Publications by authors named "Norman Delanty"

142 Publications

Post-ictal psychosis in epilepsy: A clinico-genetic study.

Ann Neurol 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.

Objective: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterised post-ictal psychosis, which comprises about one-quarter of epilepsy-related psychoses, and has unknown causation.

Methods: We conducted a case-control cohort study including patients diagnosed with post-ictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis: 49 had post-ictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with post-ictal psychosis; univariate associations with a P-value<0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated.

Results: Cases were more likely to have seizure clustering (OR 7.59, P<0.001), seizures with a recollected aura (OR 2.49, P=0.013) and a family history of psychiatric disease (OR 5.17, P=0.022). Cases showed predominance of right temporal epileptiform discharges (OR 4.87, P=0.007). There was no difference in epilepsy duration, neuroimaging findings or anti-seizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of post-ictal psychosis cases (58) were significantly higher than in 1,366 epilepsy controls (R =3%, P=6x10 ), but not significantly different from 945 independent patients with schizophrenia (R =0.1%, P=0.775).

Interpretation: Post-ictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (post-ictal psychosis) in a common disease. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26174DOI Listing
July 2021

Democratizing epilepsy care: Utility and usability of an electronic patient portal.

Epilepsy Behav 2021 Jul 14;122:108197. Epub 2021 Jul 14.

FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Neurology, St. James's Hospital, Dublin, Ireland; Academic Unit of Neurology, Trinity College Dublin.

Objectives: Electronic patient portals (ePortals) can facilitate greater healthcare democratization by providing patients and/or their authorized care partners with secure access to their medical records when and where needed. Such democratization can promote effective healthcare provider-patient partnerships, shared decision-making, and greater patient engagement in managing their health condition. This study examined the usefulness of providing individualized services and care in epilepsy (PiSCES), an epilepsy ePortal, as an enabler of more democratized epilepsy care.

Methods: Seventy-two individuals with epilepsy and 18 care partners were invited to report on their experience of interacting via PiSCES with clinical documents (epilepsy care summary record; epilepsy clinic letters) authored about them by healthcare providers. The OpenNotes reporting tool was adapted to capture participant experience.

Results: Twenty-five percent of invited patients and 44% of invited care partners reported on interacting with their epilepsy care summary; 14% of patients and 67% of care partners invited reported on their epilepsy clinic letters. Participant testimonials illustrate the value of PiSCES in: promoting autonomy, aiding memory, developing the knowledgeable patient, and enhancing healthcare partnerships. Ninety-six percent and 100% of respondents, respectively, reported understanding their epilepsy care summary and epilepsy clinic letter; 77% said the summary described their epilepsy history to date; 96% indicated that the letter provided an accurate description of their clinical encounter; 92% and 96%, respectively, valued access to their summary record and clinic letters; 77% of summary record and 73% clinic letter respondents reported learning something about their epilepsy or the healthcare service via PiSCES. Illustrating their potential patient and care partner safety role, 42% respondents identified inaccuracies in their clinical documents which were subsequently resolved by a clinician.

Significance: In the post-digital world highly customized on-demand products and services have come to be expected. Similarly, in epilepsy care, technologies such as PiSCES can enable more personalized, transparent, and engaging services.
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http://dx.doi.org/10.1016/j.yebeh.2021.108197DOI Listing
July 2021

Stick or twist: Everolimus for seizures in tuberous sclerosis complex during the COVID-19 pandemic.

Seizure 2021 Jul 5;91:271-272. Epub 2021 Jul 5.

FutureNeuro, the Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.

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http://dx.doi.org/10.1016/j.seizure.2021.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255220PMC
July 2021

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications.

Front Pharmacol 2021 9;12:688386. Epub 2021 Jun 9.

Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation. A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance. We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs. This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.
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http://dx.doi.org/10.3389/fphar.2021.688386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220970PMC
June 2021

Precision therapy in the genetic epilepsies of childhood.

