Sudden Unexplained Death in Epilepsy (SUDEP) and Dravet Syndrome

Transcription

1 2016 DSF Biennial Family and Professional Conference Coral Gables, FL June 23-26, 2016 Sudden Unexplained Death in Epilepsy (SUDEP) and Dravet Syndrome Ronald J. Kanter, MD Director, Cardiac Electrophysiology, Nicklaus Childen s Hospital Professor Emeritus, Duke University This author has no conflicts of interest to disclose.

2 Outline Definition Clinical burden Proposed pathophysiologies Electrically unstable heart and Dravet syndrome

3 SUDEP the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death of a patient with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in which postmortem examination does not reveal a structural or toxicological cause of death. Nashef. Epilepsia 1997;38:S6-S8

4 How Big a Problem? Including all causes of death, persons with epilepsy have a 20-fold risk of sudden death compared with general population (Ficker. Neurology 1998;51:1270) SUDEP accounts for 2000 deaths in US per year (Thurman. Epilepsy Curr 2013;13:9) SUDEP accounts for 15% of all epilepsy-related deaths (Shorvon. Lancet 2011;378:2028); 60% of fatalities in Dravet syndrome (89) Incidence of SUDEP among persons having epilepsy: 0.09/1000 pt-years (unselected incident cases) -> 9.3/1000 ptyears (surgical resection candidates).or, 0.09% -> 9.3% per decade (Shorvon. Lancet 2011;378:2028) If refractory epilepsy, 35% lifetime risk (Thurman. Epilepsy Curr 2013;13:9) 5.7%-10% in Dravet syndrome (30x higher than other pediatriconset epilepsies) (Delogu. Epilepsia 52:55-8)

5 Risk Factors for SUDEP From four international case-control studies, including 289 cases and 958 controls Risk factor P value Longer duration of epilepsy <0.001 Less likely to have idiopathic epilepsy More likely to be on polypharmacy <0.001 Greater frequency of GTCS More likely to be taking lamotrigine Hesdorffer. Epilepsia 2011;52:1150-9

6 Terrence. Neurology 1975;25:594-8

7 Pathophysiology: A Role for Respiratory Dysfunction? Desaturation is common during seizures, even in those that do not generalize (Bateman. Brain 2008;131:3239) SaO2<70% in 3.6%) SaO2<90% in 34% of partial seizures Central apnea or hypopnea in 50%; obstructive apnea in 9% (Bateman. Brain 2008;131:3239) Increase in ETCO2 of 18.6=17.7 mmhg when SaO2 drops below 85% Adenosine is a known suppressor of respiratory nuclei Role of excessive endogenous adenosine release?

8 Bateman. Brain 2008;131:3239

9 Pathophysiology: A Role for Postictal Arousal Deficits? [Postictal generalized EEG suppression = PGES] GTCS causes a postictal coma-like state Relationship of seizure propagation: Into (and suppressing) ascending arousal system? Into (and suppressing) cardiovascular, respiratory, and autonomic centers in hindbrain? Each second of PGES increases risk of SUDEP by 1.7% (Lhatoo. Ann Neurol 2010;68:787) 5-hydroxytryptamine (5-HT) is neurotransmitter in the nuclei of the raphe, which projects to and stimulates respiratory control nuclei Defect in 5-HT system likely could increase risk of SUDEP

10 Adapted from: Massey. Nat Rev Neurol 2014;10:271

11 The MORTality in Epilepsy Monitoring Units Study (MORTEMUS) 16 cases of presumed SUDEP from among monitored patients All occurred after GTCS 14/16 occurred at night 14/16 occurred while prone Consistent sequence of events: Rapid breathing (18-50 breaths/minute) -> apnea -> bradycardia -> PGES -> ineffective breathing -> terminal apnea ->terminal asystole Ryvlin. Lancet Neurol 2013;12:966

12 Massey. Nat Rev Neurol 2014;10:271

13 Pathophysiology: A Role for Cardiac Dysfunction? Tachycardia (sinus) occurs in 57% of all seizures (Moseley. Epilepsia 2010;51:1219), especially during seizure generalization (hypothalamic projection & SNS stim.?) Bradycardia in only 2% of seizures; 0.5% in asystole (Moseley. Epilepsia 2010;51:1219); AV block Except in neonates, hypoxia and hypercarbia -> sinus tachycardia Ictal prolongation of QTc interval in 4.8% of seizures; ictal shortening in 3.8% (Moseley. Epilepsy Res 2011;95:237) Reduced heart rate variability (HRV): Variable findings in SUDEP patients The role of channelopathies : Many ion channels common to brain and heart

