Oxford Textbook of Epilepsy and Epileptic Seizures This page intentionally left blank Oxford Textbook of Epilepsy and Epileptic Seizures Series Editor Christopher Kennard Edited by Simon Shorvon UCL Institute of Neurology, University College London, London, UK Renzo Guerrini Pediatric Neurology Unit and Laboratories, Children \200\231s Hospital A. Me yer \200\223 University of Florence, Firenze, Italy Mark Cook University of Melbourne, St Vincent \200\231s Hospital, Fitzroy, Victoria, Austra lia Samden D. Lhatoo Epilepsy Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA 1 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the Univer sity \200\231s objective of excellence in research, scholarship, and education by publishin g worldwide. 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Contents List of Contributors vii 11 The Biochemical, Hematological, Histological, Immunological, and Genetic Investigation o f Epilepsy 127 Simon Shorvon List of Abbreviations ix 1 Neurophysiology of Epilepsy 1 12 Non-Pharmacological Therapy Florin Amzica of Epilepsy 135 Peter Wolf, Katia Lin, and Marina Nikanorova 2 Neurogenetics of Epilepsy 11 Renzo Guerrini and Elena Parrini 13 Reproductive Aspects of Epilepsy 145 3 Neurochemistry of Epilepsy 27 Michael R. Johnson and John J. Craig B. Keith Day, Lawrence Eisenman, and R. Edward Hogan 14 Neonatal Seizures and Infantile-Onset Epilepsies 159 Elia Pestana Knight and Ingrid E.B. Tuxhorn 4 Developmental Neurobiology, Neuroanatomy, and Neuropathology of Epilepsy 39 Ingmar Bl mcke 15 Epileptic Encephalopathies 177 Renzo Guerrini and Carla Marini 5 De \201 nitions and Epidemiology 16 Principles of Treatment of Epilepsy in Children and Adolescents 187 Renzo Guerrini of Epilepsy 51 Shichuo Li, Ding Ding, and Jianzhong Wu 6 The Causes of Epilepsy 61 17 Epilepsy in Learning Disability 195 Simon Shorvon Tom Berney and Shoumitro Deb 7 Classi \201 cation, Clinical Symptoms, 18 Epilepsy in the Elderly 201 and Syndromes 71 Renzo Guerrini and Carmen Barba Trevor T.-J. Chong and Wendyl D \200\231Souza 19 Psychiatric Comorbidity in Epilepsy 211 8 Differential Diagnosis of Epilepsy 81 Marco Mula Kristina Malmgren, Markus Reuber, and Richard Appleton 20 Epilepsy due to Traumatic Brain Injury, Cerebrovascular Disease, Central Nervous System Infections, and Brain Tumors 221 Gagandeep Singh, J.M.K. Murthy, and Ashalatha Radhakrishnan 9 The Electroencephalogram in the Investigation of Epilepsy 95 Stephan U. Schuele, Adriana C. Bermeo, and Samden D. Lhatoo 21 Epilepsy in Renal, Hepatic, and 10 Neuroimaging in the Investigation Other Conditions 239 Aidan Neligan of Epilepsy 109 Trevor T.-J. Chong and Mark Cook contents vi 22 Management of Patients with First Seizure and Early Epilepsy 245 Zachary Grinspan and Sh lomo Shinnar 31 Other Surgeries for Epilepsy and New Approaches 327 Kitti Kaiboriboon and Samden D. Lhatoo 23 The Medical Treatment of Chronic 32 Management of Seizures and of Epilepsy Active Epilepsy 253 Simon Shorvon in the Emergency Department 337 Andrea O. Rossetti 24 Epilepsy in Remission 261 33 Management of Status Epilepticus on the Intensive Care Unit 343 Erich Schmutzhard and Be ttina Pfausler Jerry J. Shih 25 Drug Interactions 269 34 Epilepsy and Employment 349 Philip N. Patsalos Ann Jacoby 26 The Pharmacokinetics and Clinical Therapeutics of the Antiepileptic Drugs 279 Mark Cook and Simon Shorvon 35 Sexual and Emotional Behavior in Epilepsy 357 Sarah J. Wilson and Jessie Bendavid 27 Principles of Epilepsy Surgery 291 36 Epilepsy: Cognition and Memory in Adults 367 Sallie Baxendale Samden D. Lhatoo 28 Resective Surgery of Temporal Lobe Epilepsy 299 Simon V. Liubinas, Andrew P. Morokoff, and Terence J. O \200\231Brien 37 Legal Aspects of Epilepsy and Epilepsy and Driving 373 Morris Odell 29 Resective Surgery of Index 379 Extratemporal Epilepsy 307 Shahram Amina and Hans O. L ders 30 Vagal Nerve Stimulation and Deep Brain Stimulation in Epilepsy 317 Paul A.J.M. Boon and Kristl E. Vonck List of Contributors Shoumitro Deb Imperial College London, Computational, Cognitive, and Clinical Neuroimaging Laboratory Hammersmith Hospital, London, UK Shahram Amina, MD Epilepsy Center , University Hospitals Case Medical Center and Case Weste rn Reserve University School of Medicine, Cleveland, Ohio, USA Ding Ding Institute of Neurology , Fu Dan University , Shanghai, China Florin Amzica Associate Professor of Stomatology, Faculty of Dentistry, University of Montr eal, Quebec, Canada Wendyl D \200\231Souza Department of Medicine , St Vincent \200\231s Hospital Melbourne , T he University of Melbourne , Fitzroy, Victoria, Australia Richard Appleton