Dev Med Child Neurol 2021 Jun 4. Epub 2021 Jun 4.

FutureNeuro SFI Research Centre and Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland.

Despite recent advances in both the understanding and treatment of the epilepsies, the rate of refractory epilepsy has remained static for many years. However, given our greater understanding of the aetiology and genetic basis of many paediatric and adult epilepsies, there is now scope to expand treatment. In this review, we discuss the current and potential use of precision medicine in the genetic epilepsies of childhood. We will discuss how optimal control and a reduction in the rate of refractory seizures using targeted therapy could be developed and assessed. We propose a six-tier approach to defining precision therapeutics in epilepsy and discuss how this can be incorporated into a clinical trial design. The lower tiers (1-2) represent therapies in common usage that we know work for certain epilepsy syndromes but do not precisely target the underlying problem. They work to reduce seizures but do not directly or effectively attenuate the developmental phenotype. The higher tiers (5-6) are currently purely speculative and look to a future with highly disease-specific therapies based on correction of underlying genomic and proteomic issues. In order to achieve this, scientists will have to embark on a 'whole-omic' approach to understand the underlying pathophysiology in order to design a precision therapy.
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http://dx.doi.org/10.1111/dmcn.14929DOI Listing
June 2021

Predictors of seizure freedom, response and retention after 12 months of treatment with eslicarbazepine acetate: A post-hoc analysis of the Euro-Esli study.

Epilepsy Res 2021 Aug 4;174:106653. Epub 2021 May 4.

Hospital Universitario y Politécnico La Fe, Valencia, Spain. Electronic address:

Eslicarbazepine acetate (ESL) is a once-daily antiseizure medication (ASM) that is approved in Europe and the USA for the treatment of focal-onset seizures. The Euro-Esli study, which included over 2000 patients, investigated the real-world effectiveness, safety and tolerability of ESL when used in everyday clinical practice in Europe. This post-hoc analysis of Euro-Esli employed univariate and multivariate binary logistic regression analyses to investigate the relationship between demographic and baseline characteristics (including epilepsy- and treatment-related factors) and the likelihood of seizure freedom, response and retention in adult patients with focal seizures after 12 months of ESL treatment in the real-world setting. Multivariate analysis revealed that the factors associated with seizure freedom and response at 12 months (N = 1054) were generally those characterising patients who were relatively early in their disease course and/or less refractory to treatment, such as older age at onset of epilepsy, absence of seizures at baseline and lower number of concomitant ASMs at baseline. Although it was not possible to construct a multivariate model to predict retention on ESL treatment at 12 months, when the univariate regression model was adjusted for age and epilepsy duration, the factors found to be significantly associated with retention at 12 months (N = 1559) comprised shorter duration of epilepsy, absence of any seizures at baseline, lower baseline seizure frequency (<5 vs. ≥ 5 seizures/month), lower number of previous ASMs, lower number of concomitant ASMs, and the absence of concomitant use of lamotrigine at baseline. These findings therefore identify baseline characteristics that are predictive of the effectiveness of ESL treatment in clinical practice, which may help clinicians choose appropriate ASM therapy for patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106653DOI Listing
August 2021

Reversible male infertility with valproate use: A review of the literature.

Epilepsy Behav Rep 2021 31;16:100446. Epub 2021 Mar 31.

Consultant Neurologist, Beaumont Hospital, and Honorary Clinical Professor, School of Pharmacy and Biomolecular Sciences, FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Co. Dublin D09A0EA, Ireland.

