Epidemiology of Epilepsy-related Mortality Dale Hesdorffer, Ph.D., Columbia University

Transcription

1 Plenary 1 Mortality in People with Epilepsy: Epidemiology and Surveillance June 24, :30 a.m. -10:15 a.m Moderator: Vicky Whittemore, Ph.D., NINDS Epidemiology of Epilepsy-related Mortality Dale Hesdorffer, Ph.D., Columbia University Suicide Among People with Epilepsy: A Population-based Study Results from the Data of U.S. National Violent Death Reporting System, 17 States, Niu Tian, M.D., Ph.D., Center For Disease Control Case Ascertainment and Registries: What Information Is Currently Being Collected in US/UK/Australia? - David Fowler, M.D., Chief Medical Examiner for Maryland and Margaret Warner, Ph.D., Centers for Disease Control The Sudden Death in the Young Case Registry: Updates and Progress Heather Macleod, M.S., CGC, Sudden Death in the Young Registry Panel Discussion: Are we getting at the right data? What populations aren t we exploring? What additional information should be collected? How do we improve case ascertainment?

2 Disclosures Epidemiology of Epilepsy Related Mortality Cyberonics consultant Acorda advisory board Upsher Smith advisory board Epilepsia Associate Editor Epilepsia Associate Editor Consultant Mount Sinai Injury Prevention Center Dale C Hesdorffer, PhD Columbia University JUNE 2016 Learning Objectives Old definition of status epilepticus Understand the differences between status epilepticus (SE) in the old and new classifications of SE Describe risk factors and outcomes of Prolonged Refractory Status Epilepticus (PRSE) and new onset refractory status epilepticus (NORSE) A seizure lasting more than 30 minutes or a series of seizures lasting more than 30 minutes without intervening recovery of consciousness. Describe the number of SUDEP deaths and consider similarities between drowning deaths, SUDEP and SE In hospital mortality in 399 of 11,580 US patients with generalized convulsive SE, Incidence of SE in Rochester, Minnesota Percent of deaths for each age group Incidence per 100, Remote symptomatic Idiopathic Acute symptomatic Age group 0 <1 1 to 4 5 to 9 10 to to to to to to to to Koubeissi & Alshekhlee Neurology 2007 Hesdorffer et al, Neurology 1998;50:

3 Case Fatality after a First SE Risk factors for in hospital mortality in US patients with generalized convulsive SE, Percent with SE who died All SE Unprovoked Acute symptomatic 59 Increased 1.3 fold for females vs males Charlston comorbidity index Increased 2 fold for moderate vs mild comorbidity burden Increased 7 fold for severe vs mild comorbidity burden <65 years >65 years All 38 Increased 10 fold for hypoxic ischemic brain injury Increased 2 fold for cerebrovascular disease Increased 3 fold for respiratory failure requiring endotracheal intubation Logroscino Epilepsia2001; Koubeissi & Alshekhlee Neurology 2007 New Conceptual ILAE Definition of Status Epilepticus Time 1 indicates when treatment should be initiated (5 minutes) SE is a condition resulting either from failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures after time 1. Time 2 indicates when long term consequences may occur (30 minutes) It is a condition that can have long term consequences after time 2, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. New ILAE classification of SE: Four Axes Semiology Etiology EEG correlates Type of SE T1 T2 Tonic clonic SE 5 minutes 30 minutes Focal SE with impaired 10 minutes >60 minutes consciousness* Absence SE** minutes Unknown * Little information to define T1 and T2; ** No information to define T1 and T2 Trinka et al, Epilepsia 2015 Age Trinka et al, Epilepsia 2015 New ILAE classification of SE: Semiology and Etiology Semiology Presence/absence of prominent motor symptoms Degree (quantitative or qualitative) of impaired consciousness Etiology Known (i.e. symptomatic) Acute Remote Progressive Unknown Trinka et al, Epilepsia 2015 New ILAE classification of SE: EEG correlates and age EEG correlates Location Name of the pattern Morphology Time related features: (e.g., prevalence, frequency) Modulation Effect of medication on the EEG Age groups Neonatal (0 30 days) Infancy (1 month 2years) Childhood (>2 to 12 years) Adolescence and adulthood (>12 59 years) Elderly (>60 years) Trinka et al, Epilepsia

4 New compared to old ILAE SE definition: SE with motor signs in hospital based adults New compared to old ILAE SE definition: SE without motor signs in hospital based adults 60 Percent New classification Old classification Percent 20 New classification Old classification Non convusive w/ coma Generalized SP/CP SE Focal w/o w/out coma consciousness impairment Aphasic Focal w/ consciousness impairment 0 0 Autonomic Rossetti et al, Epilepsia 2016 Rossetti et al, Epilepsia 2016 Comparing mortality in the old and new SE classification New SE classification Conclusions Percent mortality 50 New classification Old classification Provides greater information for SE seizure types than the prior classification Subset of repeated focal motor Maintains the old etiology classification Introduces: Age EEG Rossetti et al, Epilepsia 2016 *Includes: repeated focal motor, epilepsia partialis continua, adversive, oculoclonic, ictal paresis Prolonged refractory status epilepticus (PRSE) SE that persists despite at least one week of induced coma 63 consecutive patients with PRSE from medical and neurointensive care units of 3 academic medical centers over 9 years Incomplete PRSE control was associated with: Persistent seizures (clinical or electrographic during treatment) Recurrent seizures within 48 hours of discontinuation of anesthetic infusions Conclusions: Prolonged Refractory Status Epilepticus Two thirds survived to discharge One fifth had a good outcome >6 months after Prolonged Refractory Status Epilepticus One tenth of those without significant disability had a good outcome Good or excellent outcomes occurred 3 months after PRSE Up to 69 years of age Killbride et al, Neurocrit Care