Consultant Pediatric Neurologist, The Roald Dahl EEG Unit, Pediatric Neuro sciences Foundation, Alder Hey Children \200\231s Hospital, Liverpool, UK Lawrence Eisenman Department of Neurology, Washington University in St. Louis, St. Louis, M O, USA Sallie Baxendale Department of Clinical & Experimental Epilepsy, Institute of Neurology, UC L, London, UK Zachary Grinspan Division of Child Neurology, Weill Cornell Medical College, New York, NY, USA Jessie Bendavid Psychological Sciences , The University of Melbourne , Victoria, Australia Renzo Guerrini Pediatric Neurology Unit and Laboratories , Children \200\231s Hospital A. M eyer \200\223 University of Florence , Firenze, Italy Adriana C. Bermeo Rush University Medical Center , Department of Neurological Sciences , Ch icago, IL, USA Tom Berney Institute of Health & Society (Child & Adolescent Psychiatry), Sir James Spence Institute, Royal Victoria In \201 rmary, Newcastle upon Tyne, UK R. Edward Hogan Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA Ann Jacoby University of Liverpool , Department of Public Health and Policy , Institute of Psychology, Health and Society , Liverpool, UK Ingmar Bl mcke Department of Neuropathology , University Hospital Erlangen , Erlangen, Ger many Paul A.J.M. Boon Reference Center for Refractory Epilepsy , Department of Neurology & Insti tute for Neuroscience , Ghent University Hospital , Gent, Belgium Michael R. Johnson Center for Neuroscience , Imperial College Healthcare , Charing Cross Ho spital , London, UK Kitti Kaiboriboon Epilepsy Center, University Hospitals Case Medical Center and Case Wester n Reserve University School of Medicine, Cleveland, Ohio, USA Trevor T.-J. Chong Department of Medicine , University of Melbourne , St Vincent \200\231s Hospital , Fitzroy, Victoria, Australia Mark Cook University of Melbourne , St Vincent \200\231s Hospital , Fitzroy, Victoria, Aust ralia Samden D. Lhatoo Epilepsy Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA John J. Craig Department of Neurology , Belfast Health and Social Care Trust , Belfast, UK Shichuo Li China Association Against Epilepsy , Beijing, China B. Keith Day Department of Neurology, Washington University in St. Louis, St. Louis, MO, US A list of contributors viii Katia Lin Neurology Unit, Department of Internal Medicine University Hospital, Federal Univ ersity of Santa Catarina, Florianopolis, SC, Brazil Bettina Pfausler Neurological Intensive Care Unit , Department of Neurology , University Ho spital Innsbruck , Innsbruck, Austria Ashalatha Radhakrishnan R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chit ra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India Simon V. Liubinas Departments of Neurosurgery and Neurology , The Royal Melbourne Hospital , Parkville, Victoria, Australia Hans O. L ders Epilepsy Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Markus Reuber Academic Neurology Unit, University of Shef \201 eld, Shef \201 eld, UK Kristina Malmgren Institute of Neuroscience and Physiology, Sahlgrenska Acedemy at Gothenbu rg University, G teborg, Sweden Andrea O. Rossetti Department of Neurosciences , Service de Neurologie , Lausanne , Switzer land Erich Schmutzhard Neurological Intensive Care Unit , Department of Neurology , University H ospital Innsbruck , Innsbruck, Austria Carla Marini Pediatric Neurology Unit and Laboratories, Children \200\231s Hospital A. Meye r-University of Florence, Florence, Italy Stephan U. Schuele Northwestern University Comprehensive Epilepsy Center , Department of Ne urology , Northwestern Memorial Hospital , Chicago, IL, USA Andrew P. Morokoff Departments of Surgery and Medicine , The Royal Melbourne Hospital , The University of Melbourne , Parkville, Victoria, Australia Jerry J. Shih Director, Comprehensive Epilepsy Program, Mayo Clinic Florida, Associate Prof essor of Neurology, Mayo Clinic College of Medicine Marco Mula Department of Clinical & Experimental Medicine , Amedeo Avogadro University , Di vision of Neurology , University Hospital Maggiore della Carit , Novara, Italy Shlomo Shinnar Comprehensive Epilepsy Management Center , Monte \201 ore Medical Center , Albert Einstein College of Medicine , Bronx, NY, USA J.M.K. Murthy The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India Aidan Neligan UCL Institute of Neurology , University College London, London, UK Simon Shorvon UCL Institute of Neurology , University College London, London, UK Marina Nikanorova Danish Epilepsy Center, Dianalund, Denmark Gagandeep Singh Professor and Head Department of Neurology, Dayanand Medical College, Ludhi ana, 141 001, Punjab, IndiaHonary Senior Research