Publications by authors named "Piero Perucca"

64 Publications

Missed, mistaken, stalled: Identifying components of delay to diagnosis in epilepsy.

Epilepsia 2021 May 20. Epub 2021 May 20.

Department of Medicine (Austin Health), Epilepsy Research Centre, University of Melbourne, Melbourne, Victoria, Australia.

A substantial proportion of individuals 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.
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http://dx.doi.org/10.1111/epi.16929DOI Listing
May 2021

Psychiatric and cognitive characteristics of older adults admitted to a Video-EEG monitoring (VEM) unit.

Epilepsy Behav 2021 Jul 9;120:107987. Epub 2021 May 9.

Department of Medicine (RMH), The University of Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Parkville, Australia; Melbourne School of Psychological Sciences, The University of Melbourne, Australia.

Objective: To compare the clinical, psychiatric, and cognitive characteristics of older with younger patients presenting to a video-EEG monitoring (VEM) unit.

Method: This was a retrospective case-control study involving patients admitted for VEM over a two-year period (from April 2018 to April 2020) at two comprehensive epilepsy units. Patients were categorized into an older (≥60 years) and a younger (<60 years) group. Younger patients were individually matched to older adults to form a matched younger group. Diagnosis was determined by a consensus opinion of epileptologists, neurologists, and neuropsychiatrists. The main diagnostic categories were epilepsy, psychogenic nonepileptic seizures (PNES), and 'other' diagnosis (non-diagnostic and other nonepileptic diagnoses). Clinical psychiatric diagnoses were obtained from neuropsychiatric reports. Objective cognitive function was measured with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). Subjective cognitive function was assessed using the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) cognitive subscales.

Results: Five-hundred and thirty three patients (71 older, 462 younger) aged 16-91 years were admitted to the VEM unit during the study period. There was a diagnosis of focal epilepsy in 55% of the older group and 48% of the younger group, generalized epilepsy in 3% of the older group and 10% of the younger group, and 'other' in 32% of the older group and 19% of the younger group. Ten percent (2 males and 5 females) of the older group were diagnosed with PNES compared to 22% of the younger group (p = 0.016). A depressive disorder was diagnosed in 34% of the older group and 24% of the younger group (p = 0.20). An anxiety disorder was diagnosed in 15% of the older group and 25% of the younger group (p = 0.15). Mild neurocognitive disorder was more common in the older group (34%) compared to the matched younger group (34% vs 3%, p < 0.001). The older group had lower mean NUCOG scores compared to the matched younger group (79.49 vs 87.73, p = <0.001). There was no evidence for a relationship between mean NUCOG score and overall subjective cognitive difficulties for the older group (r = 0.03, p = 0.83). Among older adults, those diagnosed with PNES had more experiences of childhood trauma. Measures of dissociation, depression, or general anxiety did not differ between PNES and non-PNES diagnoses in the older group.

Conclusion: Psychiatric comorbidities are common among older adults admitted for VEM. The psychological impact of epilepsy and risk factors for PNES seen in younger patients are also applicable in the older group. The older group demonstrated more cognitive impairments than the younger group, although these were usually unrecognized by individuals. Older adults admitted to VEM will benefit from psychiatric and neuropsychological input to ensure a comprehensive care approach to evaluation and management.
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http://dx.doi.org/10.1016/j.yebeh.2021.107987DOI Listing
July 2021

The prevalence of epileptic seizures in multiple sclerosis in a large tertiary hospital in Australia.

Mult Scler J Exp Transl Clin 2021 Jan-Mar;7(1):2055217321989767. Epub 2021 Feb 24.

Department of Neurology, Royal Melbourne Hospital, Parkville, Australia.

Rationale: To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features.

Methods: 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.

Results: 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 >6) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures.

Conclusion: 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.
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http://dx.doi.org/10.1177/2055217321989767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907940PMC
February 2021

Continuous EEG use and status epilepticus treatment in Australasia: a practice survey of Australian and New Zealand epileptologists.

BMJ Neurol Open 2020 15;2(2):e000102. Epub 2020 Dec 15.

Neuroscience, Monash University, Melbourne, Victoria, Australia.

