Risk Factors in Sudden Death in Epilepsy (SUDEP): The Quest for Mechanisms

Summary:  People with epilepsy may die suddenly and unexpectedly without a structural pathological cause. Most SUDEP cases are likely to be related to seizures. SUDEP incidence varies and is <1:1,000 person‐years among prevalent cases in the community and ∼1:250 person years in specialist centres. Case–control studies identified certain risk factors, some potentially amenable to manipulation, including uncontrolled convulsive seizures and factors relating to treatment and supervision. Both respiratory and cardiac mechanisms are important. The apparent protective effect of lay supervision supports an important role for respiratory factors, in part amenable to intervention by simple measures. Whereas malignant tachyarrhythmias are rare during seizures, sinus bradycardia/arrest, although infrequent, is well documented. Both types of arrhythmias can have a genetic basis. This article reviews SUDEP and explores the potential of coexisting liability to cardiac arrhythmias as a contributory factor, while acknowledging that at present, bridging evidence between cardiac inherited gene determinants and SUDEP is lacking.

[1]  V. Bennett,et al.  Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting , 2005, Current opinion in cardiology.

[2]  F. Hofmann,et al.  Regional expression and cellular localization of the alpha1 and beta subunit of high voltage-activated calcium channels in rat brain. , 1997, Journal of Neuroscience.

[3]  Vincent Gm,et al.  The molecular genetics of the long QT syndrome: genes causing fainting and sudden death. , 1998 .

[4]  A. George,et al.  Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). , 2003, The Journal of clinical investigation.

[5]  Frank B Sachse,et al.  Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Wellens,et al.  Molecular genetics of inherited long QT syndromes. , 1998, European heart journal.

[7]  S. Brown,et al.  Electrocardiograph QT lengthening associated with epileptiform EEG discharges—a role in sudden unexplained death in epilepsy? , 1996, Seizure.

[8]  W. Hauser,et al.  Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features , 2002, Nature Genetics.

[9]  A. Busjahn,et al.  Single nucleotide polymorphism map of five long-QT genes , 2005, Journal of Molecular Medicine.

[10]  G. Abbott,et al.  The MinK-related peptides , 2004, Neuropharmacology.

[11]  M Montal,et al.  A missense mutation of the Na+ channel αII subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  L. Nilsson,et al.  Risk factors for sudden unexpected death in epilepsy: a case control study , 1999, The Lancet.

[13]  Mark Leppert,et al.  A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns , 1998, Nature Genetics.

[14]  Josemir W Sander,et al.  Sudden Unexpected Death in Epilepsy: A Review of Incidence and Risk Factors , 2005, Epilepsia.

[15]  J. Towbin,et al.  Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. , 2001, JAMA.

[16]  S. Shinnar,et al.  Long-term prognosis of seizures with onset in childhood. , 1998, The New England journal of medicine.

[17]  P. Weber,et al.  Sudden unexplained death in children with epilepsy: A cohort study with an eighteen‐year follow‐up , 2005, Acta paediatrica.

[18]  Knut Holthoff,et al.  Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2 , 2003, The EMBO journal.

[19]  E. Rosenthal,et al.  Prolongation of the QT interval and the sudden infant death syndrome. , 1998, The New England journal of medicine.

[20]  Hubert Kwiecinski,et al.  Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). , 2002, The Journal of clinical investigation.

[21]  Jay Gw,et al.  Sudden death in epilepsy. A comprehensive review of the literature and proposed mechanisms. , 1981 .

[22]  I. Scheffer,et al.  A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy , 1995, Nature Genetics.

[23]  Josemir W Sander,et al.  The Mortality Associated with Epilepsy, with Particular Reference to Sudden Unexpected Death: A Review , 1997, Epilepsia.

[24]  A. Jervell,et al.  CONGENITAL DEAF‐MUTISM, FUNCTIONAL HEART DISEASE WITH PROLONGATION OF THE Q‐T INTERVAL, AND SUDDEN DEATH , 1999, American heart journal.

[25]  T. Tomson,et al.  Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs. Implications for sudden death , 1997, Seizure.

[26]  S. Butler,et al.  Sudden Unexplained Death in Epilepsy: An Intracranially Monitored Case , 1997 .