5 New Onset Refractory Status Epilepticus (NORSE) A state of persistent seizures with no identifiable etiology in patients without prior epilepsy that lasts longer than 24 hours despite optimal therapy New onset Refractory Status Epilepticus (NORSE) in 13 Centers Retrospective review of 125 complete cases with new onset refractory SE with unknown etiology within 48 hours of admission over a 5 year period 50% unknown etiology 50% known etiology after investigatrion 20% autoimmune, non paraneoplastic 18% paraneoplastic 8% infection related 4% other causes In those with unknown etiology 62% poor outcome 22% died Gaspard et al Neurology 2015 Conclusions: Treatment and complications in positive etiology and no etiology Immune system therapies greater in positive etiology Plasma exchange (p=0.02) IV immunoglobulin (p=0.01) Rituximab (p<0.001) SUDEP Complications greater in no etiology Need for vasopressors (p=0.03) Severe acidosis (p=0.04) Uncontrolled SE at death (p=0.04) SE associated complications: Poor functional outcome Mortality 7 differences out of 34 comparisons Gaspard et al Neurology 2015 Annual number of SUDEP deaths Age adjusted incidence of SUDEP in the US 1.11 SUDEPs per 1,000 people with epilepsy Adjusted for the 2000 standard population Using the US and European population estimates in 2013, there were: 2,750 SUDEPs per year in the United States 3,994 SUDEPs per year in the 28 nations of the European Union Cumulative incidence of SUDEP: By year of epilepsy onset Cumulative Risk of SUDEP 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 1 yr 15 yrs 30 yrs Age of Epilepsy Onset 0.5% 1.6% 0.7% 3.9% 3.0% 0.2% 6.0% 5.1% 2.4% 7.3% 6.5% 3.8% 7.8% 8.0% 7.0% 7.2% 4.3% 4.6% Age in Years Thurman et al, Epilepsia 2014 Thurman et al, Epilepsia

6 Distribution of SUDEP by population and by age Drowning deaths Thurman et al, Epilepsia 2014 Prevalence of drowning in bathtubs in the US SMR for drowning deaths in epilepsy by study Budnick & Ross, Am J Pub Health 1985 Bell et al. Neurology 2008 SMR for drowning death in epilepsy by population Autonomic Nervous system: effects on drowning, SUDEP and SE Drowning risk factors are similar to SUDEP: Learning disability Living in an institution Temporal lobe surgery Entered in a drug trial Tertiary clinic ALL INDICATORS OF HIGH SEIZURE FREQUENCY Autonomic Nervous System regulates involuntary body functions: Activity of the heart, respiration, intestinal tract and glands Sympathetic nervous system: Accelerates heart rate, constricts blood vessels, raises blood pressure Parasympathetic nervous system: slows heart rate, increases intestinal and gland activity, relaxes muscle sphincters Bell et al. Neurology

7 Autonomic Nervous System in Epilepsy: Drowning, SUDEP, and SE Might drowning deaths be similar to SUDEP? Death in Epilepsy Sympathetic NS Parasympathetic NS Drowning SUDEP SE Cold water receptors inhibit the respiratory center, leading to apnea & vasoconstriction Increased heart rate and blood pressure Tachycardia, hypertension, pulmonary edema, ventricular arrhythmias Atrial and pulmonary stretch receptors and apnea, leads to slowed heart rate Impaired respiration, apnea, slowed heart rate, hypotension, and bradyarrhythmia precede death Hypotension and generalized circulatory collapse Exclusion of drowning from cases of SUDEP may be inappropriate Both sympathetic and parasympathetic changes are seen with water emersion in normal populations and with seizures in epilepsy Aberrant control of cardiac or respiratory function may occur more in PWE as demonstrated in SUDEP and drowning Similar findings are seen in SE Impact on Clinical Care and Practice Old and new classifications of SE Seizure types are better represented in the new classification This may lead to better therapeutic interventions Prolonged Refractory Status Epilepticus Survival to discharge in 66% Good outcome 6 months post PRSE in 22% New onset Refractory Status Epilepticus Almost half have an autoimmune/paraneoplastic etiology after investigation Many survive and do well, despite NORSE Epilepsy develops in 57% Impact on Clinical Care and Practice Drowning, SUDEP and SE Share an aberrant control of cardiac and respiratory function pameaesnet.org 2016 PAME CONFERENCE JUNE ALEXANDRIA, VA 6

8 6/22/2016 Suicide among People with Epilepsy A Population Based Study using U.S. National Violent Death Reporting System, 17 States, Disclosure The authors have no conflicts of interest Niu Tian, MD, PhD Epilepsy Program Centers For Disease Control and Prevention (CDC) The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention June 2016 National Center for Chronic Disease Prevention and Health Promotion Division of Population Health Learning objectives Following the participation of this presentation, learners should be able to: Have an overview of epidemiology on the suicide among people with epilepsy in the general population Improve the knowledge about risk and risk factors of suicide among people with epilepsy Prepare for the suicide prevention in this special group Suicide, # 1 cause of violence related deaths and one of the major causes of death in the U.S. population In 2013, an estimated 57,786 persons died in the United States as a result of violence related death 41,149 of deaths (71%) were suicides, followed by homicides and deaths involving legal intervention Suicide deaths among all causes of deaths 2nd leading cause of death for people aged rd leading cause of death for people aged th leading cause of death for people aged th leading cause of death for people aged Source: Available at Suicide among people with epilepsy is an increasing public health concern Most epidemiologic studies showed that people with epilepsy have stronger tendency toward suicide than health controls 1 It has been proposed that suicide, epilepsy, and psychiatric disorder may share common pathophysiological mechanisms 2,3 Depression, anxiety, and suicidality could relate to negative SDOH (unemployment etc.) and the lifestyle changes imposed by sudden seizure and increased stigma perception among people with epilepsy Source: 1. Bell GS, et al. Epilepsia 2009;50: Hecimovic H, et al. Epilepsy & Behav. 2011;22: Hesdorffer DC, et al. Annals of Neurology 2012;72: The gold standard for studies on mortality (including suicide) in people with epilepsy Population based cohort of incident cases Only this type of study permits a complete collection of data and the observation of the clinical phase of the disease from the diagnosis of epilepsy to the outcome of the study, death 1 Source: 1. Logroscino G., Hesdorffer DC Epilepsia