FellowDepartment of Clinical & Experiment al Epilepsy, Institute of Neurology, Queen Square, London, UK Terence J. O \200\231Brien Departments of Surgery and Medicine , The Royal Melbourne Hospit al , The University of Melbourne , Parkville, Victoria, Australia Ingrid E.B. Tuxhorn Case Western Reserve University , Division of Pediatric Epilepsy , Rain bow Babies and Children \200\231s Hospital , Cleveland, OH, USA Morris Odell Victorian Institute of Forensic Medicine Department of Forensic Medicine, Mona sh University, Victoria, Australia Kristl E. Vonck Reference Center for Refractory Epilepsy , Department of Neurology & Instit ute for Neuroscience , Ghent University Hospital , Gent, Belgium Elena Parrini Pediatric Neurology Unit and Laboratories, , Children \200\231s Hospital A. M eyer \200\223 University of Florence , Firenze, Italy Sarah J. Wilson Psychological Sciences , The University of Melbourne , Victoria, Australia , Comprehensive Epilepsy Program , Austin Health, Melbourne, Australia Philip N. Patsalos UCL Institute of Neurology, University College London, London, UK Peter Wolf Danish Epilepsy Center, Dianalund, Denmark Elia Pestana Knight Case Western Reserve University , Division of Pediatric Epilepsy , Rain bow Babies and Children \200\231s Hospital , Cleveland, OH, USA Jianzhong Wu Beijing Neurosurgical Institute, Beijing, China List of Abbreviations DALY DAS DBS DDS DMPA DNET DTI EAAT ECG ECoG EDS EE EEG EIEE EME EMG EPO EPSP ESES ESI ESM ESRD FCD FDA FDG FER FLAIR FLE fMRI FS GABA GCD GCSE GEFS + GTCS GVG H&E H + HD HFO HIE disability-adjusted life year dialysis-associated seizures deep brain stimulation dialysis disequilibrium syndrome depot medroxyprogesterone acetate dysembryoplastic neuroepithelial tumor diffusion tensor imaging excitatory amino acid transporter electrocardiography electr ocortigogram excessive daytime sleepiness epileptic encephalopathy electroencephalogram ear ly infantile epileptic encephalopathy early myoclonic epilepsy electromyography erythropoie tin excitatory postsynaptic potential electrical status epilepticus during sleep electroenc ephalogram source imaging ethosuximide end-stage renal disease focal cortical dysplasia Foo d and Drug Administration \202 uro-2-deoxy-D-glucose facial emotion recognition \202 ui d attenuated inversion recovery frontal lobe epilepsy functional magnetic resonance imaging febrile seizure gamma-aminobutyric acid granule cell dispersion generalized convulsive sta tus epilepticus generalized epilepsy with febrile seizure plus generalized tonic \200\223cl onic seizure vigabatrin haematoxylin and eosin hydrogen haemodialysis high-frequency oscill ation hypoxic-ischaemic encephalopathy 5-HT AED ACRM ACTH ADA ADNFLE autosomal dominant nocturnal frontal lobe epilepsy ADTLE AMAC R AMPA serotonin antiepileptic drug American Congress of Rehabilitation Medicine adrenocorticotrop ic hormone acute drug administration autosomal dominant temporal lobe epilepsy alpha-methylacyl-CoA racemase alpha-amino-3-hydro xyl-5-methyl- 4-isoxazole-propionate alpha-methyl-L-tryptophan anterior nucleus arterioveno us malformation benign epilepsy of childhood with centrotemporal spikes benign familial neo natal convulsion benign familial neonatal-infantile seizures benign familial neonatal seizu res bilateral frontoparietal polymicrogyria brief ictal rhythmic electrographic discharge b lood-oxygen level dependent bilateral perisylvian polymicrogyria calcium childhood absence epilepsy carbamazepine case fatality rate comparative genomic hybridization con \201 dence interval creatine kinase chloride centromedian central nervous system copy number variant complex partial status epilepticus corticotropin-releasing hormone cortical stimulation cer ebrospinal \202 uid carotid sinus hypersensitivity computed tomography cerebrovascular di sease cytochrome P450 AMT AN AVM BECTS BFNC BFNIS BFNS BFPP BIRD BOLD BPP Ca 2 + CAE CBZ CFR CGH CI CK Cl \210\222 CM CNS CNV CPS E CRH CS CSF CSH CT CVD CYP list of abbreviations x PEHO progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy positron emission tomography phenytoin polymicrogyria proportional mortality ratio psychogenic non-epileptic seizure periventricular nodular heterotopia partial pressure of oxygen primary reading epi lepsy posterior reversible encephalopathy syndrome propofol infusion syndrome polyspike wav e quality of life rhizomelic chondrodysplasia punctata rapid eye movement responsive neuros timulator system relative risk subcortical band heterotopia status epilepticus Scottish Int ercollegiate Guidelines Network subtraction ictal SPECT coregistered to MRI systemic lupus