Objective: Continuous electroencephalography (cEEG) is increasingly used to detect non-convulsive seizures in critically ill patients but is not widely practised in Australasia. Use of cEEG is also influencing the management of status epilepticus (SE), which is rapidly evolving. We aimed to survey Australian and New Zealand cEEG use and current treatment of SE.

Methods: A web-based survey was distributed to Epilepsy Society of Australia (ESA) members, between October and November 2019. Adult and paediatric neurologists/epileptologists with ESA membership involved in clinical epilepsy care and cEEG interpretation were invited to participate.

Results: Thirty-five paediatric/adult epileptologists completed the survey, 51% with over 10 years of consultant experience. cEEG was always available for only 31% of respondents, with the majority having no or only ad hoc access to cEEG. Lack of funding (74%) and personnel (71%) were the most common barriers to performing cEEG. Although experience with SE was common, responses varied regarding treatment approaches for both convulsive and non-convulsive SE. Escalation to anaesthetic treatment of convulsive SE tended to occur later than international guideline recommendations. There was general agreement that formal training in cEEG and national guidelines for SE/cEEG were needed.

Conclusions: cEEG availability remains limited in Australia, with lack of funding and resourcing being key commonly identified barriers. Current opinions on the use of cEEG and treatment of SE vary reflecting the complexity of management and a rapidly evolving field. An Australian-based guideline for the management of SE, including the role of cEEG is recommended.
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http://dx.doi.org/10.1136/bmjno-2020-000102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871708PMC
December 2020

Newly diagnosed seizures assessed at two established first seizure clinics: Clinic characteristics, investigations, and findings over 11 years.

Epilepsia Open 2021 03 13;6(1):171-180. Epub 2021 Jan 13.

Epilepsy Research Centre Department of Medicine (Austin Health) University of Melbourne Melbourne Australia.

Objective: 'First seizure' clinics (FSCs) aim to achieve early expert assessment for individuals 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.

Methods: 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.

Results: Median patient age was 37 (IQR 26-52, range 18-94) years (AH 34 vs RMH 42 years;  < .001). Eighty-six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days;  < .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%;  < .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 (<1%) 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.

Significance: 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.
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http://dx.doi.org/10.1002/epi4.12460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918310PMC
March 2021

Interictal autonomic dysfunction.

Curr Opin Neurol 2021 Apr;34(2):197-205

Department of Neuroscience, Central Clinical School, Monash University.

Purpose Of Review: Epilepsy is associated with autonomic dysfunction. Here, we provide an up-to-date review on measures of interictal autonomic function, focusing on heart rate variability (HRV), baroreflex sensitivity (BRS) and electrodermal activity (EDA).

Recent Findings: Resting HRV, BRS and EDA are altered in patients with epilepsy compared with healthy controls. A larger body of work is available for HRV compared with BRS and EDA, and points to interictal HRV derangements across a wide range of epilepsies, including focal, generalized, and combined generalized and focal epilepsies. HRV alterations are most pronounced in temporal lobe epilepsy, Dravet syndrome and drug-resistant and chronic epilepsies. There are conflicting data on the effect of antiseizure medications on measures of interictal autonomic function. However, carbamazepine has been associated with decreased HRV. Epilepsy surgery and vagus nerve stimulation do not appear to have substantial impact on measures of interictal autonomic function but well designed studies are lacking.

Summary: Patients with epilepsy, particularly those with longstanding uncontrolled seizures, have measurable alterations of resting autonomic function. These alterations may be relevant to the increased risk of premature mortality in epilepsy, including sudden unexpected death in epilepsy, which warrants investigation in future research.
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http://dx.doi.org/10.1097/WCO.0000000000000906DOI Listing
April 2021

Prenatal valproate exposure and adverse neurodevelopmental outcomes: Does sex matter?

Epilepsia 2021 Mar 5;62(3):709-719. Epub 2021 Feb 5.

Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Objective: Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes.

Methods: The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4-11 years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient-Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed-effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores.

Results: A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644 ± 310 mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p = .006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p = .01); however, this typical sex dynamic was not evident in VPA-exposed children. There was no evidence of any dose-response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure.

Significance: Prenatal VPA exposure seems to negate the usual male sex-related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.
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http://dx.doi.org/10.1111/epi.16827DOI Listing
March 2021

Adverse events related to antiepileptic drugs.