9 6/22/2016 Limitations/problems in most epilepsy suicide studies Example Table is cited from a meta analysis from 30 studies in the US and Eur. Suicide burden is calculated by cause specific mortality ratio numbers of suicide Numbers of all causes of deaths in a group of people with epilepsy Results vary significantly Different countries Different populations Different selected patient groups Different study designs Usually small sample sizes UK USA Source: Pompili M, et al. Epilepsy & Behavior. 2006; 9: Suicide epidemiology among people with epilepsy in the general population is not clear/unknown Population based surveillance systems including both epilepsy and suicide have not been routinely available No studies have described both suicide rates and the characteristics of people with epilepsy who died from suicide in a large general population setting Study objectives To analyze suicide data among those with epilepsy in the general population from the U.S. National Violent Death Reporting System (NVDRS): Describe suicide burden (suicide rate and trend) Investigate risk factors associated with suicide Suggest measures to prevent suicide in this special group Data Source Source: U.S. National Violent Death Reporting System (NVDRS) multiple state, active surveillance system population based representative sample Components: detailed information on the circumstances of violent deaths including suicides 250 unique variables for each death from individual information sources Abstractors also compose text narratives that describe further details about the death Monitored by CDC with high quality control Purpose: accurate, timely, and comprehensive data to better understand and ultimately to prevent the occurrence of violent death including suicide in the U.S. Source: CDC, Morbidity and Mortality Weekly Report (MMWR), 2014:63(No. 1):1 33. Study design and sample States Alaska X X X X X X X X X Colorado X X X X X X X X Georgia X X X X X X X X Kentucky X X X X X X X Maryland X X X X X X X X X Massachusetts X X X X X X X X X New Jersey X X X X X X X X X New Mexico X X X X X X X North Carolina X X X X X X X X Ohio X Oklahoma X X X X X X X X Oregon X X X X X X X X X Rhode Island X X X X X X X X South Carolina X X X X X X X X X Utah X X X X X X X Virginia X X X X X X X X X Wisconsin X X X X X X X X X = data available 2

10 6/22/2016 Identify suicides with and without epilepsy Identified 82,501 suicides from NVDRS by using ICD 10 codes X60 X84 and Y87.0 at ages 10 years or older in 17 states from Calculation of suicide rates among people with epilepsy in the general population Epilepsy prevalence Searched epilepsy/seizure related key words and phrases: epilepsy, seizure, convulsion, drop attack, falling out spell, staring spell from : death certificates medical examiner/coroner records law enforcement reports abstractors narratives/descriptors Searched epilepsy/seizure related ICD 10 codes: G40, G41, P90 and R56 from: death certificates U.S. children aged years old from the U.S. National Survey of Children s Health (8.1/1,000 persons) 1 U.S. adults 18 years old or older from the U.S. National Health Interview Survey (10.0/1,000 persons) 2 Estimate the expected number of people with epilepsy in each state for each study year Excluded 43 drug induced seizure by reading abstractors narratives 1,015 suicides with epilepsy/seizure. Suicide rate= total number of suicide cases in people with epilepsy in each year / total expected number of people with epilepsy each year 972 suicides with epilepsy 81,529 suicides without epilepsy Source: 1. Russ SA, et al. Pediatrics 2012;129: CDC. Morbidity and Mortality Weekly Report (MMWR) 2012: 61(No. 45): Trends of suicide in people with and without epilepsy in the general population Other sociodemographic characteristics (covariates) Trends of the proportions of suicides deaths among people with and without epilepsy in 16 states (all but Ohio) with continual data from 2005 through 2011 The annual proportion of suicide deaths = the number of suicides each year / the total number of suicides for all years from 2005 through 2011 NVDRS collects information about characteristics such as: Age, gender, race/ethnicity Education, and marital status Location of injury Month of injury Method of injury For suicide burden Rate calculation described before Trend analysis Cochran Armitage trend test Compared the proportions of suicide deaths between people with and without epilepsy For suicide risk Statistical analysis Compared the proportions of suicide deaths between people with and without epilepsy by month, the location of death, and the method of injury by sex, age, race/ethnicity, education, and marital status Defined statistically significant differences in proportions of deaths whose two sided 95% binomial confidence intervals did NOT overlap Estimated Annual Suicide Mortality Rates among People with Epilepsy in the General Population Estimated Total Annual No. of Suicide Suicide people cases mortality Estimated numbers of people with epilepsy by participating states with vary data entering years Year with with rate epilepsy epilepsy (/100,000) AK CO GA KY MD MA NJ NM NC OH Ok OR RI SC UT VA WI 5349 x x x x x x x x x x x x x x x x x x x Total X = data not available 3