erythematosus supplementary motor area severe myoclonic epilepsy of infancy standardized mo rtality ratio Summary of Product Characteristics single-positron emission computed tomograp hy spoiled gradient recalled selective serotonin reuptake inhibitor sudden unexpected death in epilepsy spike wave susceptibility-weighted image tricyclic antidepressant drug transie nt epileptic amnesia transient global amnesia transient ischaemic attack temporal lobe epil epsy transient loss of consciousness temporal lobe sclerosis topiramate thyrotropin-releasi ng hormone tuberous sclerosis complex uridine diphosphate glucuronyltransferase voxel-based morphometry video electroencephalography monitoring vesicular glutamate transporter very l ong chain fatty acid vagus nerve stimulation valproate week of gestation X-linked lissencep haly with absent corpus callosum and ambiguous genitalia X-linked mental retardation HP HRF HS HSE HSV-1 HUS HWE ICD-10 hypothalamic \200\223pituitary haemodynamic response function hippocampal sclerosis herpes simplex encephalitis herpes simplex virus type-1 haemolytic uraemic syndrome hot-water epil epsy International Statistical Classi \201 cation of Diseases and Related Health Problems, 10th revision idiopathic childhood occipital epilepsy intensive care unit interictal dysph oric disorder interictal epileptiform discharge idiopathic generalized epilepsy ischaemic h eart disease International League Against Epilepsy idiopathic photosensitive occipital lobe epilepsy inhibitory postsynaptic potential intelligence quotient infantile spasms X-linked infantile spasms syndrome juvenile absence epilepsy juvenile myoclonic epilepsy potassium learning disability Lennox \200\223Gastaut syndrome lissencephaly lamotrigine malformation of cortical development major congenital malformation magnetoencephalography PET PHT PMG PMR PNES PNH pO 2 PRE PRES PRIS PSW QOL RCDP REM RNS RR SBH SE SIGN SISCOM SLE SMA SMEI SMR SPC SPECT SpGR SSRI SUDEP SW SWI TCI TEA TGA TIA TLE TLOC TLS TPM TRH TSC UGT VBM VEM VGLUT VLCFA VNS VPA WoG XLAG ICOE ICU IDD IED IGE IHD ILAE IPOLE IPSP IQ IS ISSX JAE JME K + LD LGS LIS LTG MCD MCM MEG MERRF myoclonus epilepsy with ragged red \201 bres MHT MMIGS multimodality image-guided s urgery MPRAGE multiple hippocampal transection magnetization-prepared rapid acquisition with gradient echo magnetic resonance imaging magn etic resonance spectroscopy magnetic source imaging multiple subpial transection mesial tem poral lobe epilepsy N-acetylaspartate neonatal adrenoleucodystrophy neuronal ceroid-lipofus cinosis non-epileptic seizures nocturnal frontal lobe epilepsy National Institute for Healt h and Clinical Excellence N-methyl-D-aspartate non-rapid eye movement odds ratio partial pr essure of carbon dioxide polycystic ovarian syndrome peritoneal dialysis paroxysmal depolar izing shift MRI MRS MSI MST MTLE NAA NALD NCL NES NFLE NICE NMDA NREM OR pCO 2 PCOS PD PDS XLMR CHAPTER 1 Neurophysiology of Epilepsy Florin Amzica triggering of pathological states such as seizures. The transition from normal (sleep) to a bnormal (paroxysms) states may rely on a multitude of factors ranging from genetic causes ( 12 ) to imbal- ances of ionic concentrations ( 13 ) or the abnormal recruitment of cellula r aggregates ( 14 \200\22316 ). As a precipitating factor, one may also consider the irregu larity of respiration during the initial stages of sleep ( 17 ). Most of the time seizures result from a combination of factors. However, a basal condition that is already present in all sleeping patients is the presence of coherent oscillations during slow-wave sleep. Thu s I will start with a brief survey of the mecha- nisms underlying slow sleep oscillations. The epileptic syndrome encompasses a complex pathological real- ity with numerous and vario us aetiological origins. Each of these induces as many structural and functional alteration s at the cellu- lar and molecular level. Despite this rich diversity that eventually trigge rs epileptic or epileptic-like paroxysms, the electrical dis- charges, and ensuing behavior al correlates, during seizures share a surprisingly reduced variety of patterns, suggesting some common underlying mechanisms. Both experimental and clinical evidence show that several types of epileptic seizures prefe rentially occur during slow-wave sleep. This is the case of absence (petit mal) seizures wi th spike-wave (SW) complexes at 2 \200\2234 Hz that appear during drowsiness or light sleep in children ( 1 ) and behaving monkeys ( 2 ), and in association with sleep spindles in st age 2 of human sleep ( 3 ). The Lennox \200\223 Gastaut syndrome ( 4 \200\2236 ), which is accompanied by SW and polyspike-wave (PSW) complexes that recur at relatively lower fre- qu encies (generally 1.5 \200\2232.5 Hz) and are associated with episodes of fast runs (10 \200\22315 Hz), is also prevalently activated during slow-wave sleep ( 5 , 7 ). Mechanisms of slow sleep oscillations The slow-wave sleep is dominated by a coherent cortic al activity that imposes a slow (less than but close to 1 Hz) oscillation to both neurons ( 18 ) and glial cells ( 19 ) belonging to cortical networks (Fig. 1. 