Sodium valproate is a broad spectrum anti-seizure medication useful in the treatment of both generalized and focal epilepsies. The association between valproate and female reproductive disorders is well understood and delineated. Male infertility however is an under-recognised adverse effect of Valproate therapy. Previous case reports have detailed reversible male infertility secondary to valproate. One report demonstrated a relationship between valproate dose and abnormal sperm parameters. We submit a case report suggesting a dose dependent effect of valproate on sperm parameters and a possible relationship between the duration of valproate therapy and its deleterious effect on male fertility. Men on valproate should be counselled about the possibility of progressive but reversible infertility. Valproate should be stopped and replaced by an alternative agent in those men who are infertile and where the couple are trying to conceive, particularly if there are associated abnormal sperm parameters while on the drug.
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http://dx.doi.org/10.1016/j.ebr.2021.100446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127004PMC
March 2021

Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.

Ann Clin Transl Neurol 2021 Jul 21;8(7):1376-1387. Epub 2021 May 21.

Université de Montréal, Montreal, Canada.

Objective: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance.

Methods: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE.

Results: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE.

Interpretation: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
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http://dx.doi.org/10.1002/acn3.51374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283173PMC
July 2021

Elevated blood purine levels as a biomarker of seizures and epilepsy.

Epilepsia 2021 Mar 18;62(3):817-828. Epub 2021 Feb 18.

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.

Objective: There is a major unmet need for a molecular biomarker of seizures or epilepsy that lends itself to fast, affordable detection in an easy-to-use point-of-care device. Purines such as adenosine triphosphate and adenosine are potent neuromodulators released during excessive neuronal activity that are also present in biofluids. Their biomarker potential for seizures and epilepsy in peripheral blood has, however, not yet been investigated. The aim of the present study was to determine whether blood purine nucleoside measurements can serve as a biomarker for the recent occurrence of seizures and to support the diagnosis of epilepsy.

Methods: Blood purine concentrations were measured via a point-of-care diagnostic technology based on the summated electrochemical detection of adenosine and adenosine breakdown products (inosine, hypoxanthine, and xanthine; SMARTChip). Measurements of blood purine concentrations were carried out using samples from mice subjected to intra-amygdala kainic acid-induced status epilepticus and in video-electroencephalogram (EEG)-monitored adult patients with epilepsy.

Results: In mice, blood purine concentrations were rapidly increased approximately two- to threefold after status epilepticus (2.32 ± .40 µmol·L [control] vs. 8.93 ± 1.03 µmol·L [after status epilepticus]), and levels correlated with seizure burden and postseizure neurodegeneration in the hippocampus. Blood purine concentrations were also elevated in patients with video-EEG-diagnosed epilepsy (2.39 ± .34 µmol·L [control, n = 13] vs. 4.35 ± .38 µmol·L [epilepsy, n = 26]).

Significance: Our data provide proof of concept that the measurement of blood purine concentrations may offer a rapid, low-volume bedside test to support the diagnosis of seizures and epilepsy.
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http://dx.doi.org/10.1111/epi.16839DOI Listing
March 2021

Ictal asystole during long-term video-EEG; semiology, localization, and intervention.

Epilepsy Behav Rep 2021 30;15:100416. Epub 2020 Dec 30.

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Ictal arrhythmias are disturbances of cardiac conduction that occur during clinical or electrographic seizures. Ictal asystole (IA) is rare, and its incidence can range from 0.3-0.4% in patients with epilepsy who were monitored by video-EEG (van der Lende et al., 2015). We report on ten patients (six males and four females) with an age ranging from 31 to 70 years old) who were monitored in our video-EEG (VEEG) unit over the last eight years. These patients were selected based on the history of documented ictal asystole during inpatient VEEG monitoring). In our series the mean latency from the seizure onset to the onset of ictal asystole was 22 seconds and the mean duration of the IA was 15.8 seconds. During the asystolic phase the seizures may clinically continue or syncopal signs may supervene. In our case series all the patients had either left or right temporal lobe epilepsy, six of which were lesional. We found two patterns of ictal semiology in our series. The first group of patients included five patients who experienced a rapid onset of IA in their seizure and the second group where the latency of ictal asystole was relatively late. All our cohort had a permanent pacemaker following the diagnosis, six of these patients have been event free since placement.
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http://dx.doi.org/10.1016/j.ebr.2020.100416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786025PMC
December 2020

LoVE in a time of CoVID: Clinician and patient experience using telemedicine for chronic epilepsy management.