11 6/22/2016 Trends of the proportions of suicides deaths with and without epilepsy from in the 16 states (excluding Ohio) Exploration of Risk factors Comparing the percentages of suicide death between with and without epilepsy by location and method With Epilepsy Without Epilepsy Total % (95% CI) N % (95% CI) % (95% N N CI) Location > ( )* 60, ( ) 61, ( ) House/Apartment Commercial Area ( ) 3, ( ) 3, ( ) Transport area: other ( ) 3, ( ) 3, ( ) Other Specified Places ( ) 2, ( ) 2, ( ) Natural Area/Countryside ( ) 3, ( ) 3, ( ) > Residential Institution ( )* 1, ( ) 1, ( ) Public Transport area ( ) 2, ( ) 2, ( ) Unknown ( ) 1, ( ) 1, ( ) Recreational Area ( ) 1, ( ) 1, ( ) Total ,529 82,501 Method > Poisoning ( )* 12, ( ) 12, ( ) Firearm ( )* 39, ( ) 39, ( ) Hanging/Strangulation/Suffocation ( )* 17, ( ) 17, ( ) Fall/Jumping ( ) 1, ( ) 1, ( ) Sharp Object ( ) 1, ( ) 1, ( ) Other Specified Means/Unspecified Means ( ) ( ) ( ) Fire and Burns ( ) ( ) ( ) Sequelae of intentional self-harm, assault, and events ( ) ( ) ( ) of undetermined intent Drowning and Submersion ( ) ( ) ( ) Explosive Material ( ) ( ) -- Blunt Object a a Motor Vehicle ( ) ( ) Total , , Exploration of Risk factors Comparing the percentages of suicide death between with and without epilepsy by sex and age Exploration of Risk factors Male Female Both Sexes With Epilepsy Without Epilepsy With Epilepsy Without Epilepsy With Epilepsy Without Epilepsy N % (95% CI) N % (95% CI) N % (95% CI) N % (95% CI) N % (95% CI) N % (95% CI) Comparing the sex-specific percentages of suicide death with and without epilepsy by marital status Age Group (Years) ( ) 1, ( ) ( ) ( ) ( ) 2, ( ) ( ) 12, ( ) ( ) 2, ( ) ( )* 14, ( ) ( ) 10, ( ) ( )* 2, ( ) ( ) 13, ( ) > > > > ( )* 13, ( ) ( )* 4, ( ) ( ) * 17, ( ) ( )* 11, ( ) ( ) 3, ( ) ( ) 15, ( ) > Male Female Both Sexes Without With Epilepsy Without Epilepsy With Epilepsy Without Epilepsy With Epilepsy Epilepsy % (95% CI) % (95% CI) N % (95% CI) N % (95% CI) % (95% CI) % (95% CI) N N N N Marital Status Married ( ) 23, ( ) ( ) 6, ( ) ( ) 30, ( ) Widowed/Divorced/ ( ) 17, ( ) ( ) 6, ( ) ( ) 23, ( ) Separated Never Married ( ) 22, ( ) ( ) 4, ( ) ( ) 26, ( ) Total , , , ( ) 6, ( ) ( ) 1, ( ) ( ) 8, ( ) 70 and Above ( )* 7, ( ) ( )* 1, ( ) ( ) * 8, ( ) Total when comparing those with epilepsy in the female group when comparing those without epilepsy in the female group Summary of major findings (for suicide burden) The annual suicide mortality rate among people with epilepsy in a large general population was 16.89/100,000 persons per year, 22% higher than that in the general population Of those total suicide deaths, 1.2% was from people with epilepsy Both annual rate of suicide and the annual percentage of suicides among all suicides in those with epilepsy increased steadily from 2005, peaking significantly in 2010 before falling Compared to those without epilepsy, those with epilepsy were more likely to die from suicide in homes, apartments, or residential institutions (81% vs. 76%) Twice as likely to poison themselves as those without epilepsy (38% vs. 17%) Summary of major findings (for risk factors) More of those with epilepsy aged died from suicide than those at same ages without epilepsy (29% vs.22%) Marital status (being unmarried) was related to the increased risk of suicide in people with epilepsy 4

12 6/22/2016 Strengths of this study For the first time, we systematically researched the basic epidemiology of suicide among people with epilepsy in a large, general population in the U.S. Suicide rate, trend, risk and risk factor Data from NVDRS, a unique, large population based surveillance system with high quality control and data collection consistency, and inclusion of all suicides from 2003 through 2011 in 17 U.S. states (about one third of the U.S population) Multiple methods to identify those suicide deaths with epilepsy/seizure. Limitations of this study The identification of epilepsy / seizure among suicide cases could have misclassified some suicide cases Overestimate suicide cases with epilepsy falling out spell, staring spell, drop attack Underestimate suicide cases with epilepsy identification of epilepsy in persons who died from suicide is usually overlooked Identification of suicide deaths in persons with epilepsy is difficulty Limitations of this study (Cont.) NVDRS includes data from only 17 States, not the whole or a necessarily representative segment of the U.S. population. The calculation of the expected number of people with epilepsy in each state was based on two national age specific prevalence estimates, which may not accurately represent these states because socioeconomic factors that may affect epilepsy prevalence may differ across the states. Finally, information about associations between epilepsy related suicide and prior history of mental illness is unknown. Impact on clinical care and practice (for suicide burden) Based on this large community data, people with epilepsy have a slightly higher suicide rate (22%) than that in the general population and suicides with epilepsy take a small portion (1.2%) of all suicide deaths The recent U.S. economic recession may have impacted the trends of annual suicide rate and proportion of annual suicide deaths among people with epilepsy. The economic crisis and its consequence Unemployment, poverty, debt, and diminished public welfare, and depression Impact on clinical care and practice (for suicide risk factors) Compared to general population, people with epilepsy are more likely to die from suicide in their residence, and by poisoning themselves People with epilepsy aged years old are the most vulnerable group Family /social support are crucial to prevent suicide risk among people with epilepsy People with epilepsy may benefit from having caregivers, relatives, and friends supervise the availability of potentially harmful materials including drugs to prevent suicide Suicide prevention efforts should focus on people with epilepsy aged years, especially in their residences Recommendations Epilepsy health and social service providers, caregivers and other members of the public should be aware of the importance of screening and treatment of depression and other mental illness in people with epilepsy to prevent suicide Population based surveillance or registry targeting both epilepsy and mortality including suicide needs to be enhanced to allow further epidemiology study among people with epilepsy in the U.S. nationwide 5