1A ). At the neuronal level, the slow oscillation is made of alternating steady depolarizations and hyperpolariza tions. The depolarizing phase is made of synaptic events (excitatory as well as inhibitory) and intrinsic membrane currents ( 18 ). In parallel with the neuronal depolarization phase , glial cells are also depolarized, but at a slower pace that re \202 ects the variation o f extracellular K + concentration ( 20 ). The persistent neuronal depolarization is asso- c iated with a progressive depletion of extracellular Ca 2 + (Fig. 1. 1B ) ( 21 ), which in t urn initiates a disfacilitation process ( 22 , 21 ) lead- ing to the onset of the persisten t hyperpolarizing phase of the slow oscillation. The behavior of neurons during paroxysmal discharges has been extensively studied. However, for reasons that will become clear in this chapter, the understanding of the neurophysiolo gical mechanisms of epilepsies has not progressed as much as one would have expected from t he bulk of means that were invested in the sole study of neurons. Some pioneering studies h ave repeatedly acknowledged the abnormal activity of glial cells during epileptic events ( 8 \200\22311 ), and only few recent studies have addressed the inter- action between neuron s and glia. Therefore I will emphasize the contribution of glial cells to the triggering of the seizures and to the oscillating process accompanying them especially because the neu- ronal activity is modulated by several ionic species (mainly potas- sium (K + ), calcium (C a 2 + ), and hydrogen (H + )) of the extracellular space. During the hyperpolarizing phase, no neurons are active, their membrane potential reaching values much more hyperpolarized than the threshold for action potential generation. In para llel, glial cells slowly repolarize, as the extracellular K + concentrations return to cont rol values ( 20 ). Extracellular Ca 2 + is restored through ionic pumps and reaches concent rations compatible with efficient synaptic transmission (Fig. 1. 1B ) ( 21 ). The analysis of the mechanisms underlying the occurrence of nocturnal SW seizures has to ta ke into consideration the precipi- tating factors acting before and throughout the paroxysm al epi- sode, as well as the (minimal) critical structures required to generate SW discharg es. Interestingly, the same elements that rule and promote the behavior of complex neuron, glia, and extracel- lular space loops during slow-wave sleep may also contribute to the Several lines of evidence support the idea that the slow oscilla- tion is generated within cortical networks. First, the slow oscilla- tion survives in the cortex after extensive tha lamic lesions and in preparations with high brainstem transactions ( 23 ). Second, the slow oscillation is absent from the thalamus of decorticated oxford textbook of epilepsy and epileptic seizures 2 A B 1 FP (DC) V m 1 V m 0 2 Intra neuron Intra neuron \210\22273 mV [Ca] out 1.1 mM M m 2 0 \210\22260 mV Intra glia \210\22289 mV . V m 0 2 0.5 s 2 - AVERAGE Field potential (a.c.) V m 5 1 s Intra neuron 0.2 s [Ca] out 1.1 mM M m 1 0 . V m 0 1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 3 Release probability [Ca] out [Ca] max a a = 2.5 V m 2 0.2 s a = 4 C D V m 2 N Neuron 20 ms 2 APs G TF Synapse V m 0 1 1 AP Fit (TF) Axon Intra neuron \210\22263 mV K+ Intra glia \210\22276 mV Glia V m 5 0 Fit (TF) 0.1 s . Fig. 1.1 Mechanisms of genesis of the slow (<1 Hz) sleep oscillation. A) Recordings from co rtical areas 5 (neuron and depth \201 eld potential) and 7 (glia), displaying periodic de polarizations of the neuronal membrane, made of synaptic potentials and triggering somatic action potentials. Depolarizations are followed by hyperpolarizations with reduced synaptic noise. In synchrony with the onset of the neuronal depolarization, the glia depolarizes. T he end of the depolarization coincides with the onset of the neuronal hyperpolarization. No te that the amplitude of the glial depolarization increases as the slow oscillation in the neuron becomes more rhythmic and of higher amplitude ( top right ; see also detail