesting a shift in autonomic balance toward sympathetic dominance. This derangement appears more severe in those with temporal lobe epilepsy and drug-resistant epilepsy. Normal diurnal variation in HRV is also disturbed in at least some people with epilepsy, but this aspect has received less study. Some therapeutic interventions, including vagus nerve stimulation and antiepileptic medications, may partially normalize altered HRV, but studies in this area are sometimes contradictory. During seizures, the changes in HRV may be complex, but the general trend is toward a further increase in sympathetic overactivity. Research in HRV in people with epilepsy has been limited by inconsistent experimental protocols and studies that are often underpowered. HRV measurement has the potential to aid clinical epilepsy management in several possible ways. HRV may be useful in predicting which patients are likely to benefit from surgical interventions such as vagus nerve stimulation and focal cerebral resection. As well, HRV could eventually have utility as a biomarker of risk for sudden unexpected death in epilepsy (SUDEP). However, at present, the inconsistent measurement protocols used in research are hindering translation into clinical practice. A minimum protocol for HRV evaluation, to be used in all studies involving epilepsy patients, is necessary to eventually allow HRV to become a useful tool for clinicians. We propose a straightforward protocol, involving 5-minute measurements of root mean square of successive differences in wakefulness and light sleep.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.EPLEPSYRES.2019.03.001
Abstract: The last decade saw impressive advances not only in the discovery of gene mutations causing epilepsy, but also in unraveling the molecular mechanisms underlying the clinical manifestations of the disease. Increasing evidence is emerging that understanding these mechanisms is relevant for selection of the most appropriate treatment in the affected in idual(s). The present article discusses the therapeutic implications of epilepsy-causing variants affecting a broad range of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. Identification of a precise genetic etiology can direct physicians to (i) prescribe treatments that correct specific metabolic defects (e.g., the ketogenic diet for GLUT1 deficiency, or pyridoxine for pyridoxine-dependent epilepsies) (ii) avoid antiepileptic drugs (AEDs) that can aggravate the pathogenic defect (e.g., sodium channel blocking drugs in SCN1A-related Dravet syndrome), or (iii) select AEDs that counteract the functional disturbance caused by the gene mutation (e.g., sodium channel blockers for epilepsies due to gain-of-function SCN8A mutations). In some instances, different pathogenic variants of the same gene can have opposite functional effects, which determines whether certain treatments can be beneficial or deleterious (e.g., gain-of-function versus loss-of-function variants in SCN2A determine whether sodium channel blockers improve or worsen seizure control). There are also cases where functional disturbances caused by the gene defect may not be corrected by existing AEDs, but can be countered by medications already available in the market for other indications (e.g., memantine has been used to treat the epileptic encephalopathy caused by a specific gain-of-function GRIN2A mutation), thus making 'drug repurposing' a valuable tool for personalized epilepsy therapies. As our understanding of pathogenic mechanisms improve, opportunities arise for development of treatments targeting the specific gene defect or its consequences. Everolimus, an mTOR inhibitor approved for the treatment of focal seizures associated with tuberous sclerosis complex, is an ex le of a medication targeting the etiological mechanisms of the disease. Several treatments aimed at correcting specific pathogenic defects responsible for rare genetic epilepsies are currently in development, and range from traditional small molecules to novel approaches involving peptides, antisense oligonucleotides, and gene therapy.
Publisher: Public Library of Science (PLoS)
Date: 19-11-2013
Publisher: Wiley
Date: 12-06-2023
DOI: 10.1002/EPI4.12772
Abstract: This study evaluated sleep and respiratory abnormalities, and their relationship with seizures, in adults with developmental and epileptic encephalopathies (DEEs). We studied consecutive adults with DEEs undergoing inpatient video‐EEG monitoring and concurrent polysomnography between December 2011 and July 2022. Thirteen patients with DEEs were included (median age: 31 years, range: 20–50 69.2% female): Lennox–Gastaut syndrome ( n = 6), Lennox–Gastaut syndrome‐like phenotype ( n = 2), Landau–Kleffner syndrome ( n = 1), epilepsy with myoclonic‐atonic seizures ( n = 1), and unclassified DEEs ( n = 3). Sleep architecture was often fragmented by epileptiform discharges and seizures resulting in arousals (median arousal index: 29.0 per h, range: 5.1–65.3). Moderate‐to‐severe obstructive sleep apnea (OSA) was observed in seven patients (53.8%). Three patients (23.1%) had tonic seizures that frequently occurred with central apnea one met criteria for mild central sleep apnea. Of the patients with tonic seizures, two had other identifiable seizure manifestations, but in one patient, central apnea was commonly the only discernable seizure manifestation. Polysomnography during video‐EEG is an effective diagnostic tool in detecting sleep and seizure‐related respiratory abnormalities. Clinically significant OSA may increase the risk of comorbid cardiovascular disease and premature mortality. Treatment of epilepsy may improve sleep quality, and conversely, improved sleep, may decrease seizure burden.
