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Sudden Unexpected Death in Epilepsy Kathryn J. Swoboda, MD, FACMG Matthew Sweney, MS, MD AHCF International Family Conference San Francisco, CA June 28.

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Presentation on theme: "Sudden Unexpected Death in Epilepsy Kathryn J. Swoboda, MD, FACMG Matthew Sweney, MS, MD AHCF International Family Conference San Francisco, CA June 28."— Presentation transcript:

1 Sudden Unexpected Death in Epilepsy Kathryn J. Swoboda, MD, FACMG Matthew Sweney, MS, MD AHCF International Family Conference San Francisco, CA June 28 th, 2012

2 What is SUDEP? Sudden, unexpected, witnessed or unwitnessed, non- traumatic, and non-drowning death of a subject affected by epilepsy, with or without evidence for a seizure Autopsy does not reveal a structural or toxicological cause of death.

3 Why talk about SUDEP The International AHC community has unfortunately witnessed several deaths of AHC children and adults over the past decade Some of these deaths were entirely unexpected, not preceded or accompanying unusually severe events, and sometimes occuring during sleep Individuals with neurologic and neurodevelopmental disorders have an increased risk for injury or death or illness due to their disabilities, ie aspiration or accidental trauma Understanding when, where and why death or injury occurs in some children and/or adults is critical for our community in order to minimize this problem and to understand it

4 Historical Perspective “Sudden death in a fit” has been noted in medical literature since the mid-19 th century Posed as potential cause of death for Gustave Flaubert, Prince John of Great Britain, and ancestors of Julius Caesar Mid 20 th century “As far as longevity is concerned, the patient should definitely understand that epilepsy per se rarely causes death and that there is no reason why an epileptic should not live as long as he would if he did not have epilepsy”— Dr. Samuel Livingstone, 1963

5 Epidemiology Mortality (Death) in Epilepsy Often categorized by epilepsy type and age category Standardized Mortality Ratio (SMR) for epilepsy = ratio of observed deaths to expected deaths, ranges in epileptic patients Lancet Neurol 2006; 5: 481–87 Challenges of Bias Epilepsy & Behavior 10 (2007) 363–376 x cases of death in epilepsy/y total cases of death from other causes Inaccurate numerator (e.g. inaccurate x  Mis- or missed diagnosis of epilepsy) Inaccurate denominator (e.g inaccurate y  total causes of death in general) Y is derived from census data, which has its own host of problems Taking confusion one step further…

6 Epidemiology SUDEP pitfalls Epilepsy & Behavior 10 (2007) 363–376 Lack of autopsy means cause of death is uncertain Death certificate reliability is often questionable Cultural and religious sensitivity in reporting death The role of the specialist center Excess of severe and rare cases Longevity selects out early deaths “lost to follow up” and database linkage Study design (prospective vs retrospective, cohort, case- control, cross-sectional)

7 Epidemiology Lancet Neurol 2008 (7):

8 SUDEP in children Considerably less attention paid Probably less frequent, some estimate cases range 1- 2/10,000 patient years (roughly 1/10 of adult SUDEP) Rarity makes organized studies challenging Emphasis on identifying underlying heart problems, promoting medication compliance (see following slides) Children with seizures and neurologic handicap have higher mortality rate in general, but influence on SUDEP rate is not clear Camfield and Camfield. Sem in Pedi Neuro 2005 (12):10-14

9 Risk Factors (typically from an adult standpoint) Epilepsy & Behavior 2009(14): Epilepsia DOI: /j x

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11 Pathophysiologic Mechanisms (Grasping at straws) Winter weather? Hibernators have unique protective cardiovascular characteristics—what can we learn from them?. Med Hypotheses 2008;70(5): Lunar phase? SUDEP most common during full moon (70%) vs waxing (20%) and new moon (10%) Epilepsy Behav Feb;14(2): probable SUDEP showing some evidence supporting link between temperatures and season in SUDEP Epilepsia 2010 May;51(5):773-6 Geomagnetic forces? In rats with limbic epilepsy, 10% died following exposure to sham EM field, 60% of died after exposure to natural EM fields Int J Biometeorol 2005 Mar;49(4): Time of day, date, international geomagnetic indices showed no correlation to SUDEP. Neurology 2000 Feb 22;54(4):903-8

12 Pathophysiologic Mechanisms Lancet 2008(7):

13 Cardiac/Autonomic Factors Autonomic “storm” or influences on heart during an epilpetic seizure Brain (i.e. seizure) related influences on heart rate R hemisphere helps contribute to fast heart rate Tachycardia is nearly universal pre, ictal, or post Associated with mesial temporal lobe epilepsy May predispose to ictal atrial fibrillation (heart rhythm abnormality occurs during an actual seizure event) L hemisphere helps contribute to slow heart rate Bradycardia (reduced heart rate) during seizure <5% of pts Asystole (heart stops) during seizure <1% of pts May be underestimated, as most of the time, spontaneous recovery occurs Pathophysiologic Mechanisms Seizure 2010 (19): Epilepsia 2010 (5):

14 Cardiac Factors Long-standing (chronic epilepsy) influences on heart rhythm Inter-beat interval (QTc) prolongation/shortening Seizure drugs may affect QT variability (GBP, LTG may prolong?) Erratic inter-beat interval (i.e. large QT dispersion) places one at risk for reentry arryhthmias (irregular heart beats) Heart Rate Variability (how nimble is your heart rate??) HRV lower in chronic epilepsy patients, resulting in loss of vagal tone and possible increased likelihood of irregular heart rhythms Some specific AEDs may influence HRV (CBZ,PHT associated with low heart rate during seizure) Vagal Nerve Stimulator and HRV—role is unclear Pathophysiologic Mechanisms Seizure 2010 (19): Epilepsia 2010 (5):