in box). In this and the following \201 gures, polarities always are depicted with positivity upw ard. B) Relationships between intracellular membrane potential, extracellular Ca 2 + ((Ca) out ) and estimated synaptic release probability. B1) Alternating neuronal depolarizations and hyperpolarization corresponding to negative and positive \201 eld potential waves, re spectively. (Ca) out dropped by about 0.25 mM during the depolarizing phase reaching a mini mum just before the onset of the hyperpolarization. Then, (Ca) out rose back until the begi nning of the next cycle. B2) Thirty oscillatory cycles were averaged (neuronal spikes clipp ed) after being extracted around the onset of the neuronal depolarization. The vertical dot ted lines tentatively indicate the boundaries of the two phases of the slow oscillation. B3 ) The transmitter release probability is contained within the black area between the estima tions with = 2.5 ( 90 ) and = 4 ( 91 ) exponents. The release probability dropped to around 50 % before the onset of the hyperpolarizing phase. C) Neuronal excitability during the oscillatory cycle of the slow oscillation. The thick traces represent the wave-triggere d averages of a neuron \200\223glia pair recorded intracellularly. The dots constitute the excitability curve and correspond to the maximum of the voltage values reached by the synap tic response elicited with a cortical volley. Arti \201 cial levels were attributed when t he synaptic potential was crowned by 1 or 2 action potentials ( dotted horizontal lines for 1AP and 2APs ). The thin curve ( \201 t ) is for the Lorentzian \201 t of the excitabi lity score. In the glial trace, the \201 tting curve is replicated in order to suggest th e relative points of intersection with the intraglial potential ( open arrows ). Maximum ne uronal excitability is achieved during the trough of the glial oscillation. The inset provi des the shape of the intracellular responses evoked by the cortical shock ( triangle ) in t he neuron ( N ) and glia ( G ). The former display and EPSP \200\223IPSP sequence, while th e latter contain a very slight initial depolarization ( \210 0.3 mV). D) Schematic function ing of the spatial buffering during the slow oscillation. During the depolarizing phase of the slow oscillation, small and local increases of extracellular K + ( circle ) may occur i n the proximity of the axon hillock. The neighboring glial cells take up the K + and redist ribute it at sites where the values of extracellular K + are normal. These locations may be close to a synapse, in which case the synaptic ef \201 ciency may be modulated, or close to a neuronal membrane such to modify the excitability of that membrane. Modi \201 ed from : A ( 19 ), B ( 21 ), C ( 28 ), and D ( 20 ). CHAPTER 1 neurophysiology of epilepsy 3 Transformation of the slow oscillation into SW seizures The smooth transition from the phys iological (slow oscillation) to the pathological (SW sequences) pattern suggests that the s low and the paroxysmal oscillations share common mechanisms. The electroencephalographic SW is made at the neuronal level by a par- oxysmal depolarizing shift (PDS). The PDS is a gia nt excitatory postsynaptic potential (EPSP) ( 38 \200\22341 ) that also contains inhibi- to ry postsynaptic potential (IPSPs) ( 42 ). Occasionally, the PDSs and their EEG counterparts , the \200\230spikes \200\231, are superimposed by faster oscillations at about 10 \200 \22315 Hz that produce corresponding indentations on the EEG \200\230spike \200\231 with a polyspike shape (Fig. 1. 2 ). This pattern of seizure is a quite typical signature for tho se occurring in the Lennox \200\223Gastaut syndrome ( 5 ) and their fre- quency appears as a resonating phenomenon within the cortical network ( 43 ). animals ( 24 ), while it is expressed by thalamic reticular and tha- lamocortical cells in intact animals ( 25 ). Moreover, the slow oscil- lation has been recently replicated in cor tical slices ( 26 ). Thus, the slow oscillation is generated within cortical neurons. The mechanisms underlying this oscillatory behavior are partly elucidated at the neuronal l evel. It was shown that the slow oscilla- tions were expressed by various cortical areas ( 18 ) and by virtually all types of neurons ( 27 ). The slow oscillation is marked by a vari - able neuronal responsiveness that is maximal during the \201 rst third of the depolariz ing phase and progressively decays during the rest of the depolarizing phase (Fig. 1. 