Summary of NIH/NINDS SUDEP Workshop Session II, June 22, Lawrence J. Hirsch, MD Yale University New Haven, CT

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1 Summary of NIH/NINDS SUDEP Workshop Session II, June 22, 2012 Lawrence J. Hirsch, MD Yale University New Haven, CT Partners Against Mortality in Epilepsy Conference June 21-24, 2012

2 Disclosures Name of Commercial Interest Type of Financial Relationship UCB, Lundbeck, Upsher-Smith Research support GlaxoSmithKline, Upsher- Smith, Lundbeck Consultation Fees

3 Learning Objectives Understand the structure and purpose of the NIH/NINDS SUDEP Workshop Appreciate the major conclusions from the workshop.

4 Report of the Scientific Work Group of the AES-EFA Task Force on Sudden Unexplained Death in Epilepsy Scientific Work Group Members: Elson L. So, MD, Mayo Clinic, Rochester MN (Task Force Chair) Elizabeth J. Donner, MD, Hosp For Sick Children, Toronto Nina M. Graves, PharmD, Medtronic Lawrence J. Hirsch, MD, Columbia Univ Margaret P. Jacobs, Ph.D, NIH/NINDS Nancy R. Temkin, PhD, U. Washington Samuel Wiebe, MD, Foothills Med Ctr, Calgary American Epilepsy Society Annual Meeting So et al, Epilepsia 2009 CP

5 Comments on nocturnal supervision There is a single, retrospective case-control study (Langan et al, Neurology 2005) that showed signifcantly reduced risk of SUDEP with nighttime supervision (presence of an individual of normal intelligence and at least 10 y.o. in the same bedroom) or special precautions (regular checks through the night or a listening device) Additional studies are needed before these precautions can be recommended Including effect on QOL of patient and family Although devices for monitoring HR, oxygenation, and body movements are available, the ability of these devices to detect seizures or prevent SUDEP is unknown. Thus, although they warrant investigation, they can not be recommended at this point.

6 Recommendations for SUDEP prevention for now Optimize seizure control as promptly as possible Re-evaluate epilepsy diagnosis and treatment as soon as 2 AEDs have failed, or when GTC szs are frequent despite initial AED treatment Consider epilepsy surgery at that point Maximize compliance with AEDs

7 NINDS-sponsored SUDEP Workshop Scientific session co-chairs: Elson So, Jeff Noebels Sub-section moderators: Clinical Factors: Elizabeth Donner, Anne Berg Cardiorespiratory and Autonomic Mechanisms: Larry Hirsch, Martin Samuels Genetics: Alica Goldman, Michael Ackerman Case Identification: Nancy Temkin, Paul Schraeder Prevention: Nina Graves, Lina Nashef Education session co-chairs: Jeff Buchhalter, Tess Sierzant L.J. Hirsch, E.J. Donner, E.L. So, M. Jacobs, L. Nashef, J.L. Noebels, J.R. Buchhalter. Report of the NIH/NINDS workshop on sudden unexpected death in epilepsy. Neurology May 2011

8 NIH/NINDS SUDEP workshop included experts in: A. SIDS B. Sudden death in healthy adult C. Takotsubo cardiomyopathy D. Cardiac effects in acute brain injuries (subarachnoid, etc) E. Sudden death in those with heart disease F. Animal models G. Genetics

9 Potential Mechanisms Underlying SUDEP Cardiac Arrhythmias Pulmonary Central apnea Role of serotonin? Obstructive apnea Most found prone in bed Pulmonary edema Other autonomic Cerebral shutdown CP

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12 14 s of asystole; From Rugg-Gunn et al. Lancet 2004.

13 SUDDEN UNEXPECTED NEAR DEATH IN EPILEPSY: MALIGNANT ARRHYTHMIA FROM A PARTIAL SEIZURE. Espinosa, P. S. et al. Neurology 2009;72: , R MTS, right temp onset sz; 8 minute arrest, resuscitated; Back to normal

14 Repetitive hyperadrenergic state theory of SUDEP Seizure, esp GTC Hyperadrenergic state Additional seizure with hyperadrenergic state Cardiac injury Contraction band necrosis Accumulating fibrosis Conduction system injury FATAL ARRHYTHMIA

15 Respiratory Mechanisms of SUDEP Believed to account for a significant proportion of SUDEP. Postmortem findings are often unrevealing except for the frequent observation of: Pulmonary edema in patients with SUDEP Same occurs in sheep model of SUDEP In sheep model of status epilepticus with sudden death: Pronounced increases in pulmonary artery pressure and pulmonary edema at autopsy.