13 6/22/2016 Acknowledgments CDC Epilepsy Program Wanjun Cui Matthew Zack Rosemarie Kobau Collaborators Katherine Fowler Matthew Gladden Dale Hesdorffer For more information please contact Centers for Disease Control and Prevention 1600 Clifton Road NE, Atlanta, GA Telephone: CDC-INFO ( )/TTY: Web: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion Division of Population Health 6

14 6/22/2016 Determining cause and manner of death Challenges and Opportunities to Understand Sudden Unexpected Death in Epilepsy (SUDEP) Using Death Certificate Data Death scene Autopsy Toxicology lab tests and other findings Cause of death Margaret Warner, PhD National Center for Health Statistics Partners Against Mortality in Epilepsy Conference June 2016 National Center for Health Statistics Division of Vital Statistics, Mortality Statistics Branch Medical Examiner or Coroner (or Physician) Mortality data Death is a key health outcome Death certificate mortality data uses include: Monitor to health of nation Understand causes of death Identify risk and protective factors Define public health response priorities Evaluate the impact of interventions Determine what public health messages to deliver National Vital Statistics Mortality Data Based on information from all death certificates filed in the States and Territories Data include: Demographic information such as age, sex, race, place of residence Disposition information Causes of death coded using the International Classification of Diseases, Tenth Revision (ICD 10) Data used to monitor the health the nation, including leading causes of death, life expectancy Mortality data Death investigation data Death certificate: literal text from Death certificate: Multiple cause of death file Death certificate: Underlying cause of death file US Standard Death Certificate Demographic information Completed by the funeral director using information from the best qualified person: spouse, parent, child, another relative, or other person who has knowledge of the facts Medical information For natural causes, completed by attending physician, nurse practitioner, physician s assistant For sudden and unexplained deaths, completed by medical examiner, coroner, Justice of the Peace Demographic information 1

15 6/22/2016 Funeral directors Death Registration in the US To Be Completed By: MEDICAL CERTIFIER CAUSE OF DEATH (See instructions and examples) 32. PART I. Enter the chain of events - - diseases, injuries, or complications - - that directly caused the death. DO NOT enter terminal events such as cardiac arrest, respiratory arrest, or ventricular fibrillation without showing the etiology. DO NOT ABBREVIATE. Enter only one cause on a line. Add additional lines if necessary. IMMEDIATE CAUSE (Final disease or condition resulting in death) a. Sequentially list conditions, if any, leading to the cause listed on line a. Enter the UNDERLYING CAUSE (disease or injury that initiated the events resulting in death) LAST b. c. Due to (or as a consequence of): Due to (or as a consequence of): Due to (or as a consequence of): d. PART II. Enter other significant conditions contributing to death but not resulting in the underlying cause given in Part I. Literal text Literal text Literal text Approximate interval: Onset to death Causal sequence leading to death 33. WAS AN AUTOPSY PERFORMED? Yes No 34. WERE AUTOPSY FINDINGS AVAILABLE TO COMPLETE THE CAUSE OF DEATH? Yes No Other significant conditions Physicians Medical examiners Coroners US Vital Registration System - 50 States - New York City - District of Columbia - 5 Territories 35. DID TOBACCO USE 36. IF FEMALE: 29. MANNER OF DEATH CONTRIBUTE TO DEATH? Not pregnant within past year Natural Pending Pregnant at time of death Accident Investigation Yes Probably Not pregnant but pregnant within 42 days of death Suicide Could not be No Unknown Not pregnant but pregnant 43 days to 1 year before death Homicide Determined Unknown if pregnant within the past year 38. DATE OF INJURY 39. TIME OF INJURY 40. PLACE OF INJURY (e.g., Decedent s home, construction 41. INJURY AT WORK? (Mo/Day/Yr)(Spell Month) site, restaurant, wooded area) Yes No 42. LOCATION OF INJURY: State: City or Town: Street & Number: Apartment No. Zip Code: 43. DESCRIBE HOW INJURY OCCURRED 44. IF TRANSPORTATION INJURY, SPECIFY Driver/Operator Literal text How injury Passengeroccurred Pedestrian Other (Specify) Vital Statistics Cooperative Program Federal State cooperative arrangement Federal government provides funding, coordination, standards and cause of death coding States maintain autonomy in their operations, but collect and provide data according to standard specifications and agreed upon timelines From death certificate to vital statistics data Literal text Literal text Literal text Literal text Literal text Mortality Medical Data System ICD-10 Codes Multiple cause of death files ICD-10 = International Classification of Diseases, Tenth Revision Promoting Consistency and Uniformity Model State Vital Statistics Act and Regulations Standard Certificates and Reports Training materials handbooks, videos, instruction manuals Technical assistance ICD 10 Software automated coding Cause of death coding Deaths coded using the Tenth Revision of the International Classification of Diseases (ICD 10) ICD 10 in use since 1999* ICD 11 revision in progress All WHO Member States use the ICD Developed by international workgroups Translated into 43 languages Many countries use ICD to report mortality data as their primary indicator of health status * ICD-10-CM (the clinical modifications) are not used for mortality coding 2