1C ) ( 28 ). Having demonstrated that the slow oscillation is synchronized between all cortical areas ( 29 ), we have sought for the mechanisms underlying this coherent behavior and found that, beyond the essential role played by syn- aptic intracortical projections ( 30 ), gli al cells, through local K + spatial buffering ( 31 \200\22333 ) and Ca 2 + -dependent neuro transmitter release ( 34 ), might modulate the neuronal excitability and activity, respecti vely (Fig. 1. 1D ) ( 20 ). The presence of a large current sink in cortical layer III durin g the depolarizing phase ( 35 ) further strengthened the contribution of intracortical link ages to the prop- agation of the slow oscillation. Thus, the slow oscillation relies on wid espread cortical networks. The wave component of the SW complex is not due to active inhibition because, as demonstrat ed with multiple intracellular recordings, virtually all neurons (local inhibitory interneu rons included) are silent during this phase of the oscillation. In addi- tion, the \201 r ing rate tends to diminish towards the end of the PDS due to the inactivation of action pot entials. Therefore, the activity of local-circuit inhibitory cells tends to weaken towards the end of the PDS and undergoes the general disfacilitation affecting all neu- rons belong ing to the cortical network. The somatic input resist- ance is lowest at the beginning of t he PDS and continuous to increase up to the next PDS, assuming its largest value during the hyperpolarization ( 44 ). This behavior would not be consistent with the possibility that gamma-aminobutyric acid (GABA)ergic currents induce the arrest of \201 ring. The disfacil itation could be promoted, as in the case of the slow oscillation, by reduced synap- tic ef \201 cacy consequent to depletion of extracellular Ca 2 + ions ( 28 ). This reduced synap tic ef \201 cacy corroborates the relative refractori- ness of cortically elicited PDSs ( 45 ). The long-lasting hyperpolarization of the neuronal membrane often de-inactivates additional excitatory currents of the low- threshold Ca 2 + spike type, which in turn will have a gre ater impact on the synchronization of the network. It has been therefore pro- posed that th e slow oscillation acts as a precursor of nocturnal SW seizures ( 14 , 16 ). Electroencephalographic correlates of the slow oscillation The synchronous nature of the sl ow oscillation has a direct impact on the electroencephalogram (EEG). Therefore the slow os cillation is detectable in the gross brain activity of the sleeping brain. First, the slow oscillation is expressed in the local \201 eld potentials re \202 ect- ing the membrane currents generated by neurons and, possibly, glial cells. Since the depolarizing phase of t he slow oscillation re \202 ects the excitation of all neurons, the corresponding extracel lu- lar \201 eld potential consists of a negative de \202 ection ( 27 ). The shape of th is negative potential has been found similar to the one of the K-complex ( 36 , 35 ). Besid es disclosing the cellular bases of the K-complex, our studies have also established that t his EEG event has a periodic and spontaneous recurrence (with the exception of occasional, sensory evoked K-complexes), and is generated in all sleep stages. Among the ions with a signi \201 cant impact on the neuronal excit- ability, K + and Ca 2 + were repeatedly investigated. The more syn- chronized the network, the higher the amplitu de of its oscillations, with more K + being expelled in the extracellular space during acti on potentials and other currents. During SW seizures, the extracellular concentration of K + increases from resting values around 3 \200\2233.5 mM to pathological levels around 9 \200\22312 mM ( 46 \200\22350 ). An increase in the extracellular K + concentration has pro ved to favor SW seizures ( 13 , 46 , 51 ). Extracellular K + is regulated by glial cells up take ( 32 , 52 , 53 ,) followed by spatial buffering through gap junctions connecting the g lial syncytium ( 54 , 55 ). The latter phenomenon evens out K + but may also contribute to the general depolarization of the neuronal membrane potential (Fig. 1. 