Epilepsy Behav 2021 02 22;115:107657. Epub 2020 Dec 22.

Department of Neurology, The Royal Melbourne Hospital, Parkville, Australia; Department of Neurology, Alfred Health, Melbourne, Australia; Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Clinical Outcomes Research (CORe) Unit, Department of Medicine (RMH), The University of Melbourne, Parkville, Australia.

Objective: Adverse events (AEs) related to antiepileptic drugs (AEDs) may interfere with adequate dosing and patient adherence, leading to suboptimal seizure control, and relatedly, increased injuries, hospitalizations, and mortality. This study investigated the clinicodemographic factors associated with AEs related to AEDs as reported by the Liverpool Adverse Events Profile (LAEP), and explored the ability of LAEP to discriminate between epilepsy and psychogenic nonepileptic seizures (PNES). We hypothesized that female sex, mood disorders, AED-polytherapy, duration, and severity of epilepsy are associated with increased endorsement of AEs related to AEDs, and that endorsement of AEs related to AEDs would significantly differ between epilepsy and PNES patients.

Methods: We prospectively enrolled adult patients admitted to two inpatient video-electroencephalogram monitoring units. Clinicodemographic variables and psychometric measures of depression, anxiety, and cognitive function were recorded. Patient-reported AE endorsement was obtained using the LAEP, which was reduced to four latent domains using exploratory structural equation modeling. General linear models identified variables associated with each domain. Logistic regression determined the ability of LAEP scores to differentiate between epilepsy and PNES.

Results: 311 patients met inclusion criteria. Mean age was 38 years and 56% of patients were female. Network analysis demonstrated strong relationships between depression and anxiety with physical, sleep, psychiatric, and dermatological AE endorsement. Depression, female sex, and AED polytherapy were associated with greater AE endorsement. Epilepsy, compared to PNES, was associated with lower AE endorsement. Fewer prescribed AEDs and greater reported physical AE endorsement were associated with PNES diagnosis.

Significance: There is a strong relationship between patient-reported AEs and psychiatric symptomatology. Those with PNES paradoxically endorse greater physical AEs despite receiving fewer AEDs. Patients who endorse AEs in clinical practice should be screened for comorbid depression or anxiety and treated accordingly.
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http://dx.doi.org/10.1016/j.yebeh.2020.107657DOI Listing
February 2021

Evaluating risk to people with epilepsy during the COVID-19 pandemic: Preliminary findings from the COV-E study.

Epilepsy Behav 2021 02 28;115:107658. Epub 2020 Nov 28.

Oxford Epilepsy Research Group, NIHR Biomedical Research Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address:

The COVID-19 pandemic has caused global anguish unparalleled in recent times. As cases rise, increased pressure on health services, combined with severe disruption to people's everyday lives, can adversely affect individuals living with chronic illnesses, including people with epilepsy. Stressors related to disruption to healthcare, finances, mental well-being, relationships, schooling, physical activity, and increased isolation could increase seizures and impair epilepsy self-management. We aim to understand the impact that COVID-19 has had on the health and well-being of people with epilepsy focusing on exposure to increased risk of seizures, associated comorbidity, and mortality. We designed two online surveys with one addressing people with epilepsy directly and the second for caregivers to report on behalf of a person with epilepsy. The survey is ongoing and has yielded 463 UK-based responses by the end of September 2020. Forty percent of respondents reported health changes during the pandemic (n = 185). Respondents cited a change in seizures (19%, n = 88), mental health difficulties (34%, n = 161), and sleep disruption (26%, n = 121) as the main reasons. Thirteen percent found it difficult to take medication on time. A third had difficulty accessing medical services (n = 154), with 8% having had an appointment canceled (n = 39). Only a small proportion reported having had discussions about epilepsy-related risks, such as safety precautions (16%, n = 74); mental health (29%, n = 134); sleep (30%, n = 140); and Sudden Unexpected Death in Epilepsy (SUDEP; 15%, n = 69) in the previous 12 months. These findings suggest that people with epilepsy are currently experiencing health changes, coupled with inadequate access to services. Also, there seems to be a history of poor risk communication in the months preceding the pandemic. As the UK witnesses a second COVID-19 wave, those involved in healthcare delivery must ensure optimal care is provided for people with chronic conditions, such as epilepsy, to ensure that avoidable morbidity and mortality is prevented during the pandemic, and beyond.
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http://dx.doi.org/10.1016/j.yebeh.2020.107658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698680PMC
February 2021

Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease.