16 Central Apnea and SUDEP? So et al. (2000) reported a 20-year old woman who had a 56-second convulsive seizure after which she developed persistent apnea, later resulting in asystole requiring resuscitation. No evidence of airway obstruction or pulmonary edema was found in this patient. Concluded that one probable mechanism of SUDEP is marked central suppression of respiratory activity after seizures. Central + obstructive mechanisms = SUDEP?? Others have concluded this might be cerebral shutdown

17 Effect of Fluoxetine on Susceptible DBA/2 Mice 100 Control Drug Recovery 80 Respiratory arrest (%) * ** ** 0 Dose (mg/kg) No *P<0.01; **P<0.005 Tupal & Faingold: Epilepsia 47:21, 2006 CP

18 Ictal hypoxia Bateman et al, USC, Brain seizures in 56 patients with focal seizures 33% of szs had desaturation <90%, 10% <80% Of szs w/out 2 nd generalization, 35% had desat <90%, and 11% <80% Desaturations lasted about a minute Most common in temp lobe seizures and szs w/ bilat spread If present in 1 sz, tended to recur in the next In subgroup w/ proper study: 44% of seizures had central apnea, 2% obstructive, 7% mixed.

19 Lessons from SIDS: risk factors Prone position Assoc d with adverse autonomic effects, decreased arousability Smoking, pre and post birth smoke exposure Assoc d with adverse autonom effects, decr arousability Autonomic dysfunction (higher symp or lower psymp; decr HRV similar to SUDEP) Recent infection Decreased sighs, gasps, and spont arousals/decreased arousability Decreased w/ room sharing without bedsharing Similar to SUDEP

20 Lessons from SIDS: risk factors Brainstem serotonin abnl s,?>50% Genetic (~10%), most or all also now known to be expressed in brain: LQTS genes (KCNQ1) RYR2 gene (catecholaminergic VTach) SCN5A (also LQTS, Brugada)

21 Specific recommendations extrapolated from SIDS lessons Study these risks in SUDEP, including in existing cohorts/databases Retrospectively: Smoke exposure, family history sudden death or SIDS, room sharing, genetics Prospectively: Respiratory measures, arousability measures, infectious and inflammatory markers, better autonomic studies, DNA banking

22 Lessons from sudden cardiac death HR variability and baroreflex sensitivity correlate with risk (decrease is bad for both) Baroreflex sens may be better predictor; measure of dynamic vagal response rather than tonic vagal tone that HRV measures Inflammation, high CRP, fever all seem to increase risk of sudden cardiac death Genes related to arrhythmias that are also expressed in brain: KCNH2 (or HERG): LQT2 syndr; HC expression, related to glial potassium buffering SCN5A (LQT3, Brugada syndr); ANK2 (LQT4); KCNE2 (LQT6); KCNJ2 (LQT7; short QT); CACNA1C (LQT8); +++ SCN1A (SMEI) also expressed in heart

23 Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death A. M. Goldman, E. Glasscock, J. Yoo, T. T. Chen, T. L. Klassen, J. L. Noebels; Science Transl Medicine 2009 Here, we find that epilepsy occurs in mouse lines bearing dominant human LQT1 mutations for the most common form of cardiac long QT syndrome, which causes syncope and sudden death. We have shown that, in these mice, this channel is found in forebrain neuronal networks and brainstem nuclei

24 Specific recommendations learned from cardiac sudden death lessons Strongly consider EKG in all epilepsy patients Take detailed family history of sudden death in all epilepsy patients Genetic studies and cardiol referral if positive

25 Pulmonary-related recommendations Study ictal and postictal apnea, CO2 and desaturation?should be standard in epil monitoring units Study effect of stimulation of patient on resumption of breathing In animal models as well

26 Cerebral Shutdown Lhatoo et al, Annals Neurology 2010 Reviewed video-eeg-ekg monitoring results of 31 seizures from 10 patients being considered for epilepsy surgery who later died of SUDEP. Control group: 92 seizures from 30 consecutive patients undergoing similar testing as part of a pre-surgical evaluation who were still alive Postictal generalized EEG suppression was highly associated with risk of SUDEP For PGES lasting >50 seconds, the odds of SUDEP increased by a factor of 5 after adjusting for other variables; for PGES > 80 seconds, by a factor of 23. When analyzing only convulsive seizures, even PGES > 20 seconds reached significance PGES > 60 seconds was seen in 30% of the seizures (and 4/10 patients) from the SUDEP cases, but only 4% of the seizures (and 3/30 patients) in controls.

27 Mortemus study (Mortality in EMUs, Europe) Most epilepsy-monitoring unit SUDEPs (5/6 well monitored ones) seemed to be related to cerebral shutdown and/or central apnea Primary cardiac much less common but occurred (1/6; arrhythmia in postictal setting).

28 Other Recommendations from the workshop, not already mentioned Develop implantable long term device that can monitor EKG, O2 saturation or respirations, and preferably EEG with alarm Can combine with treatment once mechanism known: pacer, diaphragm or phrenic stim, brainstem stim, painful or alerting stim Consider making SUDEP a reportable condition and requiring banking of DNA Done for sudden death in kids in some states Collaborate with Nat l Assoc of Medical Examiners to increase awareness of SUDEP, autopsy rate and quality, and to refer to registry

29 Other Recommendations from the workshop, not already mentioned For those working with animal models of epilepsy: If animals die, see this as a research OPPORTUNITY, not an annoyance When studying SUDEP in animals, try and monitor respiratory (including central), cardiac, EEG [consider brain shutdown ] and autonomic function during death. Is there an animal model of cerebral shutdown? Is that what is happening with DBA2 mice? Study AEDs, devices further Study Dravet syndrome (SCN1A):?high rate of SUDEP

30 The Study All high risk patients Refractory seizures (perhaps must have refr GTCs to start) While in epilepsy unit 12-lead ECG!! Consent, bank blood/dna Cardiac monitoring, incuding ictal Autonomic eval: HRV, baroreceptor sens, valsalva Resp eval: O2 sat, including ictal/postictal; nasal and chest resp n monitors; sighs/yawns/arousability measures (SIDSlike);?full polysomnography Standardized history including fam hx of sudden death, inutero smoke exposure, sleep habits/environment, etoh/drugs Give card/bracelet w/ contact info for any medical emergency (including SUDEP) Volunteer subgroup with implanted device recording O2, EKG, EEG, resp effort CRP, postictal troponin Echocardiogram

31 The Study, cont d Annual phone f/u and repeat questionnaire Meds, drugs, compliance, sleep habits, etc IF probable or possible SUDEP: Standardized autopsy, central tissue bank --detailed cardiopulmonary exam --brainstem 5-HT --further genetic studies on tissue

32 Education and Awareness: NIH/NINDS Workshop recommendations 1. Except for patients with cultural or psychological circumstances which preclude safe discussion, it was the consensus of the discussants that the benefits of disclosing the risk of SUDEP to patients outweigh the harms. This is particularly (but not only) true in patients with generalized tonic-clonic seizures. 2. The increased risk of sudden death, including SUDEP, associated with epilepsy should be disclosed as part of the overall education and counseling to patients about their condition and prognosis of living with epilepsy.

33 SUDEP Prevention: NIH/NINDS Workshop recommendations Based on current knowledge, the most effective means of SUDEP prevention is to reduce the frequency of seizures, especially but not only generalized tonic-clonic seizures, through optimized epilepsy care, including maximizing compliance with medications, avoiding seizure triggers such as sleep deprivation and heavy ethanol use, and consideration of epilepsy surgery in appropriate candidates in a timely fashion. Preliminary evidence suggests that nocturnal supervision or monitoring devices may be protective for SUDEP, but this requires further study. Multiple other suggestions regarding education and research see full report online (

34 Task Force and Workshop Recommendation Provide education to patients and families about SUDEP Create SUDEP Registry Include central site(s) for DNA and tissue storage and analysis Create ongoing SUDEP workgroup Done, with involvement of NINDS, CURE, EF, AES, CDC, ETP/FACES

35 Impact on Clinical Care and Practice: Take Home Messages (Virtually) all patients with epilepsy should be educated about SUDEP The best prevention is maximizing control of seizures There is good evidence that cerebral shutdown and respiratory factors play a significant role in SUDEP, and that cardiac/autonomic features are involved in at least some cases. Most likely multifactorial ( perfect storm ) Research, awareness and education in this area are rapidly expanding, providing true hope for progress in preventing SUDEP

36 The End Full report of the NIH/NINDS SUDEP workshop is available at

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