15 Respiratory Factors The brain (i.e. seizure) influence on respiratory rate Saturations <90% in 20-30% of all seizures Hypoxemia seen with carbon dioxide retention in some sz May be protective to some degree—stimulates respiratory drive Brain-induced fluid in the lungs (Neurogenic Pulmonary Edema) Massive adrenaline surge results in fluid accumulation in lungs Witnessed SUDEP typically occurs minutes rather than hours following seizure (based on unfortunate cases in epilepsy monitoring units Brain-induced airway tightening (i.e. Laryngospasm) Pathophysiologic Mechanisms Nature Reviews Neurology 2009 (5):

16 Cerebral Factors Cerebral Electrical Shutdown—Brain flatline Reported exclusively in cases of LTM SUDEP (when EEG monitoring records the death) Precedes heart rate slowing and respiratory depression May be more common following grand mal/generalized tonic-clonic seizures Prone position (face down) may increase risk—akin to positioning influence in sudden infant death syndrome (SIDS) Pathophysiologic Mechanisms Epilepsia 2009 (5): Epilepsia 2010 (11):

17 Genetic Factors Increased incidence of SUDEP in Dravet Syndrome, an epilepsy syndrome caused by a sodium channel mutation 2% of Dravet pts died from SUDEP based on IDEA League report (cohort of 833 individuals) Epilepsia 2010 (5): Identification of SCN5A mutation in SUDEP case Seizure 2009 (2): Expressed in both the brain and heart—the only case in which a mutated channel is expressed in both locations Long QT type 2 (VGKC mutation = voltage gated potassium channel) has higher association with epilepsy phenotypes than LQT 1 and 3 Pathophysiologic Mechanisms

18 Animal Model Studies Adenosine Mouse Model Adenosine is endogenous anticonvulsant produced by the body under extreme duress Impaired adenosine clearance can potentially lead to decreased ventilatory rate and apnea (cessation of breathing) Excess adenosine production combined with decreased clearance has lead to death in mouse models Adenosine receptor antagonist (caffeine) can extend survival time. Could be synergistic to drugs we use to control seizures No studies of this in humans Pathophysiologic Mechanisms Epilepsia 2010 (3):

19 Animal Model Studies DBA/2 Mice and audiogenic (sound-induced) seizures 88% with respiratory arrest following audiogenic seizure (remaining 12% can be induced with cyproheptadine—a serotonin blocker) Mice treated with SSRIs (pro-serotonin drugs) resulted in decreased rates of respiratory arrest and increased rates of survival Highlights the potential interaction between seizures and respiratory/arousal centers, which are dependent on serotonin No studies in humans regarding this Dr. Chugani’s work has demonstrated some involvement of the serotonergic system in AHC Pathophysiologic Mechanisms Epilepsia 2006 (1):21-26

20 Hypotheses Hypothesis for post-ictal death Post-ictal state may be due in part to stunning of serotonin-related systems Depression of serotonin-generating neurons could lead to ictal and/or postictal hypoventilation (decreased respiratory rate/effort) Genetic susceptibilities with bad luck (e.g. prone position) may prevent compensatory response (respiratory drive or arousal) Seizure/depression/SUDEP phenotype?—may be associated with activity of serotoninergic systems in brain and/or brainstem Some have hypothesized whether SSRIs may prove protective— unfortunately no answers Pathophysiologic Mechanisms Epilepsia 2011 (Suppl. 1):28-38

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22 What about SUDEP and AHC? Support for diagnosis of epilepsy in ~50% of AHC patients Many children/adults have infrequent seizures which are easily controlled with standard epilepsy medications, but status epilepticus also occurs Unclear what role specific mutations relevant in AHC may play in risk for SUDEP, cardiac arrhythmias, or neurotransmitter regulation Catastrophic deaths in AHC have other causes too details of such cases may prove helpful in understanding potential risk factors, but broad generalization of individual observations is VERY challenging

23 Management Issues Medication Compliance—suggests the importance of adhering to prescribed treatments for epilepsy, and early treatment intervention for generalized seizures Need for Bed Monitors/Supervised sleeping/“Back to sleep”—unclear; however, sleep study to rule out sleep-disordered breathing may be indicated in some cases Anticonvulsant medication selection and potential interaction with genetic factors Pacemakers indicated in rare cases identified with ictal bradycardia or asystole associated with episodes (slowing or stopped heartrate) VNS protective or harmful?—trade off between improved seizure control and disruption of vagal tone SSRIs? Caffeine?—unproven Provision of oxygen with prolonged seizure activity or spells in which oxygen levels drop below 90% for prolonged periods Consider asking your doctor about need to monitor oxygen levels if your child has color changes around lips or obvious changes in breathing patterns with any type of spells, or in association with trials of new medications

24 Future directions Work with medical advisory board members and other specialist consultant to create specific guidelines for AHC patients Diagnostic workup including laboratory and genetic evaluations Standard of care guidelines Definitions for types of episodes How to grade episodes and recommendations for interventions including monitoring safety for feeding and breathing during episodes How to prepare for seizures, and understand risks of associated seizure disorders/status and age of your child

25 Acknowledgements Patients and Families with AHC Matthew Sweney, MS, MD; Aga Lewelt MD; Sandy Reyna MD; Abby Smart RN; Tara Newcomb, MS, LCGC The national and international AHC foundations, who are the primary liasons to families and the key to our future success in effectively diagnosing, managing, and treating the many symptoms of AHC


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