Epilepsia 2021 02 14;62(2):303-324. Epub 2020 Dec 14.

Department of Neuroscience, Central Clinical School, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/epi.16788DOI Listing
February 2021

Folic acid dose, valproate, and fetal malformations.

Epilepsy Behav 2021 01 1;114(Pt A):107569. Epub 2020 Dec 1.

Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Queensland 4027, Australia.

Objective: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy.

Methods: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy.

Results: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409).

Conclusions: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.
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http://dx.doi.org/10.1016/j.yebeh.2020.107569DOI Listing
January 2021

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development.

Epilepsia 2020 11 14;61(11):2340-2364. Epub 2020 Nov 14.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
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http://dx.doi.org/10.1111/epi.16725DOI Listing
November 2020

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development.

Epilepsia 2020 11 9;61(11):2365-2385. Epub 2020 Nov 9.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.
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http://dx.doi.org/10.1111/epi.16726DOI Listing
November 2020

Twin pregnancy in women with epilepsy.

Epilepsia 2020 12 2;61(12):2748-2753. Epub 2020 Nov 2.

Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, Qld, Australia.

Objective: We report data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) to see if there are significant differences in relation to the courses and outcomes of the twin pregnancies contained in the register, as compared with the singleton ones.

Methods: The APR has been under the oversight of Melbourne institutional Human Ethics Research Committees; all women enrolled in the APR have provided written informed consent. Data from the APR were transferred to a spreadsheet and then analyzed using simple statistical techniques including logistic regression.

Results: The population studied comprised 44 twin and 2261 singleton pregnancies; thus, twin pregnancies accounted for 1.91% of all pregnancies studied. The women carrying twins tended to be older than the women with singleton pregnancies to a statistically significant extent, their pregnancies more often originated from assisted fertilization techniques, and their babies were more often delivered by cesarean section. There were no statistically significant differences in relation to antiepileptic drug (AED) therapy. Individual twins had statistically significantly lower mean birthweights than singleton babies and they were statistically significantly more often involved structurally malformed foetuses. In the first year of life, the twin pregnancies statistically significantly more often produced offspring that were affected by seizures in infancy.

Significance: The data suggest that there may be an increased hazard of fetal malformation in the offspring of twin pregnancy in women with epilepsy, but that with contemporary standards of management of epilepsy and pregnancy, there is unlikely to be an increased hazard of seizure-affected pregnancy.
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http://dx.doi.org/10.1111/epi.16727DOI Listing
December 2020

When the first seizure can be the last: ventricular fibrillation following a new-onset seizure.

Epileptic Disord 2020 Oct;22(5):669-672

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia, Departments of Neurology and Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia, Department of Neurology, Alfred Health, Melbourne, Victoria, Australia.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Its mechanisms remain incompletely understood. Post-ictal arrhythmias rather than ictal arrhythmias appear to be associated with an increased risk of SUDEP. Only a handful of individuals with epilepsy who have survived ventricular arrhythmias post seizure (near-SUDEP) are reported in the literature. We report a case of ventricular fibrillation following a first-ever unprovoked seizure in a patient without epilepsy, in whom a sinus rhythm was restored following cardioversion. A defibrillator was subsequently implanted. Our case suggests that even first seizures might account for some of the many cases of unexplained ventricular fibrillation or sudden cardiac death.
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http://dx.doi.org/10.1684/epd.2020.1207DOI Listing
October 2020

Genetic Contributions to Acquired Epilepsies.

Epilepsy Curr 2021 Jan-Feb;21(1):5-13. Epub 2020 Sep 29.

Department of Medicine, 2281Epilepsy Research Centre, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.

Whether genetic factors contribute to acquired epilepsies has long been controversial. Supporters observe that, among individuals 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.
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http://dx.doi.org/10.1177/1535759720954254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863311PMC
September 2020

Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.

Neurology 2020 10 5;95(15):e2150-e2160. Epub 2020 Aug 5.