Epilepsy Behav 2021 02 17;115:107675. Epub 2020 Dec 17.

FutureNeuro SFI Research Centre, The Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; Academic Unit of Neurology, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; Department of Neurology, St. James's Hospital, Dublin 8, Ireland.

As part of our ongoing interest in patient- and family-centered care in epilepsy, we began, before the onset of the CoVID-19 pandemic, to evaluate the concerns and preferences of those delivering and receiving care via telemedicine. CoVID-19 arrived and acted as an unexpected experiment in nature, catalyzing telemedicine's widespread implementation across many disciplines of medicine. The arrival of CoVID-19 in Ireland gave us the opportunity to record these perceptions pre- and post-CoVID. Data were extracted from the National Epilepsy Electronic Patient Record (EEPR). Power BI Analytics collated data from two epilepsy centers in Dublin. Analysis of data on reasons for using the telephone support line was conducted. A subset of patients and clinicians who attended virtual encounters over both periods were asked for their perception of telemedicine care through a mixed methods survey. Between 23rd December 2019 and 23rd March 2020 (pre-CoVID era), a total of 1180 patients were seen in 1653 clinical encounters. As part of a telemedicine pilot study, 50 of these encounters were scheduled virtual telephone appointments. Twenty eight surveys were completed by clinicians and 18 by patients during that period. From 24th March 2020 to 24th June 2020, 1164 patients were seen in 1693 encounters of which 729 (63%) patients were seen in 748 scheduled virtual encounters. 118 clinician impressions were captured through an online survey and 75 patients or carers completed a telephone survey during the post-CoVID era. There was no backlog of appointments or loss of care continuity forced by the pandemic. Clinicians expressed strong levels of satisfaction, but some doubted the suitability of new patients to the service or candidates for surgery receiving care via telemedicine. Patients reported positive experiences surrounding telephone appointments comparing them favorably to face-to-face encounters. The availability of a shared EEPR demonstrated no loss of care contact for patients with epilepsy. The survey showed that telemedicine is seen as an effective and satisfactory method of delivering chronic outpatient care.
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http://dx.doi.org/10.1016/j.yebeh.2020.107675DOI 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

Coproducing health and well-being in partnership with patients, families, and healthcare providers: A qualitative study exploring the role of an epilepsy patient portal.

Epilepsy Behav 2021 02 15;115:107664. Epub 2020 Dec 15.

FutureNeuro SFI Research Centre, For Rare and Chronic Diseases, Royal College of Surgeons in Ireland, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences (PBS), The Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address:

Background: Coproduced epilepsy care sees people with epilepsy (PwE), their care-proxies, and healthcare providers (HCPs), working together as partners to build strong relationships, improve communication, trust, and share decision-making. Coproduction underpins good quality patient- and family-centered care (PFCC) that is responsive to individual patient needs, preferences, and values. By facilitating information sharing and exchange between partners, electronic patient portals (ePortal) can enable coproduction. This paper explores what HCPs, PwE, and their care-proxies value from their user experience of PiSCES, the Irish epilepsy ePortal.

Methods: A purposeful sample of actors involved in the receipt and delivery of epilepsy care and services were recruited via adult epilepsy centers at St James's and Beaumont Hospitals in Dublin. Interactive codesign sessions, surveys, and focus groups were used to elicit perspectives from PwE, care-proxies, and HCPs to understand their perception of how PiSCES could enhance or inhibit the epilepsy care process.