[27]  M. Biel,et al.  Differential Distribution of Four Hyperpolarization-Activated Cation Channels in Mouse Brain , 1999, Biological chemistry.

[28]  H. Gormsen,et al.  The role of antiepileptics in sudden death in epilepsy , 1985, Acta neurologica Scandinavica.

[29]  G. Breithardt,et al.  Pacemaker channel dysfunction in a patient with sinus node disease. , 2003, The Journal of clinical investigation.

[30]  P. Camfield,et al.  Death in children with epilepsy: a population-based study , 2002, The Lancet.

[31]  P. Kahane,et al.  The impact of epilepsy surgery on mortality. , 2005, Epileptic disorders : international epilepsy journal with videotape.

[32]  F. Cappuccio,et al.  Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia , 2002, Science.

[33]  E. Perez-Reyes,et al.  Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants of CACNA1H, a T-Type Calcium Channel , 2005, The Journal of Neuroscience.

[34]  D. Mckinnon,et al.  MinK-Related Peptide 1: A &bgr; Subunit for the HCN Ion Channel Subunit Family Enhances Expression and Speeds Activation , 2001, Circulation research.

[35]  L. Hirsch,et al.  Heart rate and EKG changes in 102 seizures: analysis of influencing factors , 2002, Epilepsy Research.

[36]  S. Priori,et al.  A molecular link between the sudden infant death syndrome and the long-QT syndrome. , 2000, The New England journal of medicine.

[37]  Q. Gong,et al.  Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome. , 2004, Journal of molecular and cellular cardiology.

[38]  Philip Smith,et al.  Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[39]  J. Seckl,et al.  Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum , 1998, Neuroscience.

[40]  D. Stephan,et al.  Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). , 2001, Human molecular genetics.

[41]  P. C. Viswanathan,et al.  Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes , 2002, Circulation.

[42]  Katsuhiro Kobayashi,et al.  A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy , 1999, Neurology.

[43]  Diane Lipscombe,et al.  L-type calcium channels: the low down. , 2004, Journal of neurophysiology.

[44]  Josemir W Sander,et al.  Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives , 1998, Journal of neurology, neurosurgery, and psychiatry.

[45]  C. Vandenberg,et al.  Molecular cloning and expression of a human heart inward rectifier potassium channel. , 1994, Neuroreport.

[46]  D. Chadwick,et al.  Randomised study of antiepileptic drug withdrawal in patients in remission , 1991, The Lancet.

[47]  R. Siedenberg,et al.  Central apnea and acute cardiac ischemia in a sheep model of epileptic sudden death , 1997, Annals of neurology.

[48]  Ira S. Cohen,et al.  MinK-Related Peptide 1 , 2001 .

[49]  G G Davis,et al.  Comparison of anti-epileptic drug levels in different cases of sudden death. , 1998, Journal of forensic sciences.

[50]  T. Tomson,et al.  Heart rate variability in patients with epilepsy 1 Presented in part at the 2nd European Congress of Epileptology, The Hague, September, 1996. 1 , 1998, Epilepsy Research.

[51]  M. T. Medina,et al.  Mutations in EFHC1 cause juvenile myoclonic epilepsy , 2004, Nature Genetics.

[52]  T. Tomson,et al.  Postmortem changes in blood concentrations of phenytoin and carbamazepine: an experimental study. , 1998, Therapeutic drug monitoring.

[53]  L. Lagae,et al.  De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. , 2001, American journal of human genetics.

[54]  A. Goldberger,et al.  Oxygen Desaturations Triggered by Partial Seizures: Implications for Cardiopulmonary Instability in Epilepsy , 2000, Epilepsia.

[55]  S. Horvath,et al.  Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies , 2003, Nature Genetics.

[56]  Michael A Rogawski,et al.  KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy , 2000, Trends in Neurosciences.

[57]  H. Hunter.  The treatment of epilepsy. , 1948 .

[58]  E. Otto,et al.  Isolation and characterization of cDNAs encoding human brain ankyrins reveal a family of alternatively spliced genes , 1991, The Journal of cell biology.

[59]  H. Pape,et al.  Ca2+-Induced Ca2+ Release Supports the Relay Mode of Activity in Thalamocortical Cells , 2000, Neuron.

[60]  Samuel F. Berkovic,et al.  Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B , 1998, Nature Genetics.