From the Department of Neurology (H.C., C.B., P.C., M.M.) and Institute for Genomic Medicine (E.L.H.), Columbia University Medical Center, New York, NY; Department of Neurology (K.D.), University of Miami, FL; Department of Statistics and Biostatistics (S.T.), Rutgers University, Piscataway, NJ; Department of Neurology (H.T., L.J.H.), Yale University, New Haven, CT; Nuffield Department of Clinical Neurosciences (A.S.), NIHR Biomedical Research Centre, University of Oxford, UK; Department of Neurology (C.D.), Free University of Brussels, Belgium; Department of Neuroscience (P.P.), Monash University; Departments of Medicine and Neurology (P.P.), The Royal Melbourne Hospital, The University of Melbourne; Department of Neurology (P.P.), Alfred Health, Melbourne, Australia; and Department of Genetics (G.A.H.), Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ.

Objective: To develop and validate a clinical prediction model for antiepileptic drug (AED)-resistant genetic generalized epilepsy (GGE).

Method: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1212/WNL.0000000000010597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713754PMC
October 2020

Mortality in patients with psychogenic nonepileptic seizures.

Neurology 2020 08 20;95(6):e643-e652. Epub 2020 Jul 20.

From the Department of Neuroscience, Central Clinical School (R.N., S.B., C.B.M., P.P., Z.C., S.S., P.K., T.J.O.), and Clinical Epidemiology, School of Public Health and Preventive Medicine (Z.C.), Monash University, Melbourne; Departments of Medicine (R.N., C.A., G.T., C.B.M., P.P., A.M., Z.C., S.S., P.K., T.J.O.) and Neurology (R.N., C.A., G.T., C.B.M., P.P., S.S., P.K., T.J.O.) and Neuropsychiatry Unit (L.M., S.J., S.A., D.V.), The Royal Melbourne Hospital, and The Melbourne School of Psychological Sciences (C.B.M.), The University of Melbourne, Parkville; Department of Medicine (R.N.) and Epilepsy Research Centre, Department of Medicine (A.M., S.F.B.), Austin Health, The University of Melbourne, Heidelberg; Department of Neurology (C.B.M., P.P., A.M., S.S., P.K., T.J.O.), The Alfred Hospital, Melbourne; and Department of Medicine (S.I., M.J.C., W.D.), St. Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.

Objective: 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.

Methods: 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.

Results: 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%.

Conclusions: 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.
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http://dx.doi.org/10.1212/WNL.0000000000009855DOI Listing
August 2020

Cardiorespiratory and autonomic function in epileptic seizures: A video-EEG monitoring study.

Epilepsy Behav 2020 10 10;111:107271. Epub 2020 Jul 10.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne 3000, Victoria, Australia; Department of Neurology, The Royal Melbourne Hospital, Parkville 3050, Victoria, Australia; The Epilepsy Unit, Alfred Health, Melbourne 3004, Victoria, Australia; Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Parkville 3050, Victoria, Australia.

Purpose: Seizure-induced cardiorespiratory and autonomic dysfunction has long been recognized, and growing evidence points to its implication in sudden unexpected death in epilepsy (SUDEP). However, a comprehensive understanding of cardiorespiratory function in the preictal, ictal, and postictal periods are lacking.

Methods: We examined continuous cardiorespiratory and autonomic function in 157 seizures (18 convulsive and 139 nonconvulsive) from 70 consecutive patients who had a seizure captured on concurrent video-encephalogram (EEG) monitoring and polysomnography between February 1, 2012 and May 31, 2017. Heart and respiratory rates, heart rate variability (HRV), and oxygen saturation were assessed across four distinct periods: baseline (120 s), preictal (60 s), ictal, and postictal (300 s). Heart and respiratory rates were further followed for up to 60 min after seizure termination to assess return to baseline.