3 ) by positively sh ifting the Nernst equilibrium potential. The hyperpolarizing phase of the slow oscillation corresponds to a round wave that has a ne gative polarity in the cortical depth ( 27 ) when measured with alternating current (AC) am pli \201 ers (i.e. after removal of direct current (DC) and very slow components). Althoug h AC recordings are the rule in routine EEG, it should be kept in mind that the procedure i s altering the real shape of \201 eld potential and EEG waves by introducing some arti \201 cial compo- nents, like the negative wave during the hyperpolarizing phase of the slow oscillation. In fact, being the result of network disfacilita- tion, the \201 eld expres sion of the hyperpolarizing phase marks a return to resting extracellular potential (see co mparison between DC and AC recordings in \201 gure 3 from reference 37). Cortical seizures developing in a circumscribed focus generate a local increase in extracel lular K + , which is then spatially buffered through the syncytium of glial cells at more d istant locations. The neuronal population of the latter would thus become the target of syn chronous synaptic bombardment from the seizure focus and would act in an environment with i ncreased K + concentration. Hence, synchronization of neuronal activity, the striking featu re of sleep activities, creates favorable premises for seizure genesis. The protective mech anism against this seems to rely on the ability of glial cells to regulate the extracellula r K + concentration through oxford textbook of epilepsy and epileptic seizures 4 A Depth-EEG area 5 V m 0 2 2 s Intra area 5 \210\22267 mV \210\22280 mV Slow oscillation Spike-wave Fast runs 0.2 s B - Wave-triggered-average Slow oscillation Beginning of seizure Middle of seizure EEG spike K-complex PDS V m 0 1 0.2 s Fig. 1.2 Spontaneously occurring seizure, developing without discontinuity from slow sleep- like oscillation. Intracellular recording from regular-spiking area 5 neuron together with depth-EEG from the vicinity in area 5 in a cat under ketamine-xylazine anesthesia. A) Smoot h transition from slow oscillation to complex seizure consisting of SW complexes at \210 2 Hz and fast runs at \210 15 Hz. The seizure lasted for \210 25 s. Epochs of slow oscilla tion preceding the seizure, SW complexes, and fast runs are indicated and expanded below. N ote postictal depression (hyperpolarization) in the intracellularly recorded neuron ( \210 6 s), associated with suppression of EEG slow oscillation (compare to left part of trace). B) Wave-triggered-average during the slow oscillation, at the beginning of seizure and duri ng the middle part of seizure. Averaged activity was triggered by the steepest part of the depolarizing component in cortical neuron (dotted lines), during the three epochs. The dept h-negative \201 eld component of the slow oscillation (associated with cell \200\231s dep olarization) is termed K-complex . During the seizure, the depolarizing component reaches t he level of a paroxysmal depolarizing shift ( PDS ), associated with an EEG spike . Modi \201 ed from ( 16 ). uptake, since impaired glial uptake of K + may cause epileptiform activity in the hippocamp us ( 56 ). K + and Ca 2 + ) and the intracortical \201 eld activity during SW seizures ( 19 , 20 , 3 7 ) have allowed us to establish a pattern of correlation between these functional entities . Thus, it appeared that glial cells also express phasic depolarizations in relation to int erictal and ictal PDSs (Fig. 1. 3 ). Variations of the glial membrane potentials during sleep SW seizures It has been well known for a long time that epileptic seizures are accompanied by signi \201 cant increases in t he extracellular K + con- centration ( 46 \200\22348 ) and persistent depolarization of gli al cells ( 8 \200\223 10 ). Simultanous intracellular recordings of pairs of neurons and gl ia, together with extracellular ionic concentrations (mainly The estimate of neuronal and glial depolarizations during the phasic events building up the SW cycles led to high correlative values ( > 84 % ) ( 28 ). Since the neuronal phasic depo larizations are made of entry of Na + and Ca 2 + and exit of chloride (Cl \210\222 ) and K + , while the glial ones mostly re \202 ect entry of K + (and possibly Ca 2 + ), the incr eased correlation between the depolarizations of the two CHAPTER 1 neurophysiology of epilepsy 5 V m 0 1 0.5 s A B 0 mV V m 0 2 Intra glia 5 s \210\22280 mV Intra neutron \210\22276 mV Fig. 1.3 Neuron \200\223glia interaction during SW seizures. Continuous recording containin g a double neuron \200\223glia impalement (A), and neuron- \201 eld recording (B) in corti cal association area 7. The two electrodes are separated by <1 mm. The transition from A to B is marked by the withdrawal of the pipette from the glia ( oblique open arrowhead ). Epo chs within the squares are expanded above the respective panels. Modi \201 ed from ( 37 ). cell types suggests that the ionic activity of Na + and Ca 2 + is propor- tional to that of K + and/or that the neuronal phasic depolarizations depend on the amount of extracellular K + . Alternatively, it could be that SW seizures are accompanied by a more active glial up take of extracellular K + .