[61]  J. Stephenson.  Epileptic Syndromes in Infancy, Childhood and Adolescence , 2004 .

[62]  Stéphanie Baulac,et al.  Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2 , 2000, Nature Genetics.

[63]  Wei Huang,et al.  KCNQ1 Gain-of-Function Mutation in Familial Atrial Fibrillation , 2003, Science.

[64]  Robin J. Leach,et al.  A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family , 1998, Nature Genetics.

[65]  I. Gussak,et al.  Short QT Syndrome , 2005, Annals of Noninvasive Electrocardiology.

[66]  P. C. Viswanathan,et al.  A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. , 2003, The Journal of clinical investigation.

[67]  C. Binnie,et al.  Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep , 2001, Neurology.

[68]  P. Camfield,et al.  Sudden unexpected death in people with epilepsy: a pediatric perspective. , 2005, Seminars in pediatric neurology.

[69]  S. Reiken,et al.  Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak , 2004, Circulation.

[70]  Hans-Christian Pape,et al.  Novel vistas of calcium-mediated signalling in the thalamus , 2004, Pflügers Archiv.

[71]  G. Vincent,et al.  The molecular genetics of the long QT syndrome: genes causing fainting and sudden death. , 1998, Annual review of medicine.

[72]  R. Dasheiff,et al.  Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death. , 1991, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[73]  C. Dravet.  Severe myoclonic epilepsy in infants , 1992 .

[74]  B. Natelson,et al.  Patients with epilepsy who die suddenly have cardiac disease. , 1998, Archives of neurology.

[75]  J. Svendsen,et al.  Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. , 2005, The American journal of cardiology.

[76]  M. Biel,et al.  The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Josemir W Sander,et al.  Case-control study of SUDEP , 2005, Neurology.

[78]  A. Marks,et al.  Cardiac Ryanodine Receptor Function and Regulation in Heart Disease , 2004, Annals of the New York Academy of Sciences.

[79]  Wei-Yang Lu,et al.  Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy , 2002, Nature Genetics.

[80]  G. Gintant,et al.  Tissue and species distribution of mRNA for the IKr-like K+ channel, erg. , 1997, Circulation research.

[81]  D. Tester,et al.  Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases. , 2004, Mayo Clinic proceedings.

[82]  G. Breithardt,et al.  Molecular diagnosis in a child with sudden infant death syndrome , 2001, The Lancet.

[83]  G. Cascino,et al.  Population-based study of the incidence of sudden unexplained death in epilepsy , 1998, Neurology.

[84]  Alfred L George,et al.  Molecular basis of inherited epilepsy. , 2004, Archives of neurology.

[85]  S. Subramony,et al.  Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome , 2001, Cell.

[86]  J. Gargus,et al.  Ion Channel Functional Candidate Genes in Multigenic Neuropsychiatric Disease , 2006, Biological Psychiatry.

[87]  C. Dodrill,et al.  Predictors of early mortality and sudden death in epilepsy: A multidisciplinary approach , 1991 .

[88]  J. Duncan,et al.  Cardiac arrhythmias in focal epilepsy: a prospective long-term study , 2004, The Lancet.

[89]  G. Mcgwin,et al.  Comparison of Heart Mass in Seizure Patients Dying of Sudden Unexplained Death in Epilepsy to Sudden Death due to Some Other Cause , 2004, The American journal of forensic medicine and pathology.

[90]  A. Ballabio,et al.  The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy , 2000, Nature Genetics.

[91]  N. Decher,et al.  KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents , 2003, Pflügers Archiv.

[92]  T. Dwyer,et al.  Prospective cohort study of prone sleeping position and sudden infant death syndrome , 1991, The Lancet.

[93]  S. Priori,et al.  A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene , 2005, Circulation research.

[94]  K. Yamakawa,et al.  Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic–clonic seizures , 2005, The Journal of physiology.

[95]  S. Berkovic,et al.  Comparison of Antiepileptic Drug Levels in Sudden Unexpected Deaths in Epilepsy with Deaths from Other Causes , 1999, Epilepsia.

[96]  S. Berkovic,et al.  Does cardiac conduction pathology contribute to sudden unexpected death in epilepsy? , 2000, Epilepsy Research.