16 6/22/2016 Some example (simplified) certification statements for SUDEP Sudden death associated with epilepsy Epileptic seizure Complications of seizures Probable seizure Seizure disorder Complications of seizures Undetermined ICD 10 Codes for sudden unknown deaths involving epilepsy and seizures G40.9 (Epilepsy, unspecified) Includes, Epileptic seizure Complications of epilepsy Sudden death associated with epilepsy R56.9 (Other seizures and convulsions) Includes, Probable seizure Seizure disorder Complications of seizures R99 (Other ill defined conditions) Includes, Unknown Undetermined Many other ICD 10 codes for epilepsy and seizure Some example (simplified) certification statements for SUDEP Sudden death associated with epilepsy Epileptic seizure Complications of seizures Probable seizure Seizure disorder Complications of seizures Undetermined Using death certificates for public health research Methods to retrieve information from death certificates Manual review of death certificates Multiple Cause of Death (MCOD) file Text searches of the literal text from the death certificate Combination of methods Some example (simplified) certification statements for SUDEP Sudden death associated with epilepsy Epileptic seizure Complications of seizures Probable seizure Seizure disorder Complications of seizures Undetermined National Death Index Assists investigators in determining whether persons in their studies have died Provides the names of the states in which those deaths occurred, the dates of death, and the corresponding death certificate numbers Investigators can arrange to obtain copies of death certificates or specific statistical information such as cause of death from state offices 3

17 6/22/2016 Expert panel on Investigation, Diagnosis and Certification of SUDEP Researchers from National Association of Medical Examiners North American SUDEP Registry Epilepsy Foundation SUDEP Institute American Epilepsy Society Centers for Disease Control and Prevention (CDC) Review literature to recommend state of the art practice for the investigation, diagnosis and certification of sudden death in epilepsy Convened May 2016 with work on going Questions? Margaret Warner, PhD Mortality Statistics Branch, Division of Vital Statistics National Center for Health Statistics 3311 Toledo Rd. Hyattsville, MD Phone: Summary Death certificates provide information on the causes of death to help researchers to understand underlying disease mechanisms, and risk and preventive factors Death certification practices for SUDEP vary There are many ways to review the information on death certificates Work on going to improve certification and access to information for researchers Let conversation cease, let laughter flee, for this is the place where death delights to help the living." Inscribed on the wall of the NYC Medical Examiner s Office, Translated from Latin, Giovanni Morgagni 4

18 The Medical Examiner Perspective David Fowler, MD Chief Medical Examiner, Maryland Disclosure No Commercial interests. JUNE 2016 Death Investigation Considerations Case Assessment Considerations ME/C sudden unexpected natural death cases mostly cardiovascular 20% or less are CNS pathology Many deaths have terminal seizure activity Some deaths during a seizure or during post ictal period may appear to be cardiac. Death Investigation Considerations Epileptics have same risk of non natural events as the general population Does a death necessarily mean it was triggered by a seizure Sentinel seizure may be fatal Trauma Natural Death Investigation Essential elements and data collection The Scene circumstances ME/C equivalent of history Found dead Witnessed event Present with symptoms Pre hospital care death Hospital death Death Investigation Essential Elements and Data Collection History Use NASR and SDY forms Family Work Medical history from physician, family and friends Last medical visit Old CNS trauma Medications Present medical conditions Psychiatric history Social Substances/alcohol use 1

19 Essential Elements and Data Collection Screening for seizures or epilepsy in sudden death form Screening for epilepsy in other forms of unexpected deaths (suicide, accidents) NASR and SDY Death Scene Investigation forms Death Investigation Body Examination positive Trauma Cardiovascular infarct, congenital, aortic rupture/dissection CNS Meningitis, hemorrhage Other organ(s) Perforation, hemorrhage, PE etc. Autopsy Protocol Full Autopsy X ray/advanced imaging Full external examination Internal gross organ dissection Full histology Toxicology Metabolic studies Culture Viral and bacterial Death Investigation Body examination negative Full Microscopic exam All essential organs association with sudden death Heart Cardiovascular pathologist Conduction system Additional gross exam Additional histology Death Investigation Body examination negative Consultant Neuropathologist Brain malformations Additional Histology Other Studies Vitreous electrolytes/glucose Rule out metabolic Election microscopy Metabolic studies Hold blood for genetic studies (card or tube) Toxicology Rule out intoxication Identify therapeutic medication(s) Levels PM levels may well be difficult to interpret and not representative of ante mortem levels 2