Publisher: MDPI AG
Date: 28-05-2022
DOI: 10.3390/IJMS23116063
Abstract: Absence epilepsy syndromes are part of the genetic generalized epilepsies, the pathogenesis of which remains poorly understood, although a polygenic architecture is presumed. Current focus on single molecule or gene identification to elucidate epileptogenic drivers is unable to fully capture the complex dysfunctional interactions occurring at a genetic roteomic/metabolomic level. Here, we employ a multi-omic, network-based approach to characterize the molecular signature associated with absence epilepsy-like phenotype seen in a well validated rat model of genetic generalized epilepsy with absence seizures. Electroencephalographic and behavioral data was collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS, n = 6) and non-epileptic controls (NEC, n = 6), followed by proteomic and metabolomic profiling of the cortical and thalamic tissue of rats from both groups. The general framework of weighted correlation network analysis (WGCNA) was used to identify groups of highly correlated proteins and metabolites, which were then functionally annotated through joint pathway enrichment analysis. In both brain regions a large protein-metabolite module was found to be highly associated with the GAERS strain, absence seizures and associated anxiety and depressive-like phenotype. Quantitative pathway analysis indicated enrichment in oxidative pathways and a downregulation of the lysine degradation pathway in both brain regions. GSTM1 and ALDH2 were identified as central regulatory hubs of the seizure-associated module in the somatosensory cortex and thalamus, respectively. These enzymes are involved in lysine degradation and play important roles in maintaining oxidative balance. We conclude that the dysregulated pathways identified in the seizure-associated module may be involved in the aetiology and maintenance of absence seizure activity. This dysregulated activity could potentially be modulated by targeting one or both central regulatory hubs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2019
DOI: 10.1212/NXG.0000000000000340
Abstract: To map functional MRI (fMRI) connectivity within and between the somatosensory cortex, putamen, and ventral thalamus in in iduals from a family with a GABAergic deficit segregating with febrile seizures and genetic generalized epilepsy. We studied 5 adults from a family with early-onset absence epilepsy and/or febrile seizures and a GABA A receptor subunit gamma2 pathogenic variant ( GABRG2[R43Q] ) vs 5 age-matched controls. We infer differences between participants with the GABRG2 pathogenic variant and controls in resting-state fMRI connectivity within and between the somatosensory cortex, putamen, and ventral thalamus. We observed increased fMRI connectivity within the somatosensory cortex and between the putamen and ventral thalamus in all in iduals with the GABRG2 pathogenic variant compared with controls. Post hoc analysis showed less pronounced changes in fMRI connectivity within and between the primary visual cortex and precuneus. Although our s le size was small, this preliminary study suggests that in iduals with a GABRG2 pathogenic variant, raising risk of febrile seizures and generalized epilepsy, display underlying increased functional connectivity both within the somatosensory cortex and in striatothalamic networks. This human network model aligns with rodent research and should be further validated in larger cohorts, including other in iduals with generalized epilepsy with and without known GABA pathogenic variants.
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/EPI.16929
Abstract: A substantial proportion of in iduals with newly diagnosed epilepsy report prior seizures, suggesting a missed opportunity for early epilepsy care and management. Consideration of the causes and outcomes of diagnostic delay is needed to address this issue. We aimed to review the literature pertaining to delay to diagnosis of epilepsy, describing the components, characteristics, and risk factors for delay. We undertook a systematic search of the literature for full‐length original research papers with a focus on diagnostic delay or seizures before diagnosis, published 1998–2020. Findings were collated, and a narrative review was undertaken. Seventeen papers met the inclusion criteria. Studies utilized two measures of diagnostic delay: seizures before diagnosis and/or a study‐defined time between first seizure and presentation/diagnosis. The proportion of patients with diagnostic delay ranged from 16% to 77% 75% of studies reported 38% or more to be affected. Delays of 1 year or more were reported in 13%–16% of patients. Seizures prior to diagnosis were predominantly nonconvulsive, and usually more than one seizure was reported. Prior seizures were often missed or mistaken for symptoms of other conditions. Key delays in the progression to specialist review and diagnosis were (1) “decision delay” (the patient's decision to seek/not seek medical review), (2) “referral delay” (delay by primary care/emergency physician referring to specialist), and (3) “attendance delay” (delay in attending specialist review). There were few data available relevant to risk factors and virtually none relevant to outcomes of diagnostic delay. This review found that diagnostic delay consists of several components, and progression to diagnosis can stall at several points. There is limited information relating to most aspects of delay apart from prevalence and seizure types. Risk factors and outcomes may differ according to delay characteristics and for each of the key delays, and recommendations for future research include examining each before consideration of interventions is made.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-08-2020
DOI: 10.1212/WNL.0000000000010597
Abstract: To develop and validate a clinical prediction model for antiepileptic drug (AED)–resistant genetic generalized epilepsy (GGE). We performed a case-control study of patients with and without drug-resistant GGE, nested within ongoing longitudinal observational studies of AED response at 2 tertiary epilepsy centers. Using a validation dataset, we tested the predictive performance of 3 candidate models, developed from a training dataset. We then tested the candidate models' predictive ability on an external testing dataset. Of 5,189 patients in the ongoing longitudinal study, 121 met criteria for AED-resistant GGE and 468 met criteria for AED-responsive GGE. There were 66 patients with GGE in the external dataset, of whom 17 were cases. Catamenial epilepsy, history of a psychiatric condition, and seizure types were strongly related with drug-resistant GGE case status. Compared to women without catamenial epilepsy, women with catamenial epilepsy had about a fourfold increased risk for AED resistance. The calibration of 3 models, assessing the agreement between observed outcomes and predictions, was adequate. Discriminative ability, as measured with area under the receiver operating characteristic curve (AUC), ranged from 0.58 to 0.65. Catamenial epilepsy, history of a psychiatric condition, and the seizure type combination of generalized tonic clonic, myoclonic, and absence seizures are negative prognostic factors of drug-resistant GGE. The AUC of 0.6 is not consistent with truly effective separation of the groups, suggesting other unmeasured variables may need to be considered in future studies to improve predictability.