14 Low frequency High frequency

15 Gap jcn. Gap jcn. Gap jcn. Gap jcn. Ito Ikr Ikr Iks Iks Ik1 Na Ca Na Ca Na Ca Na 0 mv Phase 1 Phase 2 Phase 3-40 mv -70 mv -90 mv Phase 4 Phase 0

16 Long QT interval: Pathophysiology of ventricular tachycardia Early After-Depolarizations: Cellular hypoxia Catecholamines Other causes of intracellular calcium loading EAD EAD Etcetera Complex Intramuscular Reentry Torsade de Pointes Ventricular Tachycardia

17 SUDEP in Dravet Syndrome SCN1A gene mutation in 80% (codes for Nav1.1 channel protein) Nav1.1 exists in sinus node of mouse, rate, dogs (Maier. Proc Natl Acad Sci 2003;100:3507) In mouse model of Dravet (Nav1.1 knockout), there is decreased heart rate and decreased HRV and severe ictal-onset bradycardia (Kalume. Respir Physiol Neurobiol 2013;189:324) Another Hypothesis: Nav1.1 (reduced GABAergic interneurons) -> reduced neural traffic to cardiovagal neurons of nucleus ambiguous -> bradycardia

18 SUDEP in Dravet Syndrome: Autonomic Control of Heart Rate in Humans Dravet Epilepsy syndromes/aed Epilepsy syndromes/no AED Healthy controls Subjects Age (years) SCN1A p value QTc interval (ms) SDNN (index) VLF amplitude LF amplitude HF amplitude LF/HF From: Delogu. Epilepsia 2011;52 Authors concluded that there was reduced HRV, favoring SNS HRV (especially vagal tone) consistent with sudden death risk in many other conditions, though usually from ventricular tachyarrhythmias

19 Gene Chromosome Protein Channel LQTS1 KCNQ1 11p15.5 KvLQT1 IKs (α-sub) LQTS2 KCNH2 7q35-36 herg IKr (α-sub) LQTS3 SCN5A 3p21-24 Na+ channel INa (α-sub) LQTS4 ANK2 4q25-27 ankyrin-b (Na/Ca exch.) LQTS5 KCNE1 21q22.1 mink IKs (β-sub) LQTS6 KCNE2 21q22.1 MiRP1 IKr (β-sub) LQTS7 KCNJ2 (Andersen s synd) IKir2.1 IK1 LQTS8 Cav1.2 (Timothy synd.) l-type Ca l-type Ca LQTS9 CAV3 (Na channel ChIP) caveolin INa LQTS10 SCN4B (Na channel ChIP) β4 subunit Na ch LQTS11 AKAP9 (Ks channel ChIP) A-kinaseanchoring protein INa IKs LQTS12 SNTA1 (Na channel ChIP) syntropin (nnos/ INa SCN5A complex)

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21 Gene Channel Brugada 1 SCN5A Na v 1.5, α subunit Brugada 2 GDP1L Na v 1.5 current modulator Brugada 3 CACNA1C L-type calcium, α 1c subunit Brugada 4 CACNB2 L-type calcium, β 2b subunit Brugada 5 SCN1B Na v , β-subunit Brugada 6 KCNE3 K v 7.1, β-subunit Brugada 7 SCN3B Na v ,1.5, β-subunit Brugada 8 KCNJ8 K ir 6.1 (inward rectifier) Brugada 9 CACNA2D L-calcium, α 2d subunit Brugada 10 KCND3 K v 4.3 (transient outward) Brugada 11 MOG1 Trafficking of Na v 1.5 Brugada 12 SLMAP Brugada 13 SCN2B Na v 1.1,1.2, , β- subunit

22 Adapted from: Massey. Nat Rev Neurol 2014;10:271

23 SUDEP Prevention in Dravet Syndrome: Currently All Speculation General measures Medical or surgical control of GTCS Improved respiratory monitoring in epilepsy monitoring units Medical enhancement of 5-HT (serotonin reuptake inhibitors) Medical suppression of CNS adenosine (caffeine) Specific for Dravet syndrome Confirmation of mechanism still lacking (Bradycardia? VT/VF? Respiratory?) Parasympatholytic agents? Bradycardia pacing? Implantable cardioverter-defibrillator?

24 Thank you