drug resistant epilepsy diagnostic and treatment options：耐药性癫痫的诊断和治疗

Drug Resistant Epilepsy:Diagnostic and Treatment OptionsMark A. Granner, MDMedical Director, Epilepsy Monitoring UnitCo-Director, Iowa Comprehensive Epilepsy ProgramProfessor and Vice Chair for Clinical ProgramsDepartment of NeurologyUniversity of IowaOverview Definitions and statistics Treatment options for drug resistant epilepsy AEDs, diet, VNS Introduction to epilepsy surgery The multidisciplinary approach to epilepsy care The Iowa Comprehensive Epilepsy ProgramIowa Comprehensive Epilepsy ProgramDefinitions Seizure An episode of altered behavior or awareness Associated with too much excitation of a population of nerve cells (neurons) Epilepsy The tendency to have recurrent, unprovoked seizures (brain makes seizures happen) Acute symptomatic (provoked) seizure A seizure occurring in the setting of some systemic provoking factor (normal brain, body makes seizures happen)Iowa Comprehensive Epilepsy ProgramDefinitions Acute repetitive seizures (“cluster”) A period of increased severity or frequency of seizures in an epilepsy patient Status epilepticus A single prolonged seizure ( 5-10 min) Repeated seizures without recovery to baseline SUDEP Sudden unexpected death in epilepsy patients 1-6 per 1000 patients per year Probably under recognized, under reported Needs further studyIowa Comprehensive Epilepsy ProgramDefinitions Drug resistant epilepsy Failure of at least TWO seizure medications to completely control seizures Appropriately chosen for seizure type Taken as prescribed Well tolerated (not failed due to side effects)Iowa Comprehensive Epilepsy ProgramDrug Resistant Epilepsy 470 patients with previously untreated epilepsy Seizure-free to 1st medication 47% Seizure-free to 2nd medication 13% Seizure-free to 3rd medication or beyond 4% 36% of epilepsy patients are drug resistant! The new generation of medications are generally safer (fewer side effects), but are not significantly more effective.Kwan P, Brodie M. NEJM 2000; 342(5)Iowa Comprehensive Epilepsy ProgramEpidemiology of Seizures & Epilepsy In the U.S. 10% lifetime risk of a seizure 4% lifetime risk of recurrent seizures 3% lifetime risk of epilepsy 0.6% prevalence of epilepsy 2,000,000 Americans $15,500,000,000 U.S. annual cost Higher in developing countriesIowa Comprehensive Epilepsy ProgramEpidemiology of EpilepsyIowa Comprehensive Epilepsy ProgramEpidemiology of Epilepsy2,000,000 with epilepsy600,000 with DRE1500 surgeries a yearIowa Comprehensive Epilepsy Program120,000 surgery candidatesOptions in Drug Resistant Epilepsy Medication New, study drugs Diet Ketogenic, Atkins Vagus Nerve Stimulator Epilepsy Surgery Gamma knife Brain stimulationIowa Comprehensive Epilepsy ProgramU.S. Epilepsy Drug Development1857 1912 1937 1954 1960 1974 1975 1978 1993 1995 1997 2000 2005 2008 2009Bromide saltsClonazepamEthosuximidePrimidonePhenytoinPhenobarbital LamotrigineFelbamateGabapentinValproateCarbamazepineOxcarbazepineZonisamideLevetiracetamTopiramateTiagabineRufinamidePregabalin1999Lacosamide2012EzogabineIowa Comprehensive Epilepsy ProgramDiets in Adults With Epilepsy Ketogenic diet Effective (40% seizure reduction) Compliance challenging (about 50% dont follow or stop) Minimal short term side effects Long term consequences not known Modified Atkins diet may be as effective and better toleratedVagus Nerve Stimulator Effectiveness Average seizure reduction (24.5%) 50% responder rate (31%) Seizure free (0%) Side Effects Hoarseness/voice change (37.2%) All patients should undergo video-EEG prior to VNS Rule-out non-epileptic events Screen for surgeryVNS Study Group. Neurology 