Publisher: Wiley
Date: 27-06-2023
DOI: 10.1002/EPI4.12777
Publisher: Wiley
Date: 02-01-2023
DOI: 10.1002/ANA.26581
Abstract: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippoc al sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Nine centers from 3 continents contributed 206 patients operated for drug‐resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss‐of‐function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9–3.5, p = 1.3E‐09) and in genes encoding voltage‐gated cation channels (OR = 2.4, 95% CI = 1.4–3.8, p = 2.7E‐04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between‐group differences. Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision‐making and counseling. ANN NEUROL 2023 :752–761
Publisher: SAGE Publications
Date: 11-2018
DOI: 10.5698/1535-7597.18.6.356
Abstract: This article is based on a lecture delivered at the 2017 American Epilepsy Society Annual Meeting and provides an overview of the growing evidence supporting the strong genetic contribution to focal epilepsies. This also discusses how advances in the molecular genetics of focal epilepsies are rapidly translating to routine clinical care.
Publisher: Wiley
Date: 05-10-2011
DOI: 10.1111/J.1528-1167.2011.03283.X
Abstract: Failure to respond to the initial antiepileptic drug (AED) is a predictor of increased risk of pharmacoresistant epilepsy. Whether response to the first AED also predicts adverse health outcomes is unknown. This longitudinal study compared rates of major adverse health outcomes (loss of driving privileges, unemployment, orce/separation, injury, emergency room admission, hospitalization, and death) in 33 patients who failed the first AED (cases) and 30 patients who became seizure-free with the first AED (controls). Patient data were obtained by chart review and confirmed through a structured interview with each subject at 5-7 years after starting AED treatment. We also assessed between-group differences in quality of life, depression, and adverse AED effects by using standardized instruments completed by each subject at the end of follow-up. The number of major adverse health outcomes was similarly high during the first year of AED treatment [mean ± standard deviation (SD) 2.64 ± 0.99 for cases and 2.50 ± 1.14 for controls], but thereafter decreased to a greater extent in controls than in cases (p < 0.001). Controls had a higher cumulative probability of experiencing ≥1 year free from major adverse health outcomes compared to cases (p = 0.002). Two cases died during the follow-up, both of sudden unexpected death. Cases had worse quality of life ratings than controls, whereas no significant between-group differences were found for measures of depression and adverse AED effects. In a post hoc analysis limited to cases, patients who became seizure-free with subsequent AED treatments showed for the first 4 years major adverse health outcome rates similar to those recorded in patients with persisting seizures. After 4 years, however, cases who achieved late seizure freedom tended to show a more favorable outcome. Patients with epilepsy failing the initial AED trial are at increased risk of experiencing adverse health outcomes, at least for the first 4 years after diagnosis. Incorporating these findings into clinical decision making may aid in reducing delays in surgical referrals for pharmacoresistant epilepsy.
Publisher: Frontiers Media SA
Date: 18-03-2022
DOI: 10.3389/FNEUR.2022.858333
Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict in idual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%) mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73–0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict in idualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.NBD.2022.105863
Abstract: Malformations of cortical development (MCDs) are common causes of drug-resistant epilepsy. The mechanisms underlying the associated epileptogenesis and ictogenesis remain poorly elucidated. EEG can help in understanding these mechanisms. We systematically reviewed studies reporting scalp or intracranial EEG features of MCDs to characterise interictal and seizure-onset EEG patterns across different MCD types. We conducted a systematic review in accordance with PRISMA guidelines. MEDLINE, PubMed, and Cochrane databases were searched for studies describing interictal and seizure-onset EEG patterns in MCD patients. A classification framework was implemented to group EEG features into 20 predefined patterns, comprising nine interictal (five, scalp EEG four, intracranial EEG) and 11 seizure-onset (five, scalp EEG six, intracranial EEG) patterns. Logistic regression was used to estimate the odds ratios (OR) of each seizure-onset pattern being associated with specific MCD types. Our search yielded 1682 studies, of which 27 comprising 936 MCD patients were included. Of the nine interictal EEG patterns, five (three, scalp EEG two, intracranial EEG) were detected in ≥2 MCD types, while four (rhythmic epileptiform discharges type 1 and type 2 on scalp EEG repetitive bursting spikes and sporadic spikes on intracranial EEG) were seen only in focal cortical dysplasia (FCD). Of the 11 seizure-onset patterns, eight (three, scalp EEG five, intracranial EEG) were found in ≥2 MCD types, whereas three were observed only in FCD (suppression on scalp EEG delta brush on intracranial EEG) or tuberous sclerosis complex (TSC focal fast wave on scalp EEG). Among scalp EEG seizure-onset patterns, paroxysmal fast activity (OR = 0.13 95% CI: 0.03-0.53 p = 0.024) and repetitive epileptiform discharges (OR = 0.18 95% CI: 0.05-0.61 p = 0.036) were less likely to occur in TSC than FCD. Among intracranial EEG seizure-onset patterns, low-voltage fast activity was more likely to be detected in heterotopia (OR = 19.3 95% CI: 6.22-60.1 p 0.001), polymicrogyria (OR = 6.70 95% CI: 2.25-20.0 p = 0.004) and TSC (OR = 4.27 95% CI: 1.88-9.70 p = 0.005) than FCD. Different MCD types can share similar interictal or seizure-onset EEG patterns, reflecting common underlying biological mechanisms. However, selected EEG patterns appear to point to distinct MCD types, suggesting certain differences in their neuronal networks.