Results: Results illustrate that participants welcome the role PiSCES can play in: empowering PwE/care-proxies, strengthening confidence in the healthcare system; aiding memory; advancing health literacy, motivating PwE to understand their condition better; acting as a passport of care between different clinical settings; and creating a foundation for stronger coproduction partnerships. PiSCES was generally embraced; however, some HCPs expressed plausible concerns about how clinical implementation might impact their work practices.

Conclusion: "Nothing about me without me" is a core value of the PiSCES initiative, recognizing that people need to be included in the planning of their own treatment and care. Our data show that PwE, their care-proxies, and HCPs value PiSCES potential, particularly in bolstering healthcare partnerships that foster inclusion, confidence, and trust.
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http://dx.doi.org/10.1016/j.yebeh.2020.107664DOI Listing
February 2021

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Sci Adv 2020 Nov 18;6(47). Epub 2020 Nov 18.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
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http://dx.doi.org/10.1126/sciadv.abc6457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673818PMC
November 2020

Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy.

Neurobiol Dis 2020 10 13;144:105048. Epub 2020 Aug 13.

Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland.

Epilepsy diagnosis is complex, requires a team of specialists and relies on in-depth patient and family history, MRI-imaging and EEG monitoring. There is therefore an unmet clinical need for a non-invasive, molecular-based, biomarker to either predict the development of epilepsy or diagnose a patient with epilepsy who may not have had a witnessed seizure. Recent studies have demonstrated a role for microRNAs in the pathogenesis of epilepsy. MicroRNAs are short non-coding RNA molecules which negatively regulate gene expression, exerting profound influence on target pathways and cellular processes. The presence of microRNAs in biofluids, ease of detection, resistance to degradation and functional role in epilepsy render them excellent candidate biomarkers. Here we performed the first multi-model, genome-wide profiling of plasma microRNAs during epileptogenesis and in chronic temporal lobe epilepsy animals. From video-EEG monitored rats and mice we serially sampled blood samples and identified a set of dysregulated microRNAs comprising increased miR-93-5p, miR-142-5p, miR-182-5p, miR-199a-3p and decreased miR-574-3p during one or both phases. Validation studies found miR-93-5p, miR-199a-3p and miR-574-3p were also dysregulated in plasma from patients with intractable temporal lobe epilepsy. Treatment of mice with common anti-epileptic drugs did not alter the expression levels of any of the five miRNAs identified, however administration of an anti-epileptogenic microRNA treatment prevented dysregulation of several of these miRNAs. The miRNAs were detected within the Argonuate2-RISC complex from both neurons and microglia indicating these miRNA biomarker candidates can likely be traced back to specific brain cell types. The current studies identify additional circulating microRNA biomarkers of experimental and human epilepsy which may support diagnosis of temporal lobe epilepsy via a quick, cost-effective rapid molecular-based test.
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http://dx.doi.org/10.1016/j.nbd.2020.105048DOI Listing
October 2020

The development of an epilepsy electronic patient portal: Facilitating both patient empowerment and remote clinician-patient interaction in a post-COVID-19 world.

Epilepsia 2020 09 10;61(9):1894-1905. Epub 2020 Aug 10.

Future Neuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.

Objectives: The current coronavirus disease 2019 (COVID-19) pandemic stresses an urgency to accelerate much-needed health service reform. Rapid and courageous changes being made to address the immediate impact of the pandemic are demonstrating that the means and technology to enable new models of health care exist. For example, innovations such as electronic patient portals (ePortal) can facilitate (a) radical reform of outpatient care; (b) cost containment in the economically constrained aftermath of the pandemic; (c) environmental sustainability by reduction of unnecessary journeys/transport. Herein, the development of Providing Individualised Services and Care in Epilepsy (PiSCES), an ePortal to the Irish National Epilepsy Electronic Patient Record, is demonstrated. This project, which pre-dates the COVID-19 crisis, aims to facilitate better patient- and family-centered epilepsy care.

Methods: A combination of ethnographic research, document analysis, and joint application design sessions was used to elicit PiSCES requirements. From these, a specification of desired modules of functionality was established and guided the software development.

Results: PiSCES functional features include "My Epilepsy Care Summary," "My Epilepsy Care Goals," "My Epilepsy Clinic Letters," "Help Us Measure Your Progress," "Prepare For Your Clinic Visit," "Information for Your Healthcare Provider." The system provides people with epilepsy access to, and engages them as co-authors of, their own medical record. It can promote improved patient-clinician partnerships and facilitate patient self-management.

Significance: In the aftermath of COVID-19, it is highly unlikely that the healthcare sector will return to a "business as usual" way of delivering services. The pandemic is expected to accelerate adoption of innovations like PiSCES. It is therefore a catalyst for change that will deliver care that is more responsive to individual patient needs and preferences.
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http://dx.doi.org/10.1111/epi.16627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404863PMC
September 2020

Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy.

Brain 2020 07;143(7):2139-2153

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.

Temporal lobe epilepsy is the most common and refractory form of epilepsy in adults. Gene expression within affected structures such as the hippocampus displays extensive dysregulation and is implicated as a central pathomechanism. Post-transcriptional mechanisms are increasingly recognized as determinants of the gene expression landscape, but key mechanisms remain unexplored. Here we show, for first time, that cytoplasmic mRNA polyadenylation, one of the post-transcriptional mechanisms regulating gene expression, undergoes widespread reorganization in temporal lobe epilepsy. In the hippocampus of mice subjected to status epilepticus and epilepsy, we report >25% of the transcriptome displays changes in their poly(A) tail length, with deadenylation disproportionately affecting genes previously associated with epilepsy. Suggesting cytoplasmic polyadenylation element binding proteins (CPEBs) being one of the main contributors to mRNA polyadenylation changes, transcripts targeted by CPEBs were particularly enriched among the gene pool undergoing poly(A) tail alterations during epilepsy. Transcripts bound by CPEB4 were over-represented among transcripts with poly(A) tail alterations and epilepsy-related genes and CPEB4 expression was found to be increased in mouse models of seizures and resected hippocampi from patients with drug-refractory temporal lobe epilepsy. Finally, supporting an adaptive function for CPEB4, deletion of Cpeb4 exacerbated seizure severity and neurodegeneration during status epilepticus and the development of epilepsy in mice. Together, these findings reveal an additional layer of gene expression regulation during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.
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http://dx.doi.org/10.1093/brain/awaa168DOI Listing
July 2020

Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study.

Pharmacogenomics 2020 04 20;21(5):325-335. Epub 2020 Apr 20.

Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.

Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
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http://dx.doi.org/10.2217/pgs-2019-0179DOI Listing
April 2020

A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability.

Eur J Hum Genet 2020 08 1;28(8):1066-1077. Epub 2020 Apr 1.

School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.
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http://dx.doi.org/10.1038/s41431-020-0610-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381648PMC
August 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Seizure 2020 May 5;78:31-37. Epub 2020 Mar 5.

Neurocenter Bellevue, Zurich, Switzerland.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
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http://dx.doi.org/10.1016/j.seizure.2020.02.018DOI Listing
May 2020

Testing association of rare genetic variants with resistance to three common antiseizure medications.

Epilepsia 2020 04 6;61(4):657-666. Epub 2020 Mar 6.

Department of Applied Sciences, University of Quebec in Chicoutimi, Saguenay, Canada.

Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA).

Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants.

Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach.

Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.
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http://dx.doi.org/10.1111/epi.16467DOI Listing
April 2020

Genomic and clinical predictors of lacosamide response in refractory epilepsies.

Epilepsia Open 2019 Dec 25;4(4):563-571. Epub 2019 Sep 25.

School of Pharmacy and Biomolecular Sciences Royal College of Surgeons Dublin Ireland.

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting.

Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes.

Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis.

Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
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http://dx.doi.org/10.1002/epi4.12360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885661PMC
December 2019

Exploring the genetic overlap between psychiatric illness and epilepsy: A review.