1995Arain, et al. Epilepsy & Behavior 2011Iowa Comprehensive Epilepsy ProgramUIHC VNS Experience 100 patients currently followed 21 implant surgeries in 2012 Seizure-free about 5-10% Seizure reduction about 50% Patient satisfaction highIowa Comprehensive Epilepsy ProgramIndications for Epilepsy Surgery Drug resistant epilepsy Localized seizures Which can safely and effectively be resected Informed and willing patient Referral to surgical epilepsy center Epilepsy duration before referral 18 (2-58) years 61% sent by neurologist 39% self-referred, never advised of surgery 14% advised by neurologist not to have surgery 83% seizure freeIowa Comprehensive Epilepsy Program Benbadis et al. Seizure 2003.Epilepsy Surgery EvaluationDrug Resistant EpilepsyPhase 1(Non-invasive)Phase 2(Invasive)ConcordantDiscordantNot acandidatePhase 3- Wada test- SurgeryCase ConferenceCase ConferenceIowa Comprehensive Epilepsy ProgramEpilepsy Surgery EvaluationPhase 1 (Non-invasive) MRI (3T, sz protocol) Ictal video-EEG Neuropsychology PET, SPECT MEGPhase 2 (Invasive) Intracranial video-EEG Indications: Phase 1 data not agreeing Phase 1 data not localizing Concern of left vs. right side Concern of middle vs. surface temporal lobe Onset outside temporal lobeIowa Comprehensive Epilepsy ProgramTypes of Surgery Lobectomy (removal of all or most of lobe) Temporal frontal Corticectomy (removal of area of cortex) Hemispherectomy (removal/disconnection of hemisphere) Corpus callosotomy (disconnection) Multiple subpial transectionIowa Comprehensive Epilepsy ProgramOutcome Measures Seizure freedom Anterior temporal lobectomy 60-80% Extratemporal resection 25-50% Better if lesion on MRI Worse if widespread or multifocal seizure onset Complications Major 2% (stroke, hemorrhage) Infection Vision loss (temporal lobectomy) Memory or mood changeIowa Comprehensive Epilepsy ProgramSeizure Outcome After Anterior Temporal LobectomyIowa Comprehensive Epilepsy Program Wiebe, et al. NEJM 2001Other OutcomesMean SeizureSeverity ScoreMean GlobalQuality of LifeEmployed orAttending SchoolIowa Comprehensive Epilepsy Program Wiebe, et al. NEJM 2001Seizure Outcome at UIHC: Anterior Temporal LobectomyEngel ScorePercent2007 Surgical Outcome SurveyIowa Comprehensive Epilepsy ProgramGrade 1 Seizure freeGrade 2 Rare seizuresGrade 3 Significant reductionGrade 4 No improvementn=88Iowa Comprehensive Epilepsy ProgramSudden, unexpected death in epilepsy(SUDEP) Leading cause of premature death in epilepsy patients Sudden death 20 times greater than in general population Risks Generalized tonic clonic (“grand mal”) seizures Male gender Long duration of epilepsy Seizure medicine polytherapy Possible mechanisms Respiratory depression Cardiac arrhythmia Autonomic dysfunctionIowa Comprehensive Epilepsy Program Shorvon, Tomsen. Lancet, 2011.Incidence of SUDEPShorvon, Tomsen. Lancet, 2011.Iowa Comprehensive Epilepsy ProgramResearch at the Iowa Comprehensive Epilepsy Program Human brain physiology Auditory physiology Microdialysis Respiratory mechanisms SUDEP, SIDS Study of respiratory monitoring on EMU Human-computer interfaceIowa Comprehensive Epilepsy ProgramServices Offered: Iowa Comprehensive Epilepsy Program Consultation Episodes of unknown nature New onset seizures Drug resistant epilepsy Special populations (pregnancy, elderly) Epilepsy monitoring unit 9 beds adult / 5 beds pediatric Specialty nursing staff Epilepsy fellowship trained physicians Safety protocols 24-hour monitor observation Diagnostic tests Electroencephalography (routine, prolonged outpatient, inpatient) Imaging (MRI, fMRI, PET, SPECT) Neuropsychology Multidisciplinary team Neurosurgery Psychiatry Neuropsyc