Publisher: Wiley
Date: 14-06-2018
DOI: 10.1111/EPI.14436
Abstract: There is little detailed phenotypic characterization of bilateral hippoc al sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002 Fisher's exact test). The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.
Publisher: Wiley
Date: 13-01-2021
DOI: 10.1002/EPI4.12460
Abstract: ‘First seizure’ clinics (FSCs) aim to achieve early expert assessment for in iduals with possible new‐onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. We reviewed investigation findings over 11 years (2000‐2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new‐onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol‐driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Median patient age was 37 (IQR 26‐52, range 18‐94) years (AH 34 vs RMH 42 years P .001). Eighty‐six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days P .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy‐six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12% P .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion ( %) at each clinic. At both sites, epilepsy type could be determined in 60% of patients RMH had more focal and AH more generalized epilepsy diagnoses. Differences between the clinics’ administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-09-2020
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.YEBEH.2012.09.018
Abstract: With almost 100 years of clinical experience, antiepileptic drugs (AEDs) remain the mainstay of epilepsy treatment. They suppress epileptic seizures by acting on a variety of mechanisms and molecular targets involved in the regulation of neuronal excitability. These include inhibitory-GABAergic and excitatory-glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. On the other hand, accruing evidence indicates that these mechanisms and targets are also implicated in the regulation of mood and behavior, which may explain why each AED is associated with specific psychotropic effects. These effects, however, cannot be explained solely on the basis of the known mode of action of each AED, and other mechanisms or targets are likely to be implicated. In this article, we review positive and negative effects of AEDs on mood and behavior, discuss putative underlying mechanisms, and highlight knowledge gaps which should be addressed in future studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-01-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
DOI: 10.1212/WNL.0000000000201469
Abstract: Mosaic pathogenic variants restricted to the brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereoelectroencephalography (SEEG) electrodes. We studied a patient with nonlesional multifocal epilepsy undergoing presurgical evaluation with SEEG. After explantation, the electrodes were ided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippoc us/temporal neocortex). Tissue from each pool was processed for trace DNA that was whole genome lified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. A brain-specific glial fibrillary acidic protein (GFAP) assay enabled cell-of-origin analysis. We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant (c.530G A, p.W177X) predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings because the highest variant allele frequency was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. An elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. This study demonstrates a proof of concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-01-2021
Publisher: Wiley
Date: 23-10-2009
DOI: 10.1111/J.1528-1167.2009.02265.X
Abstract: Migralepsy is an ill-defined nosologic entity, with only a few cases described in the literature. In the 2004 International Classification for Headache Disorders (ICHD-II), the International Headache Society proposed that the following diagnostic criteria should be met: (1) migraine fulfilling criteria for 1.2 Migraine with aura (MA) and (2) a seizure fulfilling diagnostic criteria for one type of epileptic attack occurs during or within 1 h after a migraine aura. Herein, by presenting a case with symptoms suggestive of migralepsy and by reviewing all previous cases described in the literature, we discuss the challenges of differentiating this condition from epileptic seizures, as well as the inaccuracy of the current ICHD-II definition.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 2009
DOI: 10.1111/J.1528-1167.2008.01966.X
Abstract: Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels. Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16-47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non-enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies. E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI. Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2022
DOI: 10.1101/2022.07.06.22277287
Abstract: Deep learning for automated interictal epileptiform discharge (IED) detection has been topical with many published papers in recent years. All existing work viewed EEG signals as time-series and developed specific models for IED classification however, general time-series classification (TSC) methods were not considered. Moreover, none of these methods were evaluated on any public datasets, making direct comparisons challenging. This paper explored two state-of-the-art convolutional-based TSC algorithms, InceptionTime and Minirocket, on IED detection. We fine-tuned and cross-evaluated them on two private and public (Temple University Events - TUEV) datasets and provided ready metrics for benchmarking future work. We observed that the optimal parameters correlated with the clinical duration of an IED and achieved the best AUC, AUPRC and F1 scores of 0.98, 0.80 and 0.77 on the private datasets, respectively. The AUC, AUPRC and F1 on TUEV were 0.99, 0.99 and 0.97, respectively. While algorithms trained on the private sets maintained the performance when tested on the TUEV data, those trained on TUEV could not generalise well to the private data. These results emerge from differences in the class distributions across datasets and indicate a need for public datasets with a better ersity of IED waveforms, background activities and artifacts to facilitate standardisation and benchmarking of algorithms.
