Sudden Unexpected Death in Epilepsy

Kathryn J. Swoboda, MD, FACMG

Matthew Sweney, MS, MD

AHCF International Family Conference

San Francisco, CA

June 28th, 2012

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.

Why talk about SUDEPThe 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

Historical Perspective

“Sudden death in a fit” has been noted in medical literature since the mid-19th century

Posed as potential cause of death for Gustave Flaubert, Prince John of Great Britain, and ancestors of Julius Caesar

Mid 20th 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

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 1.0 - 7.0 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…

Epidemiology

SUDEP pitfalls Epilepsy & Behavior 10 (2007) 363–376

Lack of autopsy means cause of death is uncertainDeath certificate reliability is often questionableCultural and religious sensitivity in reporting deathThe role of the specialist center

Excess of severe and rare cases Longevity selects out early deaths

“lost to follow up” and database linkageStudy design (prospective vs retrospective, cohort,

case-control, cross-sectional)

Epidemiology

Lancet Neurol 2008 (7):1021-1031

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

Risk Factors (typically from an adult standpoint)

Epilepsy & Behavior 2009(14):280-287 Epilepsia 2011. DOI: 10.1111/j.1528-1167.2010.02952.x

Pathophysiologic Mechanisms(Grasping at straws)

Winter weather? Hibernators have unique protective cardiovascular characteristics—what

can we learn from them?. Med Hypotheses 2008;70(5):929-32.

Lunar phase? SUDEP most common during full moon (70%) vs waxing (20%) and new

moon (10%) Epilepsy Behav. 2009 Feb;14(2):404-6

409 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):256-61

Time of day, date, international geomagnetic indices showed no correlation to SUDEP. Neurology 2000 Feb 22;54(4):903-8

Pathophysiologic Mechanisms

Lancet 2008(7):1021-1032

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):455-460

Epilepsia 2010 (5):725-737

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):455-460

Epilepsia 2010 (5):725-737

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):492-504

Cerebral Factors

Cerebral Electrical Shutdown—Brain flatlineReported exclusively in cases of LTM SUDEP (when

EEG monitoring records the death)Precedes heart rate slowing and respiratory

depressionