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Epilepsy-Definition, Classification, Pathophysiology, and Epidemiology

Affiliation.

• 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California.
• PMID: 33155183
• DOI: 10.1055/s-0040-1718719

Seizures affect the lives of 10% of the global population and result in epilepsy in 1 to 2% of people around the world. Current knowledge about etiology, diagnosis, and treatments for epilepsy is constantly evolving. As more is learned, appropriate and updated definitions and classification systems for seizures and epilepsy are of the utmost importance. Without proper definitions and classification, many individuals will be improperly diagnosed and incorrectly treated. It is also essential for research purposes to have proper definitions, so that appropriate populations can be identified and studied. Imprecise definitions, failure to use accepted terminology, or inappropriate use of terminology hamper our ability to study and advance the field of epilepsy. This article begins by discussing the pathophysiology and epidemiology of epilepsy, and then covers the accepted contemporary definitions and classifications of seizures and epilepsies.

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Similar articles.

• ILAE Classification of Seizures and Epilepsies: An Update for the Pediatrician. Dhinakaran R, Mishra D. Dhinakaran R, et al. Indian Pediatr. 2019 Jan 15;56(1):60-62. Indian Pediatr. 2019. PMID: 30806364
• Seizures and epilepsy after ischemic stroke. Camilo O, Goldstein LB. Camilo O, et al. Stroke. 2004 Jul;35(7):1769-75. doi: 10.1161/01.STR.0000130989.17100.96. Epub 2004 May 27. Stroke. 2004. PMID: 15166395 Review.
• Pediatric seizure and epilepsy classification: why is it important or is it important? Troester M, Rekate HL. Troester M, et al. Semin Pediatr Neurol. 2009 Mar;16(1):16-22. doi: 10.1016/j.spen.2009.01.003. Semin Pediatr Neurol. 2009. PMID: 19410152 Review.
• Applicability and contribution of the new ILAE 2017 classification of epileptic seizures and epilepsies. Legnani M, Bertinat A, Decima R, Demicheli E, Higgie JR, Preve F, Braga P, Bogacz A, Scaramelli A. Legnani M, et al. Epileptic Disord. 2019 Dec 1;21(6):549-554. doi: 10.1684/epd.2019.1108. Epileptic Disord. 2019. PMID: 31843738
• Conceptual distinctions between reflex and nonreflex precipitated seizures in the epilepsies: a systematic review of definitions employed in the research literature. Illingworth JL, Ring H. Illingworth JL, et al. Epilepsia. 2013 Dec;54(12):2036-47. doi: 10.1111/epi.12340. Epub 2013 Aug 27. Epilepsia. 2013. PMID: 24032405 Review.
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Stanford Comprehensive Epilepsy Program Research

While each member of our team is involved in various clinical or basic science research projects, there are four active laboratories in the Stanford Comprehensive Epilepsy Program where investigators conduct systematic research. These laboratories are led by four of the faculty members in our program and funded by the National Institute of Health.

Buckmaster, Paul, DVM, PhD

Temporal lobe epilepsy is common, frequently refractory to treatment, and devastating to those affected. Our long-term goal is to better understand the pathophysiological mechanisms of this disease so that rational and effective therapies can be developed. We use electrophysiological, molecular, and anatomical techniques to evaluate neuronal circuitry in normal and in epileptic brains.

Huguenard, John, PhD

We are interested in the neuronal mechanisms that underlie synchronous oscillatory activity in the thalamus, cortex and the massively interconnected thalamocortical system. Such oscillations are related to cognitive processes, normal sleep activities and certain forms of epilepsy.

Our approach is an analysis of the discrete components that make up thalamic and cortical circuits, and reconstitution of components into both in vitro biological and in silico computational networks. Accordingly, we have been able to identify genes whose products, mainly ion channels, play key roles in the regulation of thalamocortical network responses.

Nuyujukian, Paul, MD, PhD (Brain Interfacing Laboratory)

The Brain Interfacing Laboratory is interested in the applicability of   brain-machine interfaces as a platform technology for a variety of   brain-related medical conditions, particularly stroke and epilepsy.  This research spans both preclinical models and human clinical   studies.

With respect to epilepsy, we are looking to better characterize and  model seizures from patients with refractory epilepsy so that we may  provide better treatments. In particular, we are seeking to develop  statistical techniques to predict seizures.

Parvizi, Josef, MD, PhD (Laboratory of Behavioral and Cognitive Neuroscience)

The general theme of our research is the study of the human brain from clinical and system neuroscience perspective using the tools of intracranial electrocorticography (ECoG), electrical brain stimulation (EBS), and functional imaging (fMRI).  The main impetus for our research is to understand the anatomical and physiological signatures of behavioral expression and cognitive experience in humans and how these might be broken in patients with epilepsy. Using our sophisticated research tools, our goal is to help patients with uncontrolled epilepsy to gain seizure freedom without cognitive deficits.

Prince, David, MD

Work in the Prince lab has focused on normal and abnormal regulation of excitability in neurons of mammalian cerebral cortex and thalamus and mechanisms underlying development and prophylaxis of epilepsy in animal models. Long-term goals are to understand how cortical injury and other pathological processes induce changes in structure and function of neurons and neuronal networks that lead to hyperexcitability and epileptogenesis. With this information, it will be possible to devise experimental strategies to prevent the occurrence of epilepsy after cortical injury and eventually apply them to individuals with significant brain trauma. We have already provided a proof in principal that prophylaxis of posttraumatic epilepsy is possible, using a rat model.

Ivan Soltesz, PhD

Dr. Soltesz's laboratory employs a combination of closely integrated experimental and theoretical techniques, including closed-loop in vivo optogenetics, paired patch clamp recordings, in vivo electrophysiological recordings from identified interneurons in awake mice, 2-photon imaging, machine learning-aided 3D video analysis of behavior, video-EEG recordings, behavioral approaches, and large-scale computational modeling methods using supercomputers. He is the author of a book on GABAergic microcircuits (Diversity in the Neuronal Machine, Oxford University Press), and editor of a book on Computational Neuroscience in Epilepsy (Academic Press/Elsevier). He co-founded the first Gordon Research Conference on the Mechanisms of neuronal synchronization and epilepsy, and taught for five years in the Ion Channels Course at Cold Springs Harbor. He has over 30 years of research experience, with over 20 years as a faculty involved in the training of graduate students (total of 16, 6 of them MD/PhDs) and postdoctoral fellows (20), many of whom received fellowship awards, K99 grants, joined prestigious residency programs and became independent faculty.

Benchmarks for Epilepsy Research

To assess progress in epilepsy research and help set an agenda for future years, NINDS hosts Curing the Epilepsies  conferences in partnership with epilepsy advocacy and professional organizations. These conferences inform the development of  Benchmarks for Epilepsy Research , which reflect priorities shared across the epilepsy community for research toward clinically meaningful advances in understanding and treating the epilepsies. Since their initial development in 2000, the Benchmarks for Epilepsy Research have brought attention to goals such as preventing epileptogenesis, addressing aspects of epilepsy beyond seizures, and confronting the challenge of sudden unexpected death in epilepsy (SUDEP).

2021 Benchmarks for Epilepsy Research

Past Benchmarks for Epilepsy Research:

• 2020 Benchmarks for Epilepsy Research
• 2014 Benchmarks for Epilepsy Research
• 2007 Benchmarks for Epilepsy Research
• 2000 Benchmarks for Epilepsy Research

Focus On Epilepsy Research

Women with Epilepsy in Child-bearing Age

Diagnosis and Treatment

• © 2024

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China

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• Be useful to improve the quality of life of such patients around the world
• Contributed by a multidisciplinary team of researchers
• Focuses on the latest scientific discoveries and precise management strategies

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About this book

This book aims to collect research findings and provide insightful recommendations on various aspects of female epilepsy patients of childbearing age. This book discusses multidisciplinary effort of brain science, reproductive medicine, endocrinology, drug metabolism, genetics, maternal and infant medicine, etc.

This book is written by a multidisciplinary team of researchers who had a passion for improving the quality of life of women with epilepsy, to demonstrate the latest scientific discoveries and precise management strategies for women with epilepsy in child-bearing age.

• sleep disorders
• emotional disorders
• psychotc disorders
• antiseizure medication in pregnancy
• quality of life

Table of contents (7 chapters)

Front matter, disease burden of women with epilepsy.

• Ding Ding, Leihao Sha, Yiling Chen

Diagnosis and Treatment of Women with Epilepsy

• Ziyi Chen, Xinling Geng, Yulong Li, Leihao Sha, Yutong Fu, Lei Chen

The Relationship Between Epilepsy, Antiseizure Medication, and Sex Hormones

• Ziyi Chen, Leihao Sha

Preconception Management of Women with Epilepsy

• Ziyi Chen, Leihao Sha, Lei Chen

Perinatal Management of Women with Epilepsy

• Ziyi Chen, Zhenlei Wang, Sijia Basang, Leihao Sha

Folic Acid Supplementation During Pregnancy

• Ziyi Chen, Yifei Duan, Lei Chen

Postpartum Management for Women with Epilepsy

• Tianhong Zhang, Ziyi Chen, Yifei Duan

Editors and Affiliations

About the editor.

Editor Lei Chen , Professor/Chief Physician, Vice President of West China Hospital, Sichuan University, China. She is engaged in the diagnosis, treatment, and research of epilepsy, migraine, and peri-pregnancy neurological disorders, population cohort studies, and clinical research management. She is the deputy director of Institute of Neurological Diseases of West China Hospital, the national coordinator of China of EURAP, the director of the Sichuan Province Engineering Research Center of Brain-Machine Interface and Sichuan Province Engineering Research Center of Neuromodulation, the academic and technical leader of the Sichuan Provincial Health and Health Commission, the deputy head of the Clinical Research Group of the Research Management Branch of the Chinese Medical Association, a member of the Education Committee of the International League Against Epilepsy, the deputy director of the Youth Committee of the Chinese Anti-Epilepsy Association, and the executive member of the World Chinese Society for Quality of Survival.

Bibliographic Information

Book Title : Women with Epilepsy in Child-bearing Age

Book Subtitle : Diagnosis and Treatment

Editors : Lei Chen

DOI : https://doi.org/10.1007/978-981-97-3921-9

Publisher : Springer Singapore

eBook Packages : Medicine , Medicine (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024

Hardcover ISBN : 978-981-97-3920-2 Due: 13 October 2024

Softcover ISBN : 978-981-97-3923-3 Due: 13 October 2025

eBook ISBN : 978-981-97-3921-9 Published: 11 September 2024

Edition Number : 1

Number of Pages : IX, 166

Number of Illustrations : 16 illustrations in colour

Topics : Neurology , Neurosurgery

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Article Contents

Introduction, materials and methods, supplementary material, acknowledgements, competing interests, data availability, code availability.

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The influence of temperature and genomic variation on intracranial EEG measures in people with epilepsy

Olivia C McNicholas, Diego Jiménez-Jiménez, Beate Diehl and Sanjay M Sisodiya contributed equally to this work.

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Olivia C McNicholas, Diego Jiménez-Jiménez, Joana F A Oliveira, Lauren Ferguson, Ravishankara Bellampalli, Charlotte McLaughlin, Fahmida Amin Chowdhury, Helena Martins Custodio, Patrick Moloney, Anna Mavrogianni, Beate Diehl, Sanjay M Sisodiya, The influence of temperature and genomic variation on intracranial EEG measures in people with epilepsy, Brain Communications , Volume 6, Issue 5, 2024, fcae269, https://doi.org/10.1093/braincomms/fcae269

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Heatwaves have serious impacts on human health and constitute a key health concern from anthropogenic climate change. People have different individual tolerance for heatwaves or unaccustomed temperatures. Those with epilepsy may be particularly affected by temperature as the electroclinical hallmarks of brain excitability in epilepsy (inter-ictal epileptiform discharges and seizures) are influenced by a range of physiological and non-physiological conditions. Heatwaves are becoming more common and may affect brain excitability. Leveraging spontaneous heatwaves during periods of intracranial EEG recording in participants with epilepsy in a non–air-conditioned telemetry unit at the National Hospital for Neurology and Neurosurgery in London from May to August 2015–22, we examined the impact of heatwaves on brain excitability. In London, a heatwave is defined as three or more consecutive days with daily maximum temperatures ≥28°C. For each participant, we counted inter-ictal epileptiform discharges using four 10-min segments within, and outside of, heatwaves during periods of intracranial EEG recording. Additionally, we counted all clinical and subclinical seizures within, and outside of, heatwaves. We searched for causal rare genetic variants and calculated the epilepsy PRS. Nine participants were included in the study (six men, three women), median age 30 years (range 24–39). During heatwaves, there was a significant increase in the number of inter-ictal epileptiform discharges in three participants. Five participants had more seizures during the heatwave period, and as a group, there were significantly more seizures during the heatwaves. Genetic data, available for eight participants, showed none had known rare, genetically-determined epilepsies, whilst all had high polygenic risk scores for epilepsy. For some people with epilepsy, and not just those with known, rare, temperature-sensitive epilepsies, there is an association between heatwaves and increased brain excitability. These preliminary data require further validation and exploration, as they raise concerns about the impact of heatwaves directly on brain health.

Climate change is happening around us: 2023 was the hottest year on record. Climate change will lead to increasing temperatures and more severe and frequent periods of extreme heat, called heatwaves. 1 A heatwave is defined as a period of at least three consecutive days of unusually hot weather, with a daily maximum above a specified threshold. 2 Climate change will have major consequences for human health. 3 Whilst there have been warnings about the impacts on human health generally, and for ‘vulnerable populations’, studies on the effects of climate change on specific diseases have been limited, with little granularity expanding on the very broad term ‘vulnerable’. Neurological diseases are burdensome in general, and epilepsy is amongst the most burdensome, as one of the most common chronic neurological conditions, affecting over 50 million people worldwide. 4 Epilepsy may also provide insights into brain health, and response to climate change, more generally. Some seizure types (e.g. febrile seizures) are more likely to happen with elevated body temperature, often in combination with a systemic inflammatory response. Some epilepsies, typically rare ‘monogenic’ conditions such as Dravet syndrome and CHD2 -related epilepsy, feature seizures that can be triggered by high ambient temperatures, or rapid change in ambient temperature. 5 Temperature elevation may provoke seizures in a broad range of epilepsies. 6 A study from Brazil reported a 4.3% increase in the risk of hospitalization for seizures with each 1°C increase in external temperature. 7 Inter-ictal epileptiform discharges (IEDs) are a marker of epileptogenic tissue in the brain. 8 IEDs can vary in frequency according to epilepsy syndrome, different physiological and non-physiological conditions including during sleep, with varying hormone levels and with anti-seizure medication (ASM) treatment. 9 , 10 A study performed during intraoperative electrocorticography in children showed that cortical irrigation with 150 cm 3 chilled (4°C) normal saline solution reduced the average number of IEDs. 11 Ion channels, whose activity is critical to brain function and whose involvement is central to seizures, demonstrate exquisite sensitivity to ambient temperature; mutated ion channels may be the cause of some epilepsies, and mutant channel function typically retains steep dependence on ambient temperature. 12 , 13 These observations suggest that brain function, in both healthy people and those with epilepsy, may show sensitivity to unaccustomed high or low ambient temperature, and raise concerns about brain function as climate change progresses, especially during associated heatwaves. We leveraged existing data sets of intracranial EEG (icEEG) recordings undertaken in people with medication-resistant focal epilepsy that encompassed heatwaves on a non-temperature–controlled video EEG monitoring unit. Our objective was to test the hypothesis that heatwaves increase brain cortical excitability, potentially aggravating specific genetic factors underpinning epilepsy. IcEEG studies are ideal for such work as they are typically long studies, enabling comparison between heatwave and non-heatwave settings in the same person under stable conditions.

We selected all participants who, as part of their ongoing assessment for epilepsy surgery, underwent icEEG, sampling mesial temporal and deep structures, around heatwaves from May to August 2015–22, and whose recording included both non-heatwave periods and the entire duration of a heatwave during the same admission. We excluded cases with only neocortical sampling, i.e. grids only.

All individuals included had given written informed consent to a study of genomic influences on epilepsy (Research Ethics Committee identifier: 11/LO/2016). Additionally, this study was undertaken as part of an independently approved (Clinical Audit and Quality Improvement Subcommittee, Queen Square Division, University College London Hospitals NHS Foundation Trust; registration number: 62-202122-SE) service evaluation on environments at our hospital with respect to the Greener NHS programme. 14

Genomic analysis

Both rare and common genomic variation can contribute to epilepsy. To test the hypothesis that different neurophysiological responses to ambient temperatures might be influenced by genetic variation, we examined both rare (potentially causal) variants and common variants [through polygenic risk scores (PRSs)]. DNA was available for eight study participants and was used to obtain whole-genome sequencing (WGS). Data were processed as previously described, 15 with further details in the Supplementary material .

PRS for epilepsy was calculated in eight of the nine participants in this study, GEL Epilepsy and GEL Control cohorts (see Supplementary Figs 1 and 2 ). On genetic analysis, one participant (#9) was of non-European ancestry, but was kept in this analysis for this pilot study given the small number of participants overall, and that this study was not intended to explore PRS differences between cohorts (see Supplementary Fig. 3 ).

Electrophysiological recording setting

IcEEG data were recorded in the National Hospital for Neurology and Neurosurgery (NHNN) telemetry unit, a west-facing environment that is not air-conditioned ( Fig. 1 ): it is situated on the eastern edge of Queen Square, London, UK, and its concrete structure was built in 1859.

Study setting. An example of an icEEG video-telemetry room, with west-facing window, at the NHNN. All rooms used for icEEG are west-facing, with large windows, which cannot fully open due to legal reasons, and have no air conditioning. The position of the Onset HOBO data logger (dry bulb temperature recorder) is outlined with the square.

Non-heatwave and heatwave characterization

A non-heatwave period was defined as a minimum of 3 days during which the daily maximum external temperature was below 28°C, whereas a heatwave period was defined as at least three consecutive days with daily maximum external temperatures exceeding 28°C (28°C is the local threshold for London, UK). 16 Where possible, non-heatwave days were sampled at least 48 h before or after the heatwave to attempt to account for potential thermal mass effects in the telemetry unit, where the building may retain heat for up to several hours after a heatwave. Heatwave and non-heatwave days were selected without knowledge of the number of seizures on any day during the icEEG recording.

Temperature data were acquired as follows. Indoor measurements of dry bulb temperature were collected between April 2022 and August 2023 at sub-hourly time intervals inside the icEEG recording room using a HOBO UX100-001 USB Temperature Data Logger (range −20 to 70°C; accuracy 0.21°C from 0 to 50°C; Onset Computer Corporation, MA, USA). The HOBO data logger was placed on a high beam out of direct sunlight and away from sources of heat ( Fig. 1 ). The time-series plot of the indoor and outdoor temperature data aggregated to daily means can be viewed in Supplementary Fig. 4 . Prior to 29 April 2022, no measurements of indoor temperature were available from the telemetry unit. A statistical approach was therefore used to model indoor temperatures on icEEG study dates when direct measurements were not available.

Indoor temperature model

The indoor temperature measurements were linked with outdoor meteorological data from the Visual Crossing Weather API at St. James Park (London, UK) monitoring station, the closest outdoor monitor to NHNN, to extrapolate indoor temperature readings for dates prior to 29 April 2022. 17 All data processing and analyses were carried out in RStudio (RStudio, 2020). Further data analysis is available in the Supplementary material .

A random forest model was used to predict study date indoor conditions from the outdoor meteorological data when indoor measurement data were not available (see Supplementary Figs 4–6 and Supplementary Table 1 for further details, including model performance), implemented in RStudio using the package Ranger. 18   Figure 2 shows the distribution of modelled indoor temperatures for each participant during heatwave and non-heatwave epochs.

Modelled indoor temperatures on heatwave and non-heatwave days. The distribution of modelled indoor temperatures on heatwave and non-heatwave days during each participant’s icEEG study, shown with the P -value between non-heatwave and heatwave days for each participant. P- values were attained via an unpaired t -test. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P <0.0001. The boxplots encompass data points for indoor temperature estimates (in °C) in the telemetry unit at hourly time intervals, aggregated by heatwave and non-heatwave days for each participant. The central line in each boxplot represents the median, whilst the box shows the interquartile range and the lower and upper whiskers show the minimum and maximum for each group, respectively. Note that modelled temperature estimates are shown for all participants except participant #7, for whom directly recorded indoor measurements were available and are shown.

EEG recording

Only pre-existing data were used. The icEEG data were recorded using a SD LTM 64 Express, Micromed amplifier (Micromed, Treviso, Italy), with a sampling rate of 1024 Hz and digital filters of 0.008–400 Hz bandpass. Implantation of electrodes was driven clinically and depended on the hypothesized epileptogenic areas as determined by the multidisciplinary team considering semiology, previous video-telemetry findings on scalp EEG and imaging data. The anatomical location of each electrode contact was verified on a post-implantation MRI brain scan. We sampled only from the electrode contacts which were implanted in the anatomical region of interest.

IED identification

EEG data were reviewed using a bipolar montage, 400 µV/cm sensitivity and a 15-s time base. The EEG was first visually screened to discard artefacts and remove faulty channels or electrodes not in contact with the brain. The following criteria for EEG segment selection were used: awake, resting recording, more than 24 h after implantation to account for anaesthetic effects, the same ASM doses during the selected heatwave and non-heatwave days, at least an hour before or after a clinical seizure and not during or within the hour after periods of additional intervention, e.g. cortical stimulation and single-pulse electrical stimulation. 19-22 Awake EEG data were examined by two independent EEG readers (O.C.M. and B.D.); reviewers were blinded to whether the EEG was from non-heatwave and heatwave epochs.

For each participant, we selected four 10-min epochs (i.e. 40 min in total) of icEEG during the daytime (between 12:00 and 19:00), and on the hour, during a selected non-heatwave and heatwave day. If we were unable to sample from the 10-min epoch on the hour (e.g. participant asleep), then the epoch sampling was moved forward to the next hour. The same 10-min epochs were used for both non-heatwave and heatwave epochs. We used 10-min epochs rather than 24-h epochs due to the burden of manual IED counting.

All IEDs were annotated and counted based on visual analysis only. There is no generally accepted definition of IEDs in icEEG: only graphoelements that stood out from the background, had a rapid upslope, were of short duration and had an aftergoing slow wave were marked as an IED. 21 , 22

We analysed IEDs in the depth electrode contact locations which had been implanted across many of the participants. These contacts sampled from the amygdala; anterior and posterior hippocampus; and anterior, posterior and middle cingulum. In addition, we evaluated the hypothesized ictal-onset zone (IOZ) for each participant who had seizures during their admission and sampled these areas for each participant during non-heatwave and heatwave epochs.

Seizure identification and seizure counting

Evaluation was undertaken on the same days as were selected for analysis of IED discharges.

All clinical and subclinical seizures were manually counted over the 24-h period (including both wake and sleep stages) and verified by two experienced EEG readers (D.J.-J. and B.D.). Seizure identification followed published methodology. 23 Seizures were classified according to international guidelines. 24 All clinical and subclinical ictal activity longer than 10 s was considered relevant. 25

Post hoc analysis

After the initial hypothesis testing, we undertook a further analysis examining whether variations in IEDs and seizures might be related to the temperature difference between the selected non-heatwave and heatwave days. We calculated the percentage change in daily maximum temperature between the non-heatwave day and the heatwave days from which epochs were sampled. We then compared the percentage change in daily maximum temperature from non-heatwave to heatwave against the percentage change in number of IEDs across all the sampled depth electrode contacts per individual participant from non-heatwave to heatwave epochs. Additionally, we compared the percentage change in daily maximum temperature from the non-heatwave to heatwave day against the percentage change in number of seizures per individual participant from the non-heatwave day to the heatwave day.

Statistical analysis

Statistical analysis was performed in GraphPad Prism (GraphPad Prism version 8.0.0, GraphPad Software, San Diego, CA, USA). We compared the total number of IEDs by sampled depth electrode contact for each individual participant over the total 40 min examined between non-heatwave and heatwave epochs using a Wilcoxon matched-pairs signed rank test to evaluate differences in overall IED numbers between the two epochs, using one tail as our hypothesis was that there would be more IEDs during the heatwave. We excluded electrodes from which no IEDs were recorded at all in either condition (heatwave and non-heatwave), as these electrodes are uninformative. Significance was set at P ≤ 0.05. We also compared the number of seizures during the selected non-heatwave and heatwave day using a one-tailed Wilcoxon matched-pairs signed rank test, comparing by participant. Significance was set at P ≤ 0.05.

For the post hoc analysis, we ranked the percentage increase in temperature between the non-heatwave and heatwave day from one (largest increase) to nine (smallest increase) for the nine participants. We also ranked the percentage increase in IED number between the non-heatwave and heatwave day from one (largest increase) to nine (smallest increase). We compared these rankings using a Spearman’s rank correlation coefficient (where 0 signifies no relationship). We used the same methodology to compare the rankings of percentage change in temperature between the non-heatwave and heatwave day with the percentage change in seizure frequency between the two days.

Eleven participants underwent icEEG during heatwaves between 01 May 2015 and 31 August 2022. Two participants were excluded: one participant was explanted on the first day of a heatwave at 0800 (outdoor temperature 23°C); the other participant was excluded from the study as no mesial temporal structures were sampled. The remaining nine participants included in the study (six men, three women) had a median age of 30 (range 24–39) years (see Table 1 for details). Non-heatwave 24-h peak temperature recordings ranged from 24.6 to 27.7°C. Heatwave 24-h peak temperatures ranged from 28.5 to 30.1°C. In four participants, non-heatwave epochs were sampled at least 48 h before the heatwave epochs, whilst in four participants, non-heatwave IED sampling was performed at least 48 h after the end of the heatwave. In one participant (#7), non-heatwave IED sampling was performed 24 h after the end of the heatwave. These variations were imposed by the timing of the heatwave with respect to the icEEG study and were not under our control.

Participant demographics

Participants demographics, habitual seizure frequency, ASM at the time of admission to the unit, relative ASM level at time of IED counting (100%, full ASM doses; 0%, ASMs completely withheld), peak temperature on non-heatwave and heatwave day of IED counting are shown. CBZ, carbamazepine; TPM, topiramate; ZNS, zonisamide; ESL, eslicarbazepine; PER, perampanel; OXC, oxcarbazepine; LTG, lamotrigine; CLB, clobazam; VPA, valproate; LCM, lacosamide; BRIV, brivaracetam; IED, inter-ictal discharge.

For the eight participants with WGS data available (participant #5 did not have any genetic data available), no qualifying causal rare variants were found. This is in keeping with their clinical syndromes ( Table 1 ) and indicates none had known genetically-driven temperature-sensitive epilepsies. The PRS for these eight participants are shown in Supplementary Fig. 2 , with 7/8 falling above the interquartile range and participant #1 having the lowest PRS score for epilepsy in this group.

IED numbers in heatwave and non-heatwave epochs

The depth EEG electrode contacts from which IEDs were sampled are listed in Supplementary Table   2 .

In three participants (#1, #4 and #7; Fig. 3 ), there were significantly more IEDs over the 40 sampled minutes during heatwave epochs compared to the non-heatwave epochs (all three were on their full admission doses of ASMs during both epochs). No significant difference was seen for the other six participants ( Fig. 4 ).

Comparison of IED numbers per depth electrode contact per individual participant between non-heatwave and heatwave days; significant differences. Number of IEDs ( y -axis) per depth electrode contact ( x -axis) during the two states, non-heatwave (dark bar, squares) and heatwave (light bar, circles), in the nine individual participants. Individual squares and circles within bars represent the IED count during the separate 10-min epochs. The top of each bar represents the median IED number per state and depth electrode contact. Bars are ordered chronologically depending on whether the heatwave or non-heatwave day occurred first. Depth electrode contacts with no sampled IEDs were omitted. The lightning bolt represents the area of the hypothesized IOZ. Please note that participant #4 was deemed non-localized (see Supplementary Table 2 ). A Wilcoxon matched-pairs signed rank test was used to evaluate the differences in overall IED numbers between the two epochs, using one tail. Significance was set at P ≤ 0.05. Stated depth electrode contact numbers correspond to the depth electrode contact sampled from. RaH, right anterior hippocampus; RpH, right posterior hippocampus; LaH, left anterior hippocampus; RpC, right posterior cingulum; RA, right amygdala; LA, left amygdala; LpH, left posterior hippocampus; LaCi, left anterior cingulum; LpCi, left posterior cingulum; LAM, left amygdala; RaCi, right anterior cingulum; RpCi, right posterior cingulum; Ram, right amygdala; LmCi, left middle cingulum; LTOJ, left temporo-occipital junction; LaPH, left anterior parahippocampal gyrus.

Comparison of IED numbers per depth electrode contact per individual participant between non-heatwave and heatwave days; non-significant differences. Number of IEDs ( y -axis) per depth electrode contact ( x -axis) during the two states, non-heatwave (dark bar, squares) and heatwave (light bar, circles), in the nine individual participants. Individual squares and circles within bars represent the IED count during the separate 10-min epochs. The top of each bar represents the median IED number per state and depth electrode contact. Bars are ordered chronologically depending on whether the heatwave or non-heatwave day occurred first. Depth electrode contacts with no sampled IEDs were omitted. The lightning bolt, if present, represents the area of the hypothesized IOZ. Please note that participants #3 and #5 were deemed non-localized (see Supplementary Table 2 ). A Wilcoxon matched-pairs signed rank test was used to evaluate the differences in overall IED numbers between the two epochs, using one tail. Significance was set at P ≤ 0.05. Stated depth electrode contact numbers correspond to the depth electrode contact sampled from. RaH, right anterior hippocampus; RpH, right posterior hippocampus; LaH, left anterior hippocampus; RpC, right posterior cingulum; RA, right amygdala; LA, left amygdala; LpH, left posterior hippocampus; LaCi, left anterior cingulum; LpCi, left posterior cingulum; LAM, left amygdala; RaCi, right anterior cingulum; RpCi, right posterior cingulum; Ram, right amygdala; LmCi, left middle cingulum; RTOJ, right temporo-occipital junction; LGC8, left inferior temporal gyrus.

Post hoc analysis examining the percentage change in daily maximum temperature between the selected non-heatwave and the heatwave day for each individual participant against the percentage change in the total IED number across all sampled areas during the non-heatwave and heatwave days showed a weak, non-significant, negative association (Spearman’s rank = −0.28).

Seizure numbers

We reviewed 432 h of EEG recordings from the nine participants on the same days used for IED analysis: in total, 216 h were during the non-heatwave epochs and 216 h were during the heatwave epochs. We identified 63 seizures: 8 seizures during non-heatwave epochs and 55 during heatwave epochs ( Table 2 ). In five participants, there were more seizures during the heatwave, including for two (#1 and #4) of the three participants with significantly more IEDs during the heatwave epoch, with participant #4 experiencing the greatest increase in seizure frequency. Two participants (#3 and #8) had partial reductions in ASMs between the earlier non-heatwave study day and the subsequent heatwave study day (see Supplementary Tables 3 and 4 for details on ASMs and seizures).

Seizures during the non-heatwave and heatwave days

Number of clinical and subclinical seizures and time (hours) in non-heatwave and heatwave conditions for each participant. Seizures were classified according to established international guidelines. 26 FM, focal motor; SC, subclinical; FNM, focal non-motor; NA, not applicable.

One participant (#5) had a reduction in seizures in the heatwave, and three participants had no change in seizures ( Fig. 5 ). There was a significant difference ( P = 0.047) when comparing the number of seizures by individual participant between the non-heatwave and heatwave day across the group as a whole. For analysis of seizure numbers, because this is a brain systems phenomenon, we included all participants, even those who had no seizures during heatwave or non-heatwave days; as a sensitivity analysis, exclusion of participants (#6, #7 and #9) who had no seizures during either epoch did not alter the statistical significance of our findings (refer to Supplementary Table 4 for seizure details with respect to study days).

Number of seizures for each participant included in the study on the non-heatwave and heatwave days. Circles represent the number of seizures during the non-heatwave day. Squares represent the number of seizures during the heatwave day. Numbers in symbols are the participant #. Symbols are presented in chronological order of the day of seizure counting. There was a significant difference ( P < 0.05) between the non-heatwave and heatwave days. A one-tailed Wilcoxon matched-pairs signed rank test was used, and significance was set at P ≤ 0.05.

Finally, in the post hoc analysis, there was no correlation (Spearman’s rank = 0) for the comparison between the percentage increase in daily maximum temperature between the non-heatwave and the heatwave days against the percentage increase in seizures during the selected non-heatwave and heatwave days.

We explored the impact of temperature on brain excitability using two measures, IED and seizure number, in a cohort of individuals with known genomic background, to test the hypothesis that higher ambient temperatures increase brain excitability, based on the known sensitivity of ion channels to ambient temperature, in the context of global climate change and its potential effects on the human brain. We show that IEDs can increase in relation to heatwaves as recorded by depth electrodes in people undergoing evaluation for possible surgical treatment of their epilepsy. In three individuals, the number of IEDs increased in the heatwave epoch; in six individuals, there was no significant change between epochs. For the other measure of brain excitability we tested, seizure frequency, we observed an increase in seizure number during heatwaves across the participants as a group. None of the participants had a known genetic epilepsy as determined both by the clinical diagnosis and evaluation of the whole-genome data. However, all had PRSs for epilepsy at the higher end of the range presented from a large group of people with epilepsy, indicating an elevated overall background common variation risk for epilepsy in keeping with the serious nature of the epilepsy in these individuals, with no obvious difference between individual participants ( Supplementary Fig. 2 ). Overall, this study supports the assertion that ambient temperature influences brain excitability and indicates the need for additional research in this important area. Of particular note, none of the participants had a known genetic epilepsy, yet 3/9 showed a significant increase in IED frequency during heatwave epochs compared to non-heatwaves epochs, and as a group, there was a marginally significant increase in seizure frequency during heatwave compared to non-heatwave epochs, which suggests that it is not only people with (typically rare) genetic epilepsies who may be particularly vulnerable to the impacts of heatwaves. These findings raise concerns about the impact of heatwaves for people with a range of different types of severe epilepsies even when these are not obviously due to a monogenic cause.

Populations distributed across latitudes show genetic adaptation to historical local climate conditions. 26-28 Moreover, at the individual level, some individuals relish hotter days, whilst others find them more challenging, the basis for which remains unclear, but with contributions postulated from genetic factors. 29 , 30 All the individuals in our study, except participant #9, are of European ancestry, and therefore in general likely adapted genetically to temperatures typically below the ranges to which they were exposed during the heatwaves included in this study, but inter-individual differences to heat tolerance are important and may exceed ethnic differences. 29 Participant #9 is of admixed American ancestry on genetic grounds: this participant did not show any differences in IEDs or seizure numbers between the heatwave and non-heatwave epochs, but we cannot draw any more conclusions from data from one individual alone. Individual thermal comfort and temperature preferences were not documented at the time of icEEG recording: it remains possible these factors influenced the observed differences in IED and seizure numbers between heatwave and non-heatwave epochs. Our study demonstrates the complexity of evaluating heat effects on human brain function: adaptations to preserve healthy brain function in worsening heatwaves expected with climate change will need to account for such complexities and will need systems approaches.

There is a lack of data on the most biologically relevant way to quantify temperature changes that may affect human brain health. Published data on climate change show extensive disparities in study parameters and reporting, with associations reported between worsening disease parameters (e.g. stroke incidence; admissions for particular conditions) and a variety of different measures of weather, such as diurnal or nocturnal peak temperatures, diurnal temperature excursions, standardized deviation from seasonal norms or the effect of cumulative or lagged (i.e. specified intervals between weather events and the disease parameter in question) measures of temperature. Here, we chose to study peak temperature observed over a 24 h period and sought to ensure a minimum interval of 48 h between these epochs (achieved for 8/9 participants). Our post hoc analysis was undertaken to evaluate the data using a second approach (percentage change in temperature versus percentage change in measure of brain excitability): the analysis did not show any significant association. We also acknowledge that the thermal mass of the building itself, metabolic activity, clothing and ventilation levels will have had effects on the indoor temperature experienced and that lagged effects may also have been important. However, by capturing both epochs during the same episode of icEEG recording and by imposing several other conditions on the selection of the studied intervals, we aimed to minimize these potential influences on IED and seizure occurrences. We acknowledge that for two participants, there was partial reduction in ASM doses after the non-heatwave day and before the heatwave day (#3 and #8, as detailed in Supplementary Table 3 ), although both were on full medications on the day of the heatwave. We consider it unlikely that this was material to our findings, noting for example that there was no change in inter-ictal findings between these days for these participants and the overall patterns of seizures by participant ( Supplementary Table 4 ). An important strength of our study is that the effect of indoor temperatures, albeit interpolated, is considered: the vast majority of published studies examining the links between temperature and human health use external temperatures, whilst in high-income countries, most people spend more than 90% of their lives indoors. Our study therefore provides information that is more likely to be relevant to human health, at least in high-income countries.

Intracranial EEG offers the unique advantage over scalp EEG that longer recordings are commonly undertaken and more tolerable and unaffected by scalp perspiration. However, our approach of using icEEG also imposes some limitations. The sample size was small: icEEG recordings are only appropriate in carefully selected people with epilepsy who may not be representative of most people with epilepsy. Despite the increasing occurrence of heatwaves in the UK, periods of warm spells occurred for an average length of only 13 days a year from 2008 to 2017, 16 limiting the number of eligible studies. IcEEG is only required in few epilepsy surgery candidates, and given its invasiveness and need for input from a range of different medical specialities, only a limited number are performed. 31 Other long-term EEG methodologies, such as those employing chronic ambulatory icEEG recording, are being developed. One study using an implanted responsive neurostimulation system showed phase locking of seizure timing with a range of monitored personal variables, including skin temperature, 32 which itself has a complex relationship to ambient temperature. We relied on modelled data prior to 2022 as we did not have indoor recordings from the telemetry unit until 29 April 2022. We are now monitoring prospectively both outdoor and indoor temperatures. Sleep deprivation can promote IEDs and seizures in people with epilepsy. 33 Heatwaves can disrupt sleep patterns, causing fatigue and sleep deprivation. 5 , 34 We did not evaluate how well the participants slept during their time in hospital. These are mechanistic details requiring prospective work and do not detract from the observed association between higher ambient temperature and brain excitability. In addition, we focused on awake EEG epochs for analysis. It is challenging to distinguish wakefulness from drowsiness and N1 sleep on icEEG recordings even for the trained observer, but we did exclude deep and rapid eye movement (REM) sleep. 35 Using comparable participant states between the non-heatwave and heatwave days was a strength of the study. 36 , 37 IED counting was performed manually. We see this as a strength of the study: whilst it is time-consuming and prohibits evaluation across longer time frames, expert manual detection avoids inclusion of false positives, a vulnerability of automated IED detection software. 38

There are few explorations published about the potential impacts of climate change on the human brain and, specifically, on the human brain in disease. 39 , 40 People with neurological diseases, their carers and clinicians are concerned about climate change. 41 The Earth has already passed, at least temporarily, the 1.5°C threshold set by the 2015 Paris Agreement far sooner than predicted. Our study raises important concerns about brain excitability during heatwaves. We urgently need more data to protect people with neurological diseases and ensure the best health outcomes from adaptation and mitigation actions being taken against climate change.

Supplementary material is available at Brain Communications online.

We thank Harry Michael Wells for the statistical support. This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.

S.M.S., D.J.-J., R.B., H.M.C. and P.M. are supported by the Epilepsy Society. H.M.C. is the Amelia Roberts Fellow at the Epilepsy Society and University College London. S.M.S. and A.M. were supported by a University College London Grand Challenges Climate Crisis Special Initiative award (number: 156425).

The authors report no competing interests.

Summary data used for the analyses are available, under appropriate data sharing agreements subject to our ethics protocol, for bona fide researchers. Individual-level data are not available due to the risk of de-identification. Research on the de-identified patient data and control data used in this publication can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient-led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers may contact [email protected] or access the relevant information on the Genomics England website: https://www.genomicsengland.co.uk/research .

No bespoke code was used for this study. All code used in the manuscript is in the public domain already and has been appropriately referenced. We have added an additional reference to the R package Ranger , which was used to implement the random forest model in RStudio, allowing readers to replicate the analysis with their own data.

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Author notes

• body temperature
• temperature
• epileptiform discharges
• electrocorticogram
• climate change
• extreme heat

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Heatwaves may increase likelihood of seizures in people with epilepsy

10 September 2024

Heatwaves can worsen abnormal excitability of the brain in people with epilepsy, finds a new small-scale patient study led by clinical scientists at UCL Queen Square Institute of Neurology.

The research, published in  Brain Communications , used intracranial electroencephalography (icEEG) tests – where small electrodes are inserted into the substance of the brain to measure electrical impulses – to track the brain activity of nine patients being evaluated for surgical treatment of medication-resistant epilepsy at the National Hospital for Neurology and Neurosurgery, in the summer months (May-August) of 2015 – 2022.

Genomic testing showed that none of the participants had known genetic epilepsies that are already associated with worsening of seizures during heatwaves.

In London, a heatwave is defined as three or more consecutive days with daily maximum temperatures of more than 28 degrees Celsius.

The nine patients involved in the study were, by chance, having icEEG recordings taken during spontaneous heatwaves in London, allowing the researchers to directly examine their brain activity during periods of unusually hot weather.

The researchers then compared this data to icEEG recordings taken from the patients during non-heatwave periods – while ensuring that all other conditions (apart from temperature) remained the same.

For each participant, the team logged any abnormal electrical activity across four 10-minute segments within and outside of heatwaves. They also tracked all seizures.

They found that, overall, more seizures were recorded by the icEEG during heatwaves compared with the non-heatwave period. Meanwhile, three patients also had more abnormal electrical brain activity aside from seizures during heatwaves.

Senior author, Professor Sanjay Sisodiya (UCL Queen Square Institute of Neurology), said: “Our research shows that for some people with epilepsy – in particular those with the most severe epilepsies – higher ambient temperatures increase the likelihood of having seizures.

“This is an important finding, providing some of the first evidence that for some people who already have epilepsy, higher temperatures seen during heatwaves can make their condition worse.

“Such information is important for the care of individual people with epilepsy, and also for broader efforts to ensure people with epilepsy can be kept safe as the climate changes.”

The current study sample size is relatively small as icEEG is not commonly undertaken and a heatwave had to have happened, by chance, during the recording.

However, the team now hope to have a bigger prospective study, and data are currently being collected.

Professor Sisodiya said: “Despite the study’s limited sample size, our findings remain valuable in the context of climate change. As global temperatures rise and extreme weather events become more frequent, understanding the effects of heatwaves on brain activity is crucial.”

Professor Sisodiya recently led a review of 332 papers published across the world, that explored that scale of potential effects of climate change on neurological diseases*.

The researchers found that the effect of climate change on weather patterns and adverse weather events is likely to negatively affect the health of people with brain conditions, including stroke, migraine, Alzheimer’s, meningitis, epilepsy and multiple sclerosis. The new research adds to this analysis.

The research was carried out in collaboration with researchers at UCLH and funded by the Epilepsy Society, The Amelia Roberts Fellowship, and a UCL Grand Challenges Climate Crisis Special Initiative award.

*  Climate change likely to aggravate brain conditions  

• Olivia C. McNicholas, Diego Jiménez-Jiménez, Joana F. A. Oliveira, Lauren Ferguson, Ravishankara Bellampalli, Charlotte McLaughlin, Fahmida Chowdhury, Helena Martins Custodio, Patrick Moloney, Anna Mavrogianni, Beate Diehl,   Sanjay M. Sisodiya, “The influence of temperature and genomic variation on intracranial EEG measures in people with epilepsy” , Brain Communications  Volume 6, Issue 5, 2024, fcae269.  https://doi.org/10.1093/braincomms/fcae269
• Professor Sisodiya's academic profile
• Credit:  Tomwang112  on iStock

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Heat waves may increase the likelihood of seizures in people with epilepsy

by University College London

Heat waves can worsen abnormal excitability of the brain in people with epilepsy, finds a new small-scale patient study by clinical scientists at UCL.

The research , published in Brain Communications , used intracranial electroencephalography (icEEG) tests.

Small electrodes were inserted into the substance of the brain to measure electrical impulses to track the brain activity of nine patients being evaluated for surgical treatment of medication-resistant epilepsy at the National Hospital for Neurology and Neurosurgery in the summer months (May–August) of 2015–2022.

Genomic testing showed that none of the participants had known genetic epilepsies that are already associated with worsening of seizures during heat waves.

In London, a heat wave is defined as three or more consecutive days with daily maximum temperatures of more than 28°C.

The nine patients involved in the study were, by chance, having icEEG recordings taken during spontaneous heat waves in London, allowing the researchers to directly examine their brain activity during periods of unusually hot weather.

The researchers then compared this data to icEEG recordings taken from the patients during non–heat wave periods, while ensuring that all other conditions (apart from temperature) remained the same.

For each participant, the team logged any abnormal electrical activity across four 10-minute segments within and outside of heat waves. They also tracked all seizures.

They found that, overall, more seizures were recorded by the icEEG during heat waves compared with the non-heat wave period. Meanwhile, three patients also had more abnormal electrical brain activity aside from seizures during heat waves.

Senior author, Professor Sanjay Sisodiya (UCL Queen Square Institute of Neurology), said, "Our research shows that for some people with epilepsy—in particular those with the most severe epilepsies—higher ambient temperatures increase the likelihood of having seizures.

"This is an important finding, providing some of the first evidence that for some people who already have epilepsy, higher temperatures seen during heat waves can make their condition worse.

"Such information is important for the care of individual people with epilepsy, and also for broader efforts to ensure people with epilepsy can be kept safe as the climate changes."

The current study sample size is relatively small as icEEG is not commonly undertaken and a heat wave had to have happened, by chance, during the recording.

However, the team now hope to have a bigger prospective study, and data are currently being collected.

Professor Sisodiya said, "Despite the study's limited sample size, our findings remain valuable in the context of climate change. As global temperatures rise and extreme weather events become more frequent, understanding the effects of heat waves on brain activity is crucial."

Professor Sisodiya recently led to a review of 332 papers published across the world, that explored the scale of potential effects of climate change on neurological diseases.

The researchers found that the effect of climate change on weather patterns and adverse weather events is likely to negatively affect the health of people with brain conditions, including stroke, migraine, Alzheimer's, meningitis, epilepsy and multiple sclerosis. The new research adds to this analysis.

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• v.10(1); 2008 Mar

Language: English | Spanish | French

Epilepsy research: a window onto function and dysfunction of the human brain

Investigación en epilepsia: una ventana hacia la función y disfunción del cerebro humano, recherche sur l'épilepsie: une fenêtre sur le fonctionnement et le dysfonctionnement du cerveau humain, christian e. elger.

Department of Epileptology, University of Bonn Medical Center, Bonn, Germany

As one of the most common neurological disorders, epilepsy has devastating behavioral, social, and occupational consequences and is associated with accumulating brain damage and neurological deficits. Epilepsy comprises a large number of syndromes, which vary greatly respect to their etiology and clinical features, but share the characteristic clinical hallmark of epilepsy recurrent spontaneous seizures. Research aimed at understanding the genetic, molecular, and cellular basis of epilepsy has to integrate various research approaches and techniques ranging from clinical expertise, functional analyses of the system and cellular levels, both in human subjects and rodent models of epilepsy, to human and mouse genetics. This knowledge may then be developed into novel treatment options with better control of seizures andlor fewer side effects. In addition, the study of epilepsy has frequently shed light on basic mechanisms underlying the function and dysfunction of the human brain.