20 Role of Molecular Autopsy Challenges with Determination of Death A cause of death vs. The cause of death Genomic testing for Long QT Catecholaminergic polymorphic ventricular tachycardia Hypertrophic cardiomyopathy Death scene Autopsy Findings Social and work history Laboratory Testing Cause of Death ICD Codes Many seizure deaths go unrecognized. Trauma (single occupant motor vehicle impact) Drowning Be consistent Seizure disorder or seizure Due to.. You can use contributory causes section E.g. In MVC trauma if seizure was witnessed or thought to play a part It is acceptable to use probable on a DC if needed There is no SUDEP Code in ICD 10 ICD 10 Epilepsy Codes Include: G40.0 to G40.9 and G40.A, G40.B ICD 9 Epilepsy Codes Include: and Consent for Further Studies? Know your local laws Consent for molecular study if needed In Maryland the ME is authorized to retain and do any tests that determine the cause of death within a reasonable degree on medical certainty There is no time limitation That allows further testing even years later should a new technology come up. Limited Resources To autopsy or Not to autopsy that is the question? MEC with resources do DX of seizure disorder is often a diagnosis of exclusion Exclude occult trauma, toxicology etc. Exclude natural disease Identify CNS abnormalities Best Specimens: Toxicology, Histology, culture, molecular 3

21 Efforts to Advance our Understanding of SUDEP Center for SUDEP Research Sam Lhatoo & Jeff Noebels, PIs NINDS NIH Center for SUDEP Research NIH-CDC Sudden Death in Young Registry North American SUDEP Registry Sudden Unexplained Death in Childhood Registry & Research Collaborative (SUDC- RRC) Human physiology EMU recordings and prospective ascertainment Neuropathology insights from pathology on mechanism, linking clinical biomarkers to epilepsy surgery tissue to brainstems Experimental physiology neurorespiratory and neurocardiac mechanisms and models Molecular diagnostics - genetics Sudden Death in Young (SDY) Registry Rationale for a SUDEP Registry Collaboration of NHLBI, NINDS, CDC Cardiac & epilepsy focus 10 States/Counties Prospective surveillance Ages 0 19 yo Surveillance and DNA San Francisco 9 counties Tidewater Selected jurisdiction All state SUDEP is rare >2,750 SUDEPs in US annually. insufficient cases to study at one center Epilepsy center based case ascertainment biases towards high risk patients Need more population based approach Large numbers of cases are needed to evaluate what are likely heterogeneous mechanisms Prevention strategies may not be generalizable Contribution of cardiac channelopathies (eg, new onset) Collaborative effort involving multiple investigators from multiple disciplines 21 Hirsch et al. Neurology 2011 Development of North American SUDEP Registry How Can You Support NASR and SDY? Registry for SUDEP cases in the United States and Canada Create a repository for clinical, imaging, tissue, genetic and physiological data Population based referrals of all decedents with epilepsy (SUDEP & non SUDEP controls with epilepsy) Partnering with Medical Examiners Referral through epilepsy patient community (EF), neurologists Eligible patients currently include Cases with DNA or Brain tissue Cases with videoeeg recorded seizures, EKG, MRI Tissue/genetic material will be freely available to any investigator after review by independent advisory board Medical Examiners, Forensic Pathologists, and Coroners are crucial partners for NASR s success. To collect high quality clinical information, tissue, and DNA from as many epilepsy related mortality cases as possible we need your help! Epidemiology all SUDs, suicide, drowning consider epilepsy Awareness inform encourage families to contact NASR. Tissue donation collect tissue and genetic material from as many epilepsy related mortality cases as possible. Blood cards genetic data and de identified clinical data Retrospective tissue collection we can accept brain tissue or DNA from previous cases with de identified medical records. 4

22 ME case number Investigator Obtained information from Relationship to deceased: Hospital or clinic where treated? Did the deceased have epilepsy or a seizure disorder? 1 Yes 2 No 9 Unknown When was the victim last seen alive and well? Date: / / Time (24 hr) : OR 9 Unknown Was the last observed seizure was on the date of death,? 1 Yes 2 No 9 Unknown Were medications found at scene? 1 Yes 2 No 9 Unknown List drugs and number of pills in bottle Drug #bottles #pills Death occurred: 1 at home 2 in a hospital/emergency room 3 Other (specify): Victim was: 1 alone at death 2 with someone Victim found: 1 prone 2 supine 3 Other (specify): Instructions described the usual seizure(s) as narrative; what happens first, then what happens & how does it end Morning Afternoon Evening During sleep Shortly after awakening Drink heavily? Use marijuana? Have meningitis or Take antidepressant Recently quit drinking? Use other illicit drugs? encephalitis? drugs? Use cocaine? Take insulin? Have prior head injury? Have brain surgery Use heroin? Have depression? brain surgery? Have chronic health problems? 1 Yes 2 No 9 Unknown, if Yes elaborate: No anti-seizure drugs Acetazolamide (Diamox) Carbamazepine (Tegretol, Tegretol XR, Carbatrol) Clobazam (Onfi, Frisium) Clonazepam (Klonopin) Clorazepate (Tranxene) Divalproex/Valproate (Depakene, Depakote, Depakote ER) Ethotoin (Peganone) Ethosuxamide (Zarontin) Ezogabine (Potiga) Name of deceased Date (mm/dd/yyyy) Time (24hourclock) Felbatol (Felbatol) Lacosamide (Lacosamide) Levetiracetam (Keppra, Keppra XR) Lorazepam (Ativan) Oxcarbazepine (Trileptal, Oxtellar XR) Paramethadione (Paradione) Perampanel (Fycompa) Phenobarbital (Luminal) Phenytoin (Dilantin, Phenytek) Pregabalin (Lyrica) Primidone (Mysoline) Rufinamide (Banzel) Stiripentol (Diacomit) Tiagabine (Gabatril) Topiramate (Topamax) Vigabatrin (Sabril) Zonisamide (Zonegran) Other specified : 2015 AES Annual Meeting How NASR Can Support ME/C Field Investigator Form Field Investigator Epilepsy Deaths Form short form v Exome sequencing Neuropathology reports & imaging Independent reviews by experts in epilepsy mortality Screen seizures/epilepsy in all SUDs, single passenger MVAs Validated screening form Field investigator forms Witness/Family information Seizure description When did seizures usually occur: Circle all that apply Did the deceased: Circle all that apply Which anticonvulsant medication(s) was the patient currently taking? Circle all that apply Process Family member calls 24 hour registry hotline ( ) Screened for history of epilepsy & possible tissue donation If candidate for tissue donation, transferred to brain banking affiliates to coordinate donation minute interview with research coordinator Referral to grief counseling networks and peer support groups (SUDEP Institute) Consent for release of medical records We can provide Genetic testing from DNA and Neuropath reports from donated brains Epilepsy Foundation SUDEP Institute Mission To prevent Sudden Unexpected Death in Epilepsy (SUDEP) and support people confronting the fear and loss caused SUDEP. Supports Death Investigators Training Support with finding death review teams Coordinating with family for consent and explaining death investigation process General bereavement support To learn more or refer a family: Call or sudep@efa.org pameaesnet.org 2016 PAME CONFERENCE JUNE ALEXANDRIA, VA 5