Results: Ictal tachycardia occurred during both convulsive and nonconvulsive seizures, but the maximum rate was higher for convulsive seizures (mean: 138.8 beats/min, 95% confidence interval (CI): 125.3-152.4) compared with nonconvulsive seizures (mean: 105.4 beats/min, 95% CI: 101.2-109.6; p < 0.001). Convulsive seizures were associated with a lower ictal minimum respiratory rate (mean: 0 breaths/min, 95% CI: 0-0) compared with nonconvulsive seizures (mean: 11.0 breaths/min, 95% CI: 9.5-12.6; p < 0.001). Ictal obstructive apnea was associated with convulsive compared with nonconvulsive seizures. The low-frequency (LF) power band of ictal HRV was higher among convulsive seizures than nonconvulsive seizures (ratio of means (ROM): 2.97, 95% CI: 1.34-6.60; p = 0.008). Postictal tachycardia was substantially prolonged, characterized by a longer return to baseline for convulsive seizures (median: 60.0 min, interquartile range (IQR): 46.5-60.0) than nonconvulsive seizures (median: 0.26 min, IQR: 0.008-0.9; p < 0.001). For postictal hyperventilation, the return to baseline was longer in convulsive seizures (median: 25.3 min, IQR: 8.1-60) than nonconvulsive seizures (median: 1.0 min, IQR: 0.07-3.2; p < 0.001). The LF power band of postictal HRV was lower in convulsive seizures than nonconvulsive seizures (ROM: 0.33, 95% CI: 0.11-0.96; p = 0.043). Convulsive seizures with postictal generalized EEG suppression (PGES; n = 12) were associated with lower postictal heart and respiratory rate, and increased HRV, compared with those without (n = 6).

Conclusions: Profound cardiorespiratory and autonomic dysfunction associated with convulsive seizures may explain why these seizures carry the greatest risk of SUDEP.
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http://dx.doi.org/10.1016/j.yebeh.2020.107271DOI Listing
October 2020

The Genetics of Epilepsy.

Annu Rev Genomics Hum Genet 2020 08 27;21:205-230. Epub 2020 Apr 27.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria 3084, Australia; email:

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.
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http://dx.doi.org/10.1146/annurev-genom-120219-074937DOI Listing
August 2020

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.

Ann Neurol 2020 06 15;87(6):897-906. Epub 2020 Apr 15.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objective: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated.

Methods: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data.

Results: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome.

Interpretation: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.
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http://dx.doi.org/10.1002/ana.25724DOI Listing
June 2020

An animal model of genetic predisposition to develop acquired epileptogenesis: The FAST and SLOW rats.

Epilepsia 2019 10 29;60(10):2023-2036. Epub 2019 Aug 29.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Vic., Australia.

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 individuals 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 individuals 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.
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http://dx.doi.org/10.1111/epi.16329DOI Listing
October 2019

High-Frequency Oscillations in the Scalp EEG of Intensive Care Unit Patients With Altered Level of Consciousness.

J Clin Neurophysiol 2020 May;37(3):246-252

Department of Clinical Neurophysiology, Hospital Israelita Albert Einstein, São Paulo, Brazil.

Purpose: 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.

Methods: Fifteen patients were included. Patients were divided 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).

Results: Patients were 23 to 106 years old (median, 68 years); 60% were female. 206 channels were eligible for analysis (median, 15 channels/patient). 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).

Conclusions: 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.
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http://dx.doi.org/10.1097/WNP.0000000000000624DOI Listing
May 2020

Human generalized epilepsy: Increased somatosensory and striatothalamic connectivity.

Neurol Genet 2019 Aug 7;5(4):e340. Epub 2019 Jun 7.

The Florey Institute of Neuroscience and Mental Health (M.P., M.K., A.O., S.P., I.E.S., G.D.J.), Parkville; Department of Neurology (I.E.S.), Royal Children's Hospital, Parkville; Department of Neuroscience (P.P.), Central Clinical School, Monash University; Department of Neurology (P.P.), The Royal Melbourne Hospital, Parkville; Department of Neurology (P.P.), Alfred Health, Melbourne; Department of Medicine (P.P., S.P.), The Royal Melbourne Hospital, The University of Melbourne, Parkville; Epilepsy Research Centre (S.G., I.E.S., S.F.B., G.D.J.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; and Department of Pediatrics (I.E.S.), The University of Melbourne, Parkville, VIC, Australia.

Objective: To map functional MRI (fMRI) connectivity within and between the somatosensory cortex, putamen, and ventral thalamus in individuals from a family with a GABAergic deficit segregating with febrile seizures and genetic generalized epilepsy.

Methods: We studied 5 adults from a family with early-onset absence epilepsy and/or febrile seizures and a GABA receptor subunit gamma2 pathogenic variant () vs 5 age-matched controls. We infer differences between participants with the pathogenic variant and controls in resting-state fMRI connectivity within and between the somatosensory cortex, putamen, and ventral thalamus.