La epilepsia es uno de los trastornos neurológicos más comunes y tiene consecuencias conductuales, sociales y ocupacionales devastadoras, y se asocia con daño cerebral acumulaiivo y déficit neurológicos. La epilepsia incluye un gran núméro de síndromes, que varían ampliamente en relación con la etiología y los aspectos clínicos, pero que comparten el sello clínico característico de la epilepsia: las crisis espontáneas recurrentes. La investigación orientada a la comprensión de las bases genéticas, moleculares y celulares de la epilepsia ha integrado varias aproximaciones y técnicas de investigación que van desde la habílidad clínica, los análisis funcionales de los sisiemas y el nivel celular, tanto en modelos de epilepsia en humanos como en roedores, hasia la genética en ratones. Este conocimienio entonces puede dar origen a nuevas opciones terapéuticas con mejor control de las convulsiones ylo menores efectos secundarios. Además, el estudio de la epilepsia frecuentemenie ha dado luces acerca de los mécanismes básicos que subyacen a la función y disfunción del cerebro humano.

Les conséquences comportementales, sociales et professionnelles de l'épilepsie, l'un des troubles neurologiques les plus courants, sont dévastatrices. L'épilepsie est associée à une accumulation d'altérations cérébrales et de déficits neurologiques. Ses syndromes sont nombreux et varient beaucoup selon leur étiologie et leurs particularités cliniques, mais partagent l'aspect clinique caractéristique de l'épilepsie : les crises spontanées récidivantes. La recherche s'est efforcée de comprendre les bases génétiques, moléculaires et cellulaires de l'épilepsie en intégrant diverses approches et techniques allant de l'expertise clinique, de l'analyse fonctionnelle des systèmes à un niveau cellulaire, à la fois chez les humains et dans des modèles murins d'épilepsie, jusqu'à la génétique humaine et la génétique murine. Grâce à cette connaissance, de nouveaux traitements pourraient être développés, les crises mieux contrôlées et/ou les effets indésirables plus restreints. L'étude de l'épilepsie a, en outre, fréquemment permis d'éclairer les mécanismes de base du fonctionnement et du dysfonctionnement du cerveau humain.

Epilepsy is one of the most common neurological disorders (~8 000 000 patients in the European Union). It has devastating behavioral, social, and occupational consequences, and is associated with accumulating brain damage and neurological deficits. Epilepsy comprises a large number of syndromes, which vary greatly with respect to their clinical features, treatment, and prognosis. However, all of these syndromes share the characteristic clinical hallmark of epilepsy - recurrent spontaneous seizures.

Even though the key manifestation of all epilepsies is recurrent seizures, the etiologies that can give rise to an increased propensity of the human brain to generate synchronized neuronal activity and seizures are diverse. Epileptic seizures are associated with overt causes, such as certain central nervous system (CNS) tumors or neurodevelopmental abnormalities, CNS trauma, or inflammation (symptomatic epilepsies). In a small number of epilepsy patients, a mutation in a single gene suffices to cause chronic seizures. Additionally, a large group of epilepsies has a yet-unknown etiology (idiopathic epilepsies). Studies of the genetic or molecular and cellular causes of epilepsy have to take account of the fact that epilepsy is not a uniform disorder, but a mixture of many different entities. A precise analysis of the clinical, neurophysiological, and neuropathological phenotype of human epilepsies with a definition of homogenous subgroups/syndromes is a prerequisite not only for genetic studies, but also for the development of appropriate animal models to study the cellular basis of seizures and epilepsy. Because of the etiological diversity of epilepsy, modern approaches to epilepsy research involve many different fields. These include clinical fields such as clinical epileptology and neurosurgery, neurology, psychiatry, and neuropathology, but also basic research areas such as human genetics, neuropsychology, immunology, neurophysiology, neurophysics, molecular biology and transgenics, developmental neurobiology, and neuropharmacology.

The ultimate goal of studies into the molecular and cellular mechanisms of epilepsy is to develop novel, and more effective, therapies. This may be approached in several ways. Firstly, a better understanding of the underlying disease mechanisms may in some instances lead to the identification of novel treatment options. Secondly, it is important to understand why currently available therapies do not help certain patients, while they are very effective in others. Finally, another goal of epilepsy research is to identify mechanisms underlying side effects of drug therapy, because these often limit drug therapy. In addition to the intrinsic value of studying disease processes in one of the most common neurological disorders, epilepsy research is an excellent model for understanding basic mechanisms of CNS function and plasticity, in particular in the human brain, for several reasons. Firstly, seizures are known to initiate a large number of plastic changes on a molecular and cellular level in the brain. Many of these plasticity mechanisms have been recognized as key components of normal brain function (ic, brain development or learning and memory) or in other neurological disorders. Secondly, understanding the cellular basis of aberrant synchronized discharges of neurons during epileptic seizures also yields insights into the mechanisms of normal synchronization in the brain. Finally, the necessity to perform invasive electrode (depth and subdural) recordings in patients with epilepsy results in unique opportunities to study human cognitive processes at extremely high time resolution by recording field or even single unit potentials during cognitive tasks. This technique can be combined with different functional imaging techniques, which ideally complement invasive recordings from the human brain by providing excellent spatial resolution.

Research into the basic mechanisms of epilepsy

The study of idiopathic genetic epilepsies : how do single gene mutations cause epilepsy.

Genetic factors are the major determinants in at least 40% of all epilepsies; these are designated as “idiopathic epilepsies.” Only about 2% of these idiopathic epilepsies are inherited as monogenic disorders, in which one gene conveys the major heritable impact, while environment and lifestyle play a limited role. Genetic studies have allowed identification of the first disease genes that define monogenic idiopathic epilepsies. 1 , 2 In these cases, genetic studies have identified causal gene variants, many of them neuronal ion channels, receptors, or associated proteins. Subsequently, the function of these variants was examined carefully in expression systems, and specific functional changes were found. These analyses, while compelling in implicating specific genes in idiopathic epilepsies, are not the last word in understanding how a gene mutation leads to a behavioral and clinical phenotype. We are beginning to obtain such an understanding in some instances from transgenic mouse models that carry disease-associated gene variants. 3 The advantage of such models is that they harbor human disease-associated gene variants, and can be examined at various points during the development of epilepsy with in vitro and molecular techniques. The limitation of such models is that the mechanisms of epileptogenesis may not be the same in mice and humans, and that disease-associated human gene variants are expressed on a background of mouse genes that may interact in unexpected ways with the human ortholog. Nevertheless, such studies are increasingly part of an integrated strategy to understand the mechanisms of monogenic epilepsies involving both human genetics and physiological, and molecular studies in transgenic mouse models.

The study of focal epilepsy

What are the mechanisms of seizures.

By far most types of epilepsies, however, are not monogenic. Rather, they most probably involve both the effects of various combinations of gene variants, environmental factors, and precipitating injuries early during development. The relative importance of these factors in common focal epilepsies such as temporal lobe epilepsy (TLE) is unknown. For obvious reasons, it is difficult to investigate how these epilepsies develop over time prior to the first clinical manifestation. This is probably why research in the field has focused more on identifying key mechanisms that govern abnormal excitability and synchronization in chronic epilepsy, in particular those which might be potential targets for therapeutic manipulation. Animal models generated for this goal have been selected with the rationale that they should reproduce the neuropathologies, clinical, and physiological features of the chronic stage of epilepsy. This has been achieved to some extent for temporal lobe epilepsy. Models of temporal lobe epilepsy (TLE) include the kainate model, 4 the pilocarpine model, 5 and the self-sustaining limbic status model. 6 All rely on the induction of status epilepticus (SE) either pharmacologically (with the ionotropic glutamate receptor agonist kainate or the muscarinic agonist pilocarpine), or via electrical stimulation (self-sustaining limbic status model). After a period of a few weeks, animals that have experienced SE exhibit several hallmarks of temporal lobe epilepsy, including (i) spontaneous seizures; (ii) a pattern of neuropathological damage similar to a subset of temporal lobe epilepsy patients with segmental hippocampal cell loss, gliosis and axonal reorganization; and (iii) dispersion of granule cells. In TLE, we have the unique possibility of validating such animal models because tissue from TLE patients is available from epilepsy surgery. From comparative neuropathological studies, we know that the pattern of damage in the abovementioned models is surprisingly close to that seen in a subgroup of TLE patients with so-called Ammon's horn sclerosis (AHS). Patients with AHS also display severe segmental neuron loss, axonal reorganization, and gliosis, along with dispersion of granule neurons. 7 - 9 It should be noted that in other instances, these epilepsy models differ from the human condition. For instance, damage in the pilocarpine model is not restricted to the hippocampus, involving instead many other brain regions. Nevertheless, these and similar models have been used extensively to study cellular and molecular changes in chronic epilepsy, and how these might lead to seizure generation. These changes have in some cases been compared with data obtained from human neurons obtained from epilepsy surgical specimens. 10

A further group of TLE patients docs not display the neuropathological features of AHS, even though they experience seizures originating from the mesial temporal lobe. 7 - 9 In this group of TLE. patients, epilepsy is often a consequence of a mesial temporal lobe tumor or developmental malformation. An animal model that is thought to replicate some features of these human patients is the kindling model. In this model, repeated application of subthreshold electrical stimulation to limbic structures results in the expression of permanent limbic hyperexcitability. In this model, significant neuropathological damage is largely absent. In comparison with studies on human and experimental TLE, work on models of epilepsies with neocortical seizure foci has been relatively scarce, even though such models can also be validated in human in vitro studies.