Publisher: Wiley
Date: 05-03-2015
DOI: 10.1111/EPI.12940
Abstract: Although a clear correlation has been observed between high-frequency oscillations (HFOs) and the seizure-onset zone in distinct lesions, the role of the underlying pathologic substrates in the generation of HFOs is not well established. We aimed to investigate HFO correlates of different pathologic substrates in patients with drug-resistant epilepsy, and to examine the relation of HFOs with the anatomic location of the dysplastic lesion and surrounding tissue in patients with focal cortical dysplasia (FCD). We studied consecutive patients with drug-resistant epilepsy who underwent intracranial electroencephalography (iEEG) investigations with depth electrodes at the Montreal Neurological Institute and Hospital, between November 2004 and May 2013. Inclusion criteria were the following: a focal lesion documented by magnetic resonance imaging (MRI) EEG recording at a 2,000 Hz s ling rate and seizures starting from depth electrode contacts placed in lesion and perilesional tissue. Thirty-seven patients (13 FCD, 12 mesial temporal sclerosis, five cortical atrophy, three polymicrogyria, three nodular heterotopia, and one tuberous sclerosis) were included 18 were women (median age 34). Ripples and fast ripples were found in all lesion types, except tuberous sclerosis, which showed no fast ripples. There was a significant difference in rates of ripples and fast ripples across different lesions (p < 0.001), with higher rates in FCD, mesial temporal sclerosis, and nodular heterotopia than in atrophy, polymicrogyria, and tuberous sclerosis. Regarding patients with FCD, HFOs rates differed significantly across the three types of tissue (lesional, perilesional, and nonlesional p < 0.001), being higher within the borders of the MRI-visible dysplastic lesion, followed by the surrounding area, and rare in the remote cortex. Our findings suggest that in patients who are all intractable, the HFO rates vary with different pathologies, and reflect different types of neuronal derangements. Our results also emphasize the potential usefulness of HFOs as an additional method to better define the extent of the epileptogenic dysplastic tissue in FCD.
Publisher: SAGE Publications
Date: 29-09-2021
Abstract: Whether genetic factors contribute to acquired epilepsies has long been controversial. Supporters observe that, among in iduals exposed to seemingly the same brain insult, only a minority develops unprovoked seizures. Yet, only in relatively recent years have studies started to build a case for genetic contributions. Here, we appraise this emerging evidence, by providing a critical review of studies published in the field.
Publisher: Wiley
Date: 29-07-2009
DOI: 10.1111/J.1528-1167.2009.02178.X
Abstract: Neuroactive sex steroids influence neuron excitability, which is enhanced by estradiol (E2) and decreased by progesterone (Pg). In epilepsy, the production, metabolism, biologic availability, and activity of sex hormones may be affected by seizures themselves or by antiepileptic drugs (AEDs). This cross-sectional observational study was aimed at evaluating the relationships between sex steroids, seizure frequency, and other clinical parameters in women with partial epilepsy (PE) on AED treatments. Serum E2, Pg, sex hormone binding globulin (SHBG) levels, free E2 (fE2), and E2/Pg ratios were determined during the follicular and luteal phases in 72 adult women with PE, and in 30 healthy controls. Hormonal data were correlated with seizure frequency, age, body weight, body mass index (BMI), disease onset and duration, and AED therapies. In patients, E2, fE2, and Pg levels were lower in both ovarian phases, whereas those of SHBG were higher than in controls. No significant changes in hormone levels and in prevalence of anovulatory cycles were observed between patients grouped according to their seizure frequency. However, when compared with those in healthy controls, luteal fE2 and Pg levels were chiefly impaired in women with more frequent seizures, mostly undergoing AED polytherapies, but not in those with absent or rarer seizures. The actual changes in sex steroid levels and E2/Pg ratios did not explain an increased seizure frequency in adult women with AED-treated PE, but patients with more severe disease showed more relevant changes in their sex hormone profile and impaired Pg levels during the luteal phase.
Publisher: Elsevier BV
Date: 11-2012
Publisher: Informa UK Limited
Date: 22-09-2021
DOI: 10.1080/14737175.2021.1981288
Abstract: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
Publisher: SAGE Publications
Date: 17-11-2022
DOI: 10.1177/00048674211058684
Abstract: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of erse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for ex le with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2] parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
Publisher: Wiley
Date: 31-08-2023
DOI: 10.1002/ANA.26765
Abstract: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippoc al sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in in iduals with FMTLE. We studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one in idual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippoc al sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007) in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023
Publisher: Wiley
Date: 14-02-2011
DOI: 10.1111/J.1528-1167.2010.02966.X
Abstract: Despite the widespread use of antiepileptic drugs (AEDs) across different neurologic and psychiatric disorders, no study has systematically reviewed all available randomized controlled trials (RCTs) of a given AED to fully uncover its tolerability profile. We aimed at identifying treatment emergent adverse events (AEs) associated with pregabalin through a systematic review and meta-analysis of all available RCTs. We also assessed the association between serious AEs and pregabalin, and investigated whether pregabalin AEs display a dose-response relationship. We searched MEDLINE, EMBASE, and Cochrane CENTRAL to February 2010 for RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs investigating the therapeutic effects of pregabalin in adults with any condition. Studies had to include at least 20 subjects per arm and have a duration of at least 4 weeks. AEs were assessed for their association with pregabalin after identification/exclusion of synonyms, rare AEs, and nonassessable AEs due to methodologic limitations. We used relative risks (RRs) to assess the association of any [99% confidence intervals (CIs)] or serious AEs (95% CIs) with pregabalin, and risk differences (RDs, 95% CIs) to investigate dose-response relationships of pregabalin AEs. Thirty-eight RCTs were included in our study. Of 39 AEs, 20 (51%) were significantly associated with pregabalin (dizziness, vertigo, incoordination, balance disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema, peripheral edema, dry mouth, constipation). The highest RRs were found for cognition/coordination AEs. There was no significant association between serious AEs and pregabalin. There was a selective dose-response pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others. In iduals starting treatment with pregabalin are at increased risk for several AEs, particularly those affecting cognition/coordination. Pregabalin AEs appear according to a selective dose-response pattern, possibly reflecting the severity of dysfunction of distinct anatomic structures. These findings may aid clinicians in providing better patient management, and support the value of including in meta-analyses of AED tolerability profiles RCTs performed in different conditions.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2016
DOI: 10.1038/NBT.3428
Abstract: High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-07-2010
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2022
DOI: 10.1101/2022.07.22.22277802
Abstract: More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures (auras) before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than auras, using Cox proportional hazards regression in a derivation cohort (n=231). Independent predictors of seizure recurrence, other than auras, following the start of ASM withdrawal were focal-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n=500). A secondary model predicting recurrence of any seizures (including auras) was developed and validated in a subgroup that did not have auras before withdrawal (n=639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools ( predictepilepsy.github.io ), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients.