Results: We observed increased fMRI connectivity within the somatosensory cortex and between the putamen and ventral thalamus in all individuals with the pathogenic variant compared with controls. Post hoc analysis showed less pronounced changes in fMRI connectivity within and between the primary visual cortex and precuneus.

Conclusions: Although our sample size was small, this preliminary study suggests that individuals with a 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 individuals with generalized epilepsy with and without known GABA pathogenic variants.
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http://dx.doi.org/10.1212/NXG.0000000000000340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563517PMC
August 2019

Harmonization of the pipeline for seizure detection to phenotype post-traumatic epilepsy in a preclinical multicenter study on post-traumatic epileptogenesis.

Epilepsy Res 2019 10 27;156:106131. Epub 2019 Apr 27.

The Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Australia; Department of Neurology, The Alfred Hospital, Commercial Road, Melbourne, Victoria, 3004, Australia; Department of Neurology, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3050, Australia. Electronic address:

Rationale: The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Centre without walls is an NIH funded multicenter consortium. One of EpiBioS4Rx projects is a preclinical post-traumatic epileptogenesis biomarker study that involves three study sites: The University of Eastern Finland, Monash University (Melbourne) and the University of California Los Angeles. Our objective is to create a platform for evaluating biomarkers and testing new antiepileptogenic treatments for post-traumatic epilepsy (PTE) using the lateral fluid percussion injury (FPI) model in rats. As only 30-50% of rats with severe lateral FPI develop PTE by 6 months post-injury, prolonged video-EEG monitoring is crucial to identify animals with PTE. Our objective is to harmonize the surgical and data collection procedures, equipment, and data analysis for chronic EEG recording in order to phenotype PTE in this rat model across the three study sites.

Methods: Traumatic brain injury (TBI) was induced using lateral FPI in adult male Sprague-Dawley rats aged 11-12 weeks. Animals were divided into two cohorts: a) the long-term video-EEG follow-up cohort (Specific Aim 1), which was implanted with EEG electrodes within 24 h after the injury; and b) the magnetic resonance imaging (MRI) follow-up cohort (Specific Aim 2), at 5 months after lateral FPI. Four cortical epidural screw electrodes (2 ipsilateral, 2 contralateral) and three intracerebral bipolar electrodes were implanted (septal CA1 and the dentate gyrus, layers II and VI of the perilesional cortex both anterior and posterior to the injury site). During the 7th post-TBI month, animals underwent 4 weeks of continuous video-EEG recordings to diagnose of PTE.

Results: All centers harmonized the induction of TBI and surgical procedures for the implantation of EEG recordings, utilizing 4 or more EEG recording channels to cover areas ipsilateral and contralateral to the brain injury, perilesional cortex and the hippocampus and dentate gyrus. Ground and reference screw electrodes were implanted. At all sites the minimum sampling rate was 512 Hz, utilizing a finite impulse response (FIR) and impedance below 10 KΩ through the entire recording. As part of the quality control criteria we avoided electrical noise, and monitoring changes in impedance over time and the appearance of noise on the recordings. To reduce electrical noise, we regularly checked the integrity of the cables, stability of the EEG recording cap and the appropriate connection of the electrodes with the cables. Following the pipeline presented in this article and after applying the quality control criteria to our EEG recordings all of the sites were successful to phenotype seizure in chronic EEG recordings of animals after TBI.

Discussion: Despite differences in video-EEG acquisition equipment used, the three centers were able to consistently phenotype seizures in the lateral fluid-percussion model applying the pipeline presented here. The harmonization of methodology will help to improve the rigor of preclinical research, improving reproducibility of pre-clinical research in the search of biomarkers and therapies to prevent antiepileptogenesis.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814157PMC
October 2019

Harmonization of pipeline for detection of HFOs in a rat model of post-traumatic epilepsy in preclinical multicenter study on post-traumatic epileptogenesis.

Epilepsy Res 2019 10 15;156:106110. Epub 2019 Mar 15.