Models of TLE have proven useful as a complementary strategy to investigations on human epileptic brain tissue. In experiments on human tissue, a fundamental problem is the lack of living control tissue. Very rarely, nonepileptic human control tissue is available from the penumbra of tumor resections in the temporal lobe. Other than this rare commodity, experimenters are left with the option of comparing epileptic tissue with autopsy control tissue, which is impossible for physiological and some molecular biological approaches. A further, commonly used approach is to compare tissue from patients with AHS vs lesion-associated epilepsy. This strategy has allowed the investigation of the expression of candidate molecules associated with changes present only in one of these patient groups. For instance, molecules important in synaptic reorganization would be expected to be present in specific areas in AHS, but not in lesion-associated epilepsy. Studies in animal models, on the other hand, always require validation with studies on human tissue to demonstrate their relevance to the human disorder unequivocally 11 However, animal models do complement human studies in important ways. Firstly, animal models allow molecular and functional changes to be studied in detail without the constraints imposed by the lack of control material in experiments with human tissue. Further, having identified clear molecular changes, animal models allow us to determine the importance of such changes for hyperexcitability and epileptogenesis. This question is important because a large number of regulated candidate molecules have been identified, all of which may be potentially important in the development of epilepsy. A major challenge will be to determine which of these manifold changes are functionally important in common forms of epilepsy. To decipher the causal role of candidate genes, it has become increasingly accepted that it is necessary to generate cell-specific and inducible gain - as well as loss-of-function models on a more systematic scale than previously attempted. Such approaches may be realized using viral transfer of small interfering RNAs (siRNAs), or transgenic models that allow cell-specific and inducible genetic modifications. Finally, animal models allow to study some aspects of epileptogenesis, which is virtually impossible in human tissue, because specimens are only obtained late during the disease course.

What are the mechanisms of epileptogenesis?

Broadly speaking, epileptogenesis can be defined as a plastic process leading from a normal to a chronically epileptic brain. Precipitating brain insults (ie, febrile seizures, local infections, SE, ischemia, or trauma) in concert with genetic susceptibility factors are thought to trigger such persistent changes. As explained above, to directly address this issue in human subjects is extremely difficult. In recent years, investigators have therefore increasingly turned to animal models for this purpose. In the case of TLE, most investigators have studied epileptogenesis after an initial SE. It is important to realize that TLE models replicate the chronic features of TLE reasonably well. It is however not clear how much the mechanisms underlying SE-induced epileptogenesis overlap with the mechanisms underlying epileptogenesis in TLE patients, in whom this process is likely multifactorial and not triggered by SE. Nevertheless, studies of epileptogenesis in SE models have been worthwhile because they have resulted in an increased understanding of the basic mechanisms underlying key features of AHS, such as sprouting, cell death, and gliosis.

It may seem easier to establish models of epileptogenesis in symptomatic epilepsies, for instance epilepsy associated with CNS tumors, developmental malformations, or CNS trauma, for the simple reason that the initial precipitating injury is known, and can be replicated quite well in many cases. However, developing such models has proven surprisingly elusive. Models for tumor-associated epilepsy are scarce, and have relied on the injection of rapidly proliferating tumor cell lines into the brain of rodents. 12 While potentially valuable to assess the consequences of a rapidly growing malignancy in the CNS, these models are probably not that informative on mechanisms of epileptogenesis and seizure generation involved in human epilepsy patients. This is mainly because the tumors that are likely to cause epilepsy are mostly low-grade tumors with slow proliferation. The reasons for this association are unknown. It will be necessary to create additional models aimed at replicating features of these tumors. Regarding developmental malformations, there are several models in which the proper formation of cortical structures has been disrupted. These include models in which drugs are applied during cortical development that arrest neuronal migration, or in which lesions are applied to the cortex during cortex formation, which also lead to formation of a cortex with a disturbed laminar organization. 13 In trauma models, fluid percussion injury results in a circumscribed traumatic cortical injury zone. 14 These models have been informative because they have revealed manifold changes in excitability in and surrounding the abnormal cortical areas, and address the underlying mechanisms. However, it is not yet clear if these models lead to symptomatic epilepsy. More recently, genetic models of cortical malformations have been introduced. These models rely on the temporally selective and cell-type specific disruption of genes important in neuronal differentiation and migration. A further intriguing model that may address a common mechanism in many epilepsies is disruption of the blood-brain barrier. It has been recently shown that focal disruption of the blood-brain barrier results in development of a hyperexcitablc focus. 15 , 16 Since blood-brain barrier disruption is a common feature of status epilepticus, ischemia, trauma, and CNS tumors, it may be that this is a common mechanism for hyperex citability in these models. The proliferation of these and other models has led to an intense discussion in the field regarding the validity of such models for the human condition. A worthwhile aspect of this discussion is that it has led to an awareness that animal models only replicate specific aspects of any human condition, and it is paramount to be aware of the areas where a specific model is informative versus the ones where it is not.

What are the key questions that have been addressed in studies of epileptogenesis? Firstly, experiments primarily in post-status models of epileptogenesis have addressed the role of changes in voltage-and transmitter-operated ion channels in epileptogenesis. Generally, activity-dependent changes in neuronal function can be subdivided into changes in synaptic communication between neurons (termed synaptic plasticity), and changes in intrinsic membrane properties of neurons (termed intrinsic plasticity) that govern how synaptic input is integrated. Work on synaptic plasticity has focused on changes in the expression and function of neurotransmitter receptors at synapses, as well as changed properties of presynaptic neurotransmitter release. Research on intrinsic plasticity has addressed changes in voltage-gated ion channels in the somatic, dendritic, and axonal membrane of neurons. 17 There have been multiple such changes described convincingly in the literature. A crucial question is how to evaluate the role of individual molecular changes seen in animal models in the development of epilepsy. There are several strategies that could be used to this end. Perhaps the most straightforward of these is to specifically interfere genetically or pharmacologically with ion channel regulation. Due to the novel genetic tools available in recent years, this is becoming more and more feasible. To transfer these types of studies to the human is more difficult. As stated above, human tissue obtained from epilepsy patients reflects the end stage of chronic epilepsy in most cases. It is therefore doubtful that human tissue can serve as a useful control for animal models at an early stage of epileptogenesis. One avenue which may provide a useful link between animal models and human epilepsy, however, is the use of genetic techniques to address whether polymorphisms in ion channel genes, associated proteins, or relevant transcription factors are associated with an increased propensity to develop epilepsy.

What causes changes in ion-channel function? The underlying molecular mechanisms are just beginning to be unraveled. One feature of epileptogenesis is the selective and coordinated regulation of transcription. This regulation affects mRNA levels encoding for groups of ion channels. The mechanisms that drive altered transcription have been identified in only few cases. Identification of the responsible transcription factors is one possible avenue to inhibit specific features of epileptogenesis. Persistent changes in transcription, however, are not only determined by a persistent activation of transcription factors, but can also be caused by changes in the chromatin state or autoregulatory feedback loops involving key transcription factors. Following transcription, alterations at the post-transcriptional level may be caused by changes in translational regulation. Finally, trafficking of ion-channel subunit proteins, as well as post-translational modifications, are important determinants of function that may be altered in chronic epilepsy. Understanding changes in intrinsic neuronal properties and synaptic function are also relevant for understanding mechanisms of drug actions, as well as why resistance to these drugs occurs. A large number of voltage-gated ion channels and some presynaptic proteins are targets for antiepilcptic drugs, and changes in these targets may cause reduced drug sensitivity (explained in more detail below).

In addition to changes in membrane-bound ion channels, epileptogenesis is associated with large changes in mitochondrial function, including mitochondrial DNA depletion, failure of energy supply, and production of reactive oxygen species. 18 , 19 Such changes play a large role in the initiation of cell death cascades. Studies on mitochondrial function have been conducted in chronic experimental and human epilepsy. As above, studies on the mechanisms underlying the development of mitochondrial dysfunction are difficult in human tissue obtained at chronic stages. Here also, genetic studies provide an important link to epileptogenesis. An increasing number of studies have addressed whether genetic variability in genes encoding mitochondrial proteins confers susceptibility to epileptogenesis. 20

An intriguing novel facet of epileptogenesis, that will likely necessitate the development of new model systems, is the involvement of immune cells in the development of epilepsy. Immune cells profoundly influence processes in the normal brain, such as neurogenesis or synaptic plasticity. The link between neuroimmunological processes and epilepsy is highlighted by inflammatory/autoinflammatory epileptic syndromes (eg, Rasmussen encephalitis or limbic encephalitis). Innate immune cells may not only play a role in the pathogenesis of these relatively rare epileptic syndromes, but also in the process of epileptogenesis in common chronic epilepsies which were not previously considered to have “encephalitic” components. 21 - 23

How does epilepsy research lead to improved therapies?

In many patients with epilepsy, seizures are well-controlled with currently available antiepilcptic drugs. However, seizures persist in a considerable proportion of these patients. 24 The exact fraction of epilepsy patients that are considered refractory varies in the literature, mostly because the criteria for classification as pharmacoresistant have varied. Nevertheless, a substantial fraction (~30%) of epilepsy patients does not respond to any of two to three first-line antiepilcptic drugs (AEDs), despite administration in an optimally monitored regimen. 25 Despite the clinical relevance of this phenomenon, the cellular basis of pharmacoresistance has remained elusive. However, integrated strategics integrating clinical, genetic, and molecular physiological techniques are providing some insight into possible mechanisms. What are the key strategies that can be used to unravel mechanisms of pharmacoresistance?