Publisher: American Medical Association (AMA)
Date: 04-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-10-2018
DOI: 10.1212/WNL.0000000000006472
Abstract: To identify clinical and EEG biomarkers of drug resistance in adults with idiopathic generalized epilepsy. We conducted a case-control study consisting of a discovery cohort and a replication cohort independently assessed at 2 different centers. In each center, patients with the idiopathic generalized epilepsy phenotype and generalized spike-wave discharges on EEG were classified as drug-resistant or drug-responsive. EEG changes were classified into predefined patterns and compared between the 2 groups in the discovery cohort. Factors associated with drug resistance in multivariable analysis were tested in the replication cohort. The discovery cohort included 85 patients (29% drug-resistant and 71% drug-responsive). Their median age at assessment was 32 years and 50.6% were female. Multivariable analysis showed that higher number of seizure types ever experienced (3 vs 1: odds ratio [OR] = 31.1, 95% confidence interval [CI]: 4.5–214, p 0.001 3 vs 2: OR = 14.6, 95% CI: 2.3–93.1, p = 0.004) and generalized polyspike train (burst of generalized rhythmic spikes lasting less than 1 second) during sleep were associated with drug resistance (OR = 10.8, 95% CI: 2.4–49.4, p = 0.002). When these factors were tested in the replication cohort of 80 patients (27.5% drug-resistant and 72.5% drug-responsive 71.3% female median age 27.5 years), the proportion of patients with generalized polyspike train during sleep was also higher in the drug-resistant group (OR = 4.0, 95% CI: 1.35–11.8, p = 0.012). Generalized polyspike train during sleep may be an EEG biomarker for drug resistance in adults with idiopathic generalized epilepsy.
Publisher: Wiley
Date: 11-08-2022
DOI: 10.1111/EPI.17376
Abstract: The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22–25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK‐001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin‐dependent kinase‐like 5 deficiency disorder in patients 2 years of age and older.
Publisher: Oxford University Press (OUP)
Date: 23-11-2022
Abstract: More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7–11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9–2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8–0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9–1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63–0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64–0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.
Publisher: Oxford University Press (OUP)
Date: 29-08-2022
DOI: 10.1093/BRAINCOMMS/FCAC218
Abstract: The application of deep learning approaches for the detection of interictal epileptiform discharges is a nascent field, with most studies published in the past 5 years. Although many recent models have been published demonstrating promising results, deficiencies in descriptions of data sets, unstandardized methods, variation in performance evaluation and lack of demonstrable generalizability have made it difficult for these algorithms to be compared and progress to clinical validity. A few recent publications have provided a detailed breakdown of data sets and relevant performance metrics to exemplify the potential of deep learning in epileptiform discharge detection. This review provides an overview of the field and equips computer and data scientists with a synopsis of EEG data sets, background and epileptiform variation, model evaluation parameters and an awareness of the performance metrics of high impact and interest to the trained clinical and neuroscientist EEG end user. The gold standard and inter-rater disagreements in defining epileptiform abnormalities remain a challenge in the field, and a hierarchical proposal for epileptiform discharge labelling options is recommended. Standardized descriptions of data sets and reporting metrics are a priority. Source code-sharing and accessibility to public EEG data sets will increase the rigour, quality and progress in the field and allow validation and real-world clinical translation.