23 Learning Objectives The Sudden Death in the Young (SDY) Case Registry: Updates and Progress Following participation in this activity, learners should be able to: Describe the goals of the SDY Case Registry Share the progress of the SDY Case Registry Identify future research opportunities in SUDEP Heather MacLeod, MS CGC SDY Case Registry JUNE 2016 What Causes Sudden Death? Goals Autopsy Positive Aneurysm Cardiomyopathy Congenital Heart Disease Coronary Artery Disease Infection Metabolic Disease Stroke Other Autopsy Negative Arrhythmia SUDEP Unexplained Establish the incidence of sudden death in the young in the United States Investigate etiologies and risk factors for sudden death in the young 3 Sudden Death Incidence Estimates The sudden death of a child is a tragic event Estimates for SCD and SUDEP vary greatly Incidence SCD in the young per 100,000 Incidence of SUDEP about cases/year (all ages) Genetic Counselor Cardiologist/ Neurologist Multidisciplinary Approach Family Physician Medical Examiner The Family with Sudden Death Patient Support Groups DNA Banks Genetic Testing Labs Researchers Adopted from Ingles and Semsarian (2007) 1

24 Focus on the Family Developing protocols and processes to include: Saving appropriate samples Consenting procedures focused on the family Providing recommendations and referral information for family screening, genetic counseling and psychosocial support DNA Sample Diagnostic Genetic Testing Research DNA Banking for Family Use Grantees Case Process Statewide Selected Jurisdictions SDY Case Information Collected Medical records Symptoms Previous serious injury Exercise Previous diagnoses Medications Family history Genetic testing 2

25 Challenges barriers exist. One is cost, but just as significant is the ability of the medical examiner to order the right test and communicate the results to the family of the deceased person. Arch Pathol Lab Med Vol 138 November 2014 Diagnostic Genetic Testing Genetic testing to elucidate cause of death in autopsy negative cases for the Sudden Death in the Young (SDY) Case Registry: A collaboration between Invitae, the Michigan Public Health Institute and the University of Michigan. Process for Diagnostic Genetic Testing Funded Researchers: Sudden Death in the Young Initiative IF No cause of death determined through autopsy = autopsy negative AND Family consented to the diagnostic genetic testing option AND gdna sample meets minimum requirements AND SDY Autopsy Summary or equivalent AND SDY Field and Family Form or equivalent Medical Examiner involved with case places online order with Invitae Biorepository Channelopathies and cardiomyopathies among sudden deaths in the young; PIs: Alfred George and Elizabeth McNally (Northwestern) Role of genetic variants in sudden death in the young; PI: Prince Kannankeril (Vanderbilt) Integrating genomic and clinical approaches to sudden death in the young; PIs: Martin Tristani and Mark Yandell (University of Utah) Acknowledgements Centers for Disease Control and Prevention (CDC) Carrie Shapiro Mendoza, Lena Camperlengo, Carri Cottengim, Alexa Lambert, Sharyn Parks, Christine Olson, Rosemarie Kobau, Niu Tian, and Dave Thurman National Center for the Review and Prevention of Child Death Theresa Covington, Heather Dykstra, Esther Shaw, Meghan Faulkner, Linda Potter National Institutes of Health (NIH) Jonathan Kaltman, Kristin Burns, Vicky Whittemore, and Ellen Rosenberg MPHI Data Coordinating Center and University of Michigan Biorepository Theresa Covington, Meghan Faulkner, Heather MacLeod, Mark Russell, Lauren Chapman, Heather Dykstra and Esther Shaw SDY Registry Grantees Minnesota, Nevada, New Jersey, New Hampshire, Wisconsin, Delaware, Georgia, Tennessee, San Francisco County in California, Tidewater Region of Virginia 3

26 Acknowledgements Questions? SDY Advisory Committee: Lisa Bateman, Robert Campbell, Sumeet Chugh, Laura Crandall, Sam Gulino, Gardiner Lapham, Martha Lopez Anderson, Kurt Nolte, David Thurman and Vicki Vetter SDY Autopsy Protocol Committee: Karen Chancellor, Beau Clark, Tim Corden, Kim Fallon, Corinne Fligner, Sam Gulino, Wendy Gunther, Jennifer Hammers, Owen Middleton and Michael Murphy SDY Ethicists: Amy McGuire and Sonia Suter 20 Contact Information Heather MacLeod, MS, CGC pameaesnet.org 2016 PAME CONFERENCE JUNE ALEXANDRIA, VA 4