The first approach is pharmacogenomic. The ultimate goal of pharmacogenomics is to define the contributions of genetic differences in drug response. 26 The variability of an individual's response to a given drug can be considerable, and identifying causal genetic factors is expected to lead to improved safety and efficacy of drug therapy through use of genetically guided, individualized treatment. Pharmacogenomic approaches require both substantial clinical and genetic expertise. Following delineation of pharmacoresistant and pharmacoresponsive patient groups, powerful tools for disease gene mapping and identification afforded by the human genome project can be exploited. These tools, which include a large number of catalogued sequence variants, permit genomewide studies for the identification of genetic loci underlying diseases and related phenotypes, including the response to drug treatment. These studies may allow identification of novel gene variations conferring risk for the development of epilepsy and pharmacoresistance. While this approach sounds straightforward, it is far from simple in practice. This is also clear from the large number of polymorphisms found in such association studies which could not be reproduced in replication studies. Major problems that still have to be overcome are firstly, that pharmacoresponse may not be determined by a single gene polymorphisms, rather, it may be the result of a combination of polymorphisms. Accordingly, the impact of single genes may be rather small, requiring large patient cohorts. In addition, gathering large patient cohorts prospectively, which are carefully matched according to their drug response, is extremely difficult and requires collaboration between epilepsy centers. Finally, it will be necessary to address experimentally in those cases in which polymorphisms are found in association studies whether they have biologically plausible effects that may result in pharmacoresistance. It is clearly worthwhile to exploit such strategies to the utmost, because genetic approaches can nowadays provide a genome-wide analysis at comparatively low cost. Thus, we are not limited by our preconceptions regarding the specific molecules important in pharmacoresistance.

An alternate approach to the problem of pharmacoresistance has been to examine directly the response of drug targets in epileptic tissue. This work has focused on targets such as voltage-gated sodium channels, for which AFT) responsiveness is well established. 27 Subsequently, the response of channels to AEDs was investigated in both animal models of TLE and human epilepsy. 10 In some cases, as for voltage-gated sodium channels, a loss of sensitivity of the channel complex to AEDs was found, both in experimental and human epilepsy. Importantly, such in-vitro data can be correlated with the clinical phenotype. Indeed, in the case of carbamazepine, pharmacoresistance observed clinically was found to correlate with a loss of carbamazepine sensitivity of voltage-gated sodium channels. This strategy may be integrated with genetic approaches to provide a potentially very informative approach to pharmacoresistance. The increasing availability of genetic information also on epilepsy patients who undergo epilepsy surgery opens the possibility to perform genetic analyses on key molecules implicated in the response to AEDs (ie, ion channels, presynaptic proteins, or drug transporters). Subsequent to the epilepsy surgery, a number of experiments can be done on human tissue from these patients. Firstly, ion channel or drug transporter function can be assessed directly. Secondly, seizure activity can be elicited in human brain slices, and the pharmacoresponse of this activity can be quantitatively determined. In both cases, a correlation with genetic information can provide useful information on the functional relevance of genetic variability.

The analyses in human tissue - while potentially very useful - are hampered by the fact that human tissue is only available from a subgroup of epilepsy patients. This has sparked a quest for other suitable human model systems. One possibility is to use cells generated from human embryonic stem cells and differentiated into either neurons or glial cells in vitro. This approach would permit to test the effects of antiepilcptic drugs in a cell model with a human background. Alternatively, it may be possible to isolate adult human stem cells from epilepsy surgical specimens, amplify them and generate appropriate neural populations. The latter approach has the advantage that the genetic phenotype of the patient is available for individual interpretation of differential drug responses. In addition to experiments aimed at understanding mechanisms of drug resistance, and the development of new drugs, other avenues for treatment of epilepsy have been explored. One of these avenues is the transplantation of defined neuronal populations into either the epileptic focus itself or into sites that contribute to seizure generalization. It has been shown that such approaches can ameliorate seizure activity. 28 An alternate approach is to predict and prevent seizures with invasive recording and stimulation techniques. 29 Seizure prediction is a field of great interest in the clinical and basic neuroscience communities. This is not only because of its potential clinical application in warning and therapeutic antiepilcptic devices, but also for its promise of increasing our understanding of the mechanisms underlying epilepsy and seizure generation.

Mechanisms of cognitive deficits associated with epilepsy

Epilepsy is frequently associated with cognitive deficits that may be due to an a-priori brain pathology, plastic changes induced by the epilepsy, adverse effects of drug treatment, or epilepsy surgery. The prevalence and clinical importance of cognitive deficits has triggered intense research activity in this field, in particular concerning preand postsurgical memory and language impairments. However, epilepsy and the employed invasive diagnostic and therapeutic procedures also provide neuroscientists with a unique and unprecedented opportunity to study the neurophysiological basis of cognition and emotions in vivo. The specific techniques that can be used for such clinical and cognitive analyses are, for instance, recordings from implanted depth electrodes, which provide a high temporal resolution of activity in the cortex or deeper brain structures, in particular the hippocampus. 30 - 32 In addition to recording activity from collective neuronal behavior, single unit activity from temporal lobe neurons can be analyzed, thereby enabling the analysis of cognitive functions at the single cell level. 33 Complementing these techniques, functional imaging techniques offer high spatial resolution but less precise temporal information about neuronal activity. They also permit functional analysis of areas in which electrode placement is clinically unnecessary, and allow the analysis of structural and functional changes of connectivity. The combination of these techniques is of considerable interest, primarily because they are complementary with regard to spatial and temporal resolution. It will therefore constitute a fundamental advance to acquire combined (ic, simultaneous) intracranial electroencephalogram (EEG)/single unit and functional magnetic resonance imaging (fMRT) data during cognitive tasks. While this will also contribute significantly to resolving the current debate about the neuronal correlate of fMRI signals in humans, combining these technologies will enable the investigation of the “brain at work” at an unprecedented degree of accuracy. A clinical demand also exists for such combined recordings (ie, the detection of seizure foci with spike-triggered fMRI). A simultaneous recording of intracranial EEG/single units and fMRI is in principle possible. Several companies are currently performing safety evaluations with pending applications for approval of their intracranial electrodes for use within fMRI scanners.

So far, analyses utilizing intracranial EEG recordings have allowed important insights into the function of mesial temporal lobe structures in the human, and have allowed to directly study mechanisms underlying episodic memory processes and their plasticity due to hippocampal dysfunction in the human. They have also resulted in an increased understanding of the perception and production of language, and declarative memory functions related to language. Interesting areas that can be studied using such techniques are also those aimed at understanding how the human amygdala and hippocampus process fear and emotional stimuli. Interaction with researchers of other disciplines, such as economy and social sciences, may permit the investigation of human problem-solving mechanisms employing realistic paradigms. A further interesting avenue is to conduct pharmacological in-vivo studies, in which pharmacological manipulations are performed in healthy subjects and epilepsy patients (ie, N-methyl-D-aspartate [NMDA] receptor antagonists), both during invasive depth electrode recordings and fMRI experiments. 34 These approaches have proven important to dissect out the contribution of specific neurotransmitter systems to cognitive functions. They also potentially provide an endophenotype that may predict drug efficacy or side effects.

Apart from functional imaging techniques, modem imaging technologies provide an unprecendented look at structural changes in the human brain associated with epilepsy. It has become increasingly clear that both functional (ie, an hyperexcitablc focus) or structural lesions can lead to shifts in the local representation of function in the brain, and to substantial changes in functional and structural connectivity between brain areas. Using modern structural and functional MRI techniques, such as diffusion tensor imaging or dynamic causal modeling, allows analysis of such changes in human subjects with excellent spatial resolution, with respect to the functions described above. Such experiments will reveal the properties and time course of structural and functional disease associated plasticity, as well as which aspects of this plasticity can be influenced (ie, by seizure suppression or epilepsy surgery).

Relationship of epilepsy to other neurological disorders

It is becoming increasingly clear that key molecules and mechanisms responsible for the development of epilepsy may also be pivotal in other neurological disorders. For instance, evidence from animal studies suggests that mechanisms of neuronal degeneration may be very similar in models of epilepsy, trauma, ischemia, and perhaps other chronic neurodegenerative disorders. Furthermore, the conversion of glial cells to a reactive phenotype occurs not only in epilepsy, but also in a wide range of neurological disorders. There are numerous other examples for stereotypical, disease-associated plastic changes in neurons in different neurological disorders. In addition to these similarities, genetic studies also suggest shared susceptibility factors. These shared molecular mechanisms are thought to underlie the phenomenon of comorbidity (ie, an epidemiological association of epilepsy with other disorders). Since it is likely that comorbidity results from a shared genetic susceptibility, genetic approaches are well-suited for identifying these common pathways. An important further aspect is the availability of human brain tissue in the context of an epilepsy surgical center for cellular and molecular analyses, as well as in-vitro physiology and pharmacology experiments. These human brain materials represent a unique resource for the assessment of specific pathophysiological hypotheses, especially in combination with tissues from appropriate animal models. Furthermore, frequent comorbid disorders, such as depression, occur often enough within epilepsy patient collectives to allow relevant numbers of experiments using a combination of in-vivo physiology and fMRI, on matched groups of epilepsy patients with and without comorbid disorders. In contrast to electrophysiological recordings, which can only be done on epilepsy patients, fMRI studies can be performed on both epilepsy patients, nonepileptic patients with comorbidity (ie, depression or migraine), and control subjects. These experiments will yield unique insights as to the relationship between epilepsy, comorbid disorders, and cognitive processes. They will also allow us to examine the effects of drugs used in other CNS disorders on cognitive processes with high resolution.

In summary, the study of the neurobiological basis of epilepsy using approaches that integrate genetic, human functional and behavioral studies, and work on animal models, is important for developing novel therapeutic strategies. It is also one of the few existing research approaches that can be utilized to examine the function of the human brain at high temporal, spatial, and cellular resolution.

Selected abbreviations and acronyms