Epilepsy Behav 2020 01 27;102:106669. Epub 2019 Nov 27.

FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Molecular and Cellular Therapeutics, RCSI Dublin, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland. Electronic address:

There is a long-documented epidemiological link between epilepsy and psychiatric disorders. People with epilepsy are at an increased risk for a variety of psychiatric illnesses, as are their family members, and people with epilepsy may experience psychiatric side effects because of their antiepileptic drugs (AEDs). In recent years, large-scale, collaborative international studies have begun to shed light on the role of genetic variation in both epilepsy and psychiatric illnesses, such as schizophrenia, depression, and anxiety. But so far, finding shared genetic links between epilepsy and psychiatric illness has proven surprisingly difficult. This review will discuss the prevalence of psychiatric comorbidities in epilepsy, recent advances in genetic research into both epilepsy and psychiatric illness, and the extent of our current knowledge of the genetic overlap between these two important neurobiological conditions.
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http://dx.doi.org/10.1016/j.yebeh.2019.106669DOI Listing
January 2020

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy.

Epilepsia Open 2019 Sep 4;4(3):420-430. Epub 2019 Jul 4.

Department of Neurology Hôpital Erasme, Université Libre de Bruxelles Brussels Belgium.

Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME).

Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females.

Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13],  < 0.001) and female sex (1.41 [1.07-1.85],  = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02],  < 0.001 and 1.93 [1.31-2.86],  < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%,  = 0.001).

Significance: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.
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http://dx.doi.org/10.1002/epi4.12349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698679PMC
September 2019

Tackling Epilepsy With High-definition Precision Medicine: A Review.

JAMA Neurol 2019 Sep;76(9):1109-1116

FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.

Importance: Various types of epilepsy are a leading cause of neurological disability worldwide; they have in common a propensity to recurrent unprovoked seizures. There is increasing interest in the concept of precision medicine for therapy. While treatment aimed at the level of an ion channel or single pathway has provided benefits for a small number of individuals with genetically mediated cases, a high-definition approach extending beyond genes to a broader array of personalized factors may improve outcomes.

Observations: Advances in sequencing technologies have driven genetic discovery in epilepsy. This has provided targets for precision medicine in monogenic types of epilepsy. However, these typically represent a small subset of all types of epilepsy, and to date, precision medicine in epilepsy has primarily focused on seizure reduction. Such a unifocal view may overlook neurodevelopmental and neuropsychiatric comorbidities, which can be more challenging than the seizures themselves. Therefore, a panoramic approach to treatment encompassing both molecular diagnostic techniques and amelioration of network function by addressing factors beyond seizure reduction may be considered as part of a high-definition approach to tackling epilepsy.

Conclusions And Relevance: High-definition medicine will require the development of analytical techniques, including artificial intelligence, that use and combine behavioral, environmental, molecular genomic, chronotype, and microbiomic data to offer the best individualized therapeutic options for disease management in each person with epilepsy. While an accurate molecular diagnosis remains the first step of the iterative process to the development of a precision medicine for an epilepsy, treatment targeted at a single molecular pathway may reduce seizure frequency but are not likely to address the multiple comorbidities associated with involved aberrant neural networks. To provide an improvement in precision medicine for epilepsy, a high-definition approach may be required that encompasses a panoramic view of factors that can be manipulated either directly or indirectly, now and in the future.
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http://dx.doi.org/10.1001/jamaneurol.2019.2384DOI Listing
September 2019

Development of a genomics module within an epilepsy-specific electronic health record: Toward genomic medicine in epilepsy care.

Epilepsia 2019 08 11;60(8):1670-1677. Epub 2019 Jul 11.

Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland.

Objectives: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease.

Methods: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system.

Results: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management.

Significance: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.
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http://dx.doi.org/10.1111/epi.16278DOI Listing
August 2019
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