Publisher: SAGE Publications
Date: 19-02-2023
DOI: 10.1177/13524585231151400
Abstract: Multiple sclerosis patients experience 3–6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying therapy recipients remains unknown. The objective of this study was to compare seizure risk in multiple sclerosis patients receiving disease-modifying therapy versus placebo. MEDLINE(OVID), Embase, CINAHL, and ClinicalTrials.gov were searched from database inception until August 2021. Phase 2–3 randomized, placebo-controlled trials reporting efficacy and safety data for disease-modifying therapies were included. Network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using Bayesian random effects model for in idual and pooled (by drug target) therapies. Main outcome was log e seizure risk ratios [95% credible intervals]. Sensitivity analysis included meta-analysis of non-zero-event studies. A total of 1993 citations and 331 full-texts were screened. Fifty-six included studies (29,388 patients—disease-modifying therapy = 18,909 placebo = 10,479) reported 60 seizures (therapy = 41 placebo = 19). No in idual therapy was associated with altered seizure risk ratio. Exceptions were daclizumab (−17.90 [−65.31 −0.65]) and rituximab (−24.86 [−82.71 −1.37]) trending toward lower risk ratio cladribine (25.78 [0.94 4.65]) and pegylated interferon-beta-1a (25.40 [0.78 85.47]) trended toward higher risk ratio. Observations had wide credible intervals. Sensitivity analysis of 16 non-zero-event studies revealed no difference in risk ratio for pooled therapies (l0.32 [−0.94 0.29]) No evidence of association was found between disease-modifying therapy and seizure risk—this informs seizure management in multiple sclerosis patients.
Publisher: IOP Publishing
Date: 10-2022
Abstract: Automated interictal epileptiform discharge (IED) detection has been widely studied, with machine learning methods at the forefront in recent years. As computational resources become more accessible, researchers have applied deep learning (DL) to IED detection with promising results. This systematic review aims to provide an overview of the current DL approaches to automated IED detection from scalp electroencephalography (EEG) and establish recommendations for the clinical research community. We conduct a systematic review according to the PRISMA guidelines. We searched for studies published between 2012 and 2022 implementing DL for automating IED detection from scalp EEG in major medical and engineering databases. We highlight trends and formulate recommendations for the research community by analyzing various aspects: data properties, preprocessing methods, DL architectures, evaluation metrics and results, and reproducibility. The search yielded 66 studies, and 23 met our inclusion criteria. There were two main DL networks, convolutional neural networks in 14 studies and long short-term memory networks in three studies. A hybrid approach combining a hidden Markov model with an autoencoder was employed in one study. Graph convolutional network was seen in one study, which considered a montage as a graph. All DL models involved supervised learning. The median number of layers was 9 (IQR: 5–21). The median number of IEDs was 11 631 (IQR: 2663–16 402). Only six studies acquired data from multiple clinical centers. AUC was the most reported metric (median: 0.94 IQR: 0.94–0.96). The application of DL to IED detection is still limited and lacks standardization in data collection, multi-center testing, and reporting of clinically relevant metrics (i.e. F1, AUCPR, and false-positive/minute). However, the performance is promising, suggesting that DL might be a helpful approach. Further testing on multiple datasets from different clinical centers is required to confirm the generalizability of these methods.
Publisher: Wiley
Date: 09-08-2022
DOI: 10.1111/EPI.17373
Abstract: The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22–25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO‐3‐02, GRT‐X, NBI‐921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Wiley
Date: 15-04-2020
DOI: 10.1002/ANA.25724
Publisher: Wiley
Date: 10-2022
Abstract: Epilepsy genetics is a rapidly developing field, in which novel disease‐associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre‐ and post‐test counseling, and follow‐up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve in idual care. We emphasize the importance of genetic testing for in iduals with epilepsy as we enter the era of precision therapy.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-04-2009
Publisher: Annual Reviews
Date: 31-08-2020
DOI: 10.1146/ANNUREV-GENOM-120219-074937
Abstract: Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Mary Ann Liebert Inc
Date: 10-2023
Publisher: Elsevier BV
Date: 02-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2020
DOI: 10.1212/WNL.0000000000009855
Abstract: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0–3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4–19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%. Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.YEBEH.2021.108406
Abstract: To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy. Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy. The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.SEIZURE.2022.02.004
Abstract: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 in iduals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 in iduals with no abnormality, 50% reported prior seizures (p 50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older in iduals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.
Publisher: Wiley
Date: 11-2020
DOI: 10.1111/EPI.16726
Publisher: Wiley
Date: 02-11-2020
DOI: 10.1111/EPI.16727
Publisher: Wiley
Date: 29-08-2019
DOI: 10.1111/EPI.16329
Abstract: Epidemiological data and gene association studies suggest a genetic predisposition to developing epilepsy after an acquired brain insult, such as traumatic brain injury. An improved understanding of genetic determinants of vulnerability is imperative for early disease diagnosis and prognosis prediction, with flow‐on benefits for the development of targeted antiepileptogenic treatments as well as optimal clinical trial design. In the laboratory, one approach to investigate why some in iduals are more vulnerable to acquired epilepsy than others is to examine unique rodent models exhibiting either vulnerability or resistance to epileptogenesis. This review focuses on the most well‐characterized of these models, the FAST (seizure‐prone) and SLOW (seizure‐resistant) rat strains, which were derived by selective breeding for differential amygdala electrical kindling rates. We describe how these strains differ in their seizure profiles, neuroanatomy, and neurobehavioral phenotypes, both at baseline and after a brain insult, with this knowledge proving fruitful to identify common pathological abnormalities associated with seizure susceptibility and psychiatric comorbidities. It is important to note that accruing data on strain differences in multiple biological processes provides insight into why some in iduals may be more vulnerable to epileptogenesis, although future studies are evidently needed to identify the precise molecular and genetic risk factors. Together, the FAST and SLOW rat strains, and other similar experimental models, are invaluable neurobiological tools to investigate the effect of genetic background on acquired epilepsy risk, as well as the poorly understood relationship between epilepsy development and associated comorbidities.