[97]  I. Scheffer,et al.  Sodium-channel defects in benign familial neonatal-infantile seizures , 2002, The Lancet.

[98]  David A. Williams,et al.  Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures , 2001, Nature Genetics.

[99]  H. Pape,et al.  Calcium-dependent inactivation of neuronal calcium channels , 2002, Nature Reviews Neuroscience.

[100]  G. Breithardt,et al.  Life-threatening Arrhythmias Genotype-phenotype Correlation in the Long-qt Syndrome : Gene-specific Triggers for Genotype-phenotype Correlation in the Long-qt Syndrome Gene-specific Triggers for Life-threatening Arrhythmias , 2022 .

[101]  W. Hauser,et al.  Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study , 2001 .

[102]  W. Catterall,et al.  Distinct Subcellular Localization of Different Sodium Channel &agr; and &bgr; Subunits in Single Ventricular Myocytes From Mouse Heart , 2004, Circulation.

[103]  Josemir W Sander,et al.  Cause‐Specific Mortality in Epilepsy , 2005, Epilepsia.

[104]  V. Lee,et al.  The cardiac sodium channel mRNA is expressed in the developing and adult rat and human brain , 2000, Brain Research.

[105]  James H. Davis.  Sudden death in the young. , 2009, EMS magazine.

[106]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[107]  J. Brugada,et al.  Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG , 2003, Circulation.

[108]  P. Smith,et al.  Sudden unexplained death in epilepsy (SUDEP) following previous seizure-related pulmonary oedema: case report and review of possible preventative treatment , 2002, Seizure.

[109]  T. Tomson,et al.  Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy , 2003, Epilepsy Research.

[110]  Jörg Striessnig,et al.  Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[111]  Ying Wang,et al.  KCNQ1 gain-of-function mutation in familial atrial fibrillation. , 2003, Science.

[112]  Y. Zhang,et al.  Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. , 1998, Circulation research.

[113]  L. Nashef.  Sudden Unexpected Death in Epilepsy: Terminology and Definitions , 1997, Epilepsia.

[114]  Carlo Napolitano,et al.  A cardiac arrhythmia syndrome caused by loss of ankyrin-B function , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Yelena Kryukova,et al.  MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes* , 2004, Journal of Biological Chemistry.

[116]  Ling Wu,et al.  Localization of Nav1.5 sodium channel protein in the mouse brain , 2002, Neuroreport.

[117]  A Konnerth,et al.  Ryanodine receptor‐mediated intracellular calcium release in rat cerebellar Purkinje neurones. , 1995, The Journal of physiology.

[118]  P. Striano,et al.  A Novel SCN2A Mutation in Family with Benign Familial Infantile Seizures , 2006, Epilepsia.

[119]  J Robbins,et al.  KCNQ potassium channels: physiology, pathophysiology, and pharmacology. , 2001, Pharmacology & therapeutics.

[120]  F. Hofmann,et al.  Regional Expression and Cellular Localization of the α1 and β Subunit of High Voltage-Activated Calcium Channels in Rat Brain , 1997, The Journal of Neuroscience.

[121]  G. Breithardt,et al.  Genetic basis and molecular mechanism for idiopathic ventricular fibrillation , 1998, Nature.

[122]  C R Smith,et al.  Sudden unexplained death in children with epilepsy , 2001, Neurology.

[123]  J. Hell,et al.  Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits , 1993, The Journal of cell biology.

[124]  S. Priori,et al.  Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia , 2001, Circulation.

[125]  A. V. van Ginneken,et al.  Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome , 2004, Circulation.

[126]  M. Biel,et al.  Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. , 2001, European journal of biochemistry.

[127]  S. Priori,et al.  CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism , 2004, Cell.

[128]  E. So,et al.  Postictal Central Apnea as a Cause of SUDEP: Evidence From Near‐SUDEP Incident , 2000, Epilepsia.

[129]  M. Horie,et al.  Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation , 2002, Circulation.

[130]  J. A. Levisky,et al.  Premature deaths in persons with seizure disorders--subtherapeutic levels of anticonvulsant drugs in postmortem blood specimens. , 1978, Journal of forensic sciences.

[131]  Chien-Chang Chen,et al.  Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. , 2003, Science.