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Studies of chronic epilepsy show pathological high frequency oscillations (HFOs) are associated with brain areas capable of generating epileptic seizures. Only a few of these studies have focused on HFOs during the development of epilepsy, but results suggest pathological HFOs could be a biomarker of epileptogenesis. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy" (EpiBioS4Rx) is a multi-center project designed to identify biomarkers of epileptogenesis after a traumatic brain injury (TBI) and evaluate treatments that could modify or prevent the development of post-traumatic epilepsy. One goal of the EpiBioS4Rx project is to assess whether HFOs could be a biomarker of post-traumatic epileptogenesis. The current study describes the work towards this goal, including the development of common surgical procedures and EEG protocols, an interim analysis of the EEG for HFOs, and identifying issues that need to be addressed for a robust biomarker analysis. At three participating sites - University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and University of California, Los Angeles (UCLA) - TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. After injury and in sham-operated controls, rats were implanted with screw and microwire electrodes positioned in neocortex and hippocampus to record EEG. A separate group of rats had serial magnetic resonance imaging after injury and then implanted with electrodes at 6 months. Recordings 28 days post-injury were available from UEF and UCLA, but not Melbourne due to technical issues with their EEG files. Analysis of recordings from 4 rats - UEF and UCLA each had one TBI and one sham-operated control - showed EEG contained evidence of HFOs. Computer-automated algorithms detected a total of 1,819 putative HFOs and of these only 40 events (2%) were detected by all three sites. Manual review of all events verified 130 events as HFO and the remainder as false positives. Review of the 40 events detected by all three sites was associated with 88% agreement. This initial report from the EpiBioS4Rx Consortium demonstrates the standardization of EEG electrode placements, recording protocol and long-term EEG monitoring, and differences in detection algorithm HFO results between sites. Additional work on detection strategy, detection algorithm performance, and training in HFO review will be performed to establish a robust, preclinical evaluation of HFOs as a biomarker of post-traumatic epileptogenesis.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736751PMC
October 2019

Identifying mutations in epilepsy genes: Impact on treatment selection.

Epilepsy Res 2019 05 4;152:18-30. Epub 2019 Mar 4.

Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy.

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 individual(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 example 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.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.001DOI Listing
May 2019

Genetics of Focal Epilepsies: What Do We Know and Where Are We Heading?

Authors:
Piero Perucca

Epilepsy Curr 2018 Nov-Dec;18(6):356-362

Senior Research Fellow, Department of Neuroscience, Central Clinical School, Monash University, Melbourne; Consultant Neurologist, Department of Neurology, The Royal Melbourne Hospital, Melbourne; Consultant Neurologist, Department of Neurology, Alfred Health, Melbourne; Honorary Senior Fellow, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.5698/1535-7597.18.6.356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278742PMC
December 2018

Sleep-disordered breathing among patients admitted for inpatient video-EEG monitoring.

Neurology 2019 01 14;92(3):e194-e204. Epub 2018 Dec 14.

From the Departments of Medicine (S.S., Z.C., A.P., C.J.R., N.C.J., C.F., P.P., P.K., T.J.O.), Neurology (S.S., E.J.W., A.P., C.H., J.C., C.J.R., R.Y., C.F., P.P., P.K., T.J.O.), and Respiratory and Sleep Disorders Medicine (T.M., J.G.), The Royal Melbourne Hospital, The University of Melbourne, Parkville; Department of Neuroscience (S.S., Z.C., A.P., N.C.J., C.F., P.P., P.K., T.J.O.), Central Clinical School, Monash University; Department of Neurology (S.S., A.P., P.P., P.K., T.J.O.), The Alfred Hospital; and Neuropsychiatry Unit (S.F., D.V.), The Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, Australia.

Objective: To examine the prevalence and risk factors of sleep-disordered breathing (SDB) in individuals with epilepsy and psychogenic nonepileptic seizures (PNES).

Methods: 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.

Results: 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 individuals, and did not differ across subgroups: epilepsy 26.3% (67/255), PNES 29.0% (27/93), or both disorders 18.2% (4/22; = 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; = 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; < 0.001) and higher body mass index (OR 1.06, 95% CI 1.01-1.11; = 0.029), and in PNES older age (OR 1.10, 95% CI 1.03-1.16; = 0.002).

Conclusion: 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.
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http://dx.doi.org/10.1212/WNL.0000000000006776DOI Listing
January 2019