Publisher: Wiley
Date: 11-2020
DOI: 10.1111/EPI.16725
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/EPI4.12693
Abstract: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine ( P = 0.166), one NaM‐ASM ( P = 0.80), or ≥2NaM‐ASMs ( P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56 P = 0.054), one NaM‐ASM (aHR = 0.8 P = 0.588) or ≥2 NaM‐ASMs (aHR = 0.49 P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic–clonic seizures at EMU admission associated with ‐fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24 P = 0.031) or NaM‐ASM use (aHR = 2.25 P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow‐up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM‐ASMs are unlikely to be associated with an increased long‐term risk of SUDEP, up to 16 years post‐EMU admission.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.NBD.2014.05.016
Abstract: Gender differences in the incidence and clinical course of acquired and "cryptogenic" epilepsy are reviewed based on a literature search. We emphasized incidence and population-based studies because they are best suited to assess the effect of gender on susceptibility and clinical evolution of these epilepsies and may control for potential confounding factors. However, such studies were only available for a few acquired etiologies. These included tumor, prenatal and perinatal brain insults, cerebrovascular disease, infection, trauma, neurodegenerative disease, and autoimmune disorders. None of these acquired causes has been consistently shown to affect women or men to a greater or lesser degree, although some of the literature is contradictory or inadequate. There is almost no literature that addresses the effect of gender on the clinical course of epilepsy associated with these acquired causes. In addition, most studies of acquired causes do not take into account the incidence of the cause in the population with or without associated epilepsy. In children, "cryptogenic" epilepsy (non-syndromic and without causative MRI lesion) does not appear to have a gender preference and gender does not seem to affect the likelihood of remission. As further population-based studies of the etiology and clinical course of epilepsy are undertaken, it may be worthwhile to more specifically define the role of gender.
Publisher: Oxford University Press (OUP)
Date: 31-01-2018
DOI: 10.1093/SLEEP/ZSY015
Abstract: Epilepsy is a group of neurological conditions in which there is a pathological and enduring predisposition to generate recurrent seizures. Evidence over the last few decades suggests that epilepsy may be associated with increased sleep-disordered breathing, which may contribute towards sleep fragmentation, daytime somnolence, reduced seizure control, and cardiovascular-related morbidity and mortality. Chronic sleep-disordered breathing can result in loss of gray matter and cause deficits to memory and global cognitive function. Sleep-disordered breathing is a novel and independent predictor of sudden cardiac death and, as such, may be involved in the mechanisms leading to sudden unexpected death in epilepsy. Despite this, the long-term consequences of sleep-disordered breathing in epilepsy remain unknown, and there are no guidelines for screening or treating this population. There is currently insufficient evidence to indicate continuous positive airway pressure (CPAP) for the primary or secondary prevention of cardiovascular disease, and recent evidence has failed to show any reduction of fatal or nonfatal cardiovascular endpoints. Treatment of sleep-disordered breathing may potentially improve seizure control, daytime somnolence, and neurocognitive outcomes, but few studies have examined this relationship. In this review, we examine sleep-disordered breathing in epilepsy, and discuss the potential effect of epilepsy treatments. We consider the role of CPAP and other interventions for sleep-disordered breathing and discuss their implications for epilepsy management.
Publisher: Wiley
Date: 31-01-2023
DOI: 10.1002/EPI4.12692
Abstract: Epilepsy is associated with an increased risk of cardiovascular disease and mortality. Whether cardiac structure and function are altered in epilepsy remains unclear. To address this, we conducted a systematic review and meta‐analysis of studies evaluating cardiac structure and function in patients with epilepsy. We searched the electronic databases MEDLINE, PubMed, COCHRANE, and Web of Science from inception to 31 December 2021. Primary outcomes of interest included left ventricular ejection fraction (LVEF) for studies reporting echocardiogram findings and cardiac weight and fibrosis for postmortem investigations. Study quality was assessed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tools. Among the 10 case‐control studies with epilepsy patients (n = 515) and healthy controls (n = 445), LVEF was significantly decreased in epilepsy group compared with controls (MD: −1.80 95% confidence interval [CI]: −3.56 to −0.04 P = 0.045), whereas A‐wave velocity (MD: 4.73 95% CI: 1.87‐7.60 P = 0.001), E/e' ratio (MD: 0.39 95% CI: 0.06‐0.71 P = 0.019), and isovolumic relaxation time (MD: 10.18 95% CI: 2.05‐18.32 P = 0.014) were increased in epilepsy, compared with controls. A pooled analysis was performed in sudden unexpected death in epilepsy (SUDEP) cases with autopsy data (n = 714). Among SUDEP cases, the prevalence of cardiac hypertrophy was 16% (95% CI: 9%–23%) cardiac fibrosis was 20% (95% CI: 15%–26%). We found no marked differences in cardiac hypertrophy, heart weight, or cardiac fibrosis between SUDEP cases and epilepsy controls. Our findings suggest that epilepsy is associated with altered diastolic and systolic echocardiogram parameters compared with healthy controls. Notably, SUDEP does not appear to be associated with a higher incidence of structural cardiac abnormalities, compared with non‐SUDEP epilepsy controls. Longitudinal studies are needed to understand the prognostic significance of such changes. Echocardiography may be a useful noninvasive diagnostic test in epilepsy population.
No related grants have been discovered for Piero Perucca.