[132]  J. G. Netzeband,et al.  L-Type Calcium Channels Mediate Calcium Oscillations in Early Postnatal Purkinje Neurons , 2000, The Journal of Neuroscience.

[133]  Jørgen K. Kanters,et al.  Mutations in the HERG K+-ion channel: a novel link between long QT syndrome and sudden infant death syndrome. , 2005, The American journal of cardiology.

[134]  Matti Sillanpää,et al.  Mortality of Epilepsy in Developed Countries: A Review , 2005, Epilepsia.

[135]  O. Steinlein,et al.  The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy. , 1999, Neuroreport.

[136]  C. Elger,et al.  Cardiac Asystole in Epilepsy: Clinical and Neurophysiologic Features , 2003, Epilepsia.

[137]  Chien-Chang Chen,et al.  Abnormal Coronary Function in Mice Deficient in α1H T-type Ca2+ Channels , 2003, Science.

[138]  M Ericson,et al.  Preoperative heart rate variability in relation to surgery outcome in refractory epilepsy , 2005, Neurology.

[139]  H. Morita,et al.  Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia* , 2004, Journal of Biological Chemistry.

[140]  S. Berkovic,et al.  A potassium channel mutation in neonatal human epilepsy. , 1998, Science.

[141]  Josemir W Sander,et al.  Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[142]  T. Tomson,et al.  Antiepileptic Drug Therapy and Its Management in Sudden Unexpected Death in Epilepsy: A Case–Control Study , 2001, Epilepsia.

[143]  M. Lazdunski,et al.  M‐type KCNQ2–KCNQ3 potassium channels are modulated by the KCNE2 subunit , 2000, FEBS letters.

[144]  P. Schwartz.  Stillbirths, sudden infant deaths, and long-QT syndrome: puzzle or mosaic, the pieces of the Jigsaw are being fitted together. , 2004, Circulation.

[145]  Y Langan,et al.  Sudden unexpected death in epilepsy: a series of witnessed deaths , 2000, Journal of neurology, neurosurgery, and psychiatry.

[146]  Claudia Stöllberger,et al.  Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP) , 2004, Epilepsy Research.

[147]  Steven Petrou,et al.  Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. , 2002, American journal of human genetics.

[148]  G. Jay,et al.  Sudden death in epilepsy. A comprehensive review of the literature and proposed mechanisms. , 1981, Acta neurologica Scandinavica. Supplementum.

[149]  P. Tchou,et al.  SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family , 2002, Journal of medical genetics.

[150]  Maromi Nei,et al.  EKG Abnormalities During Partial Seizures in Refractory Epilepsy , 2000, Epilepsia.

[151]  Michel Baulac,et al.  First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene , 2001, Nature Genetics.

[152]  I. Scheffer,et al.  Benign familial neonatal‐infantile seizures: Characterization of a new sodium channelopathy , 2004, Annals of neurology.

[153]  S. Priori,et al.  Genetics of Cardiac Arrhythmias and Sudden Cardiac Death , 2004, Annals of the New York Academy of Sciences.

[154]  I. Scheffer,et al.  Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. , 2001, Nature genetics.

[155]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[156]  M. O'Regan,et al.  Abnormalities in cardiac and respiratory function observed during seizures in childhood , 2005, Developmental medicine and child neurology.

[157]  Robert Kloster,et al.  Sudden unexpected death in epilepsy (SUDEP): a clinical perspective and a search for risk factors , 1999, Journal of neurology, neurosurgery, and psychiatry.

[158]  P. Lichter,et al.  Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[159]  P. Timmings.  Sudden unexpected death in epilepsy: is carbamazepine implicated? , 1998, Seizure.

[160]  A. Moss,et al.  Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias. , 2003, The Journal of clinical investigation.

[161]  J. Annegers,et al.  United States Perspective on Definitions and Classifications , 1997, Epilepsia.

[162]  A. Wilde,et al.  Cardiac conduction defects associate with mutations in SCN5A , 1999, Nature Genetics.

[163]  M. Dam,et al.  Sudden Unexpected Death in Epilepsy: Is Death by Seizures a Cardiac Disease? , 2005, The American journal of forensic medicine and pathology.

[164]  Matthew W State,et al.  A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. , 2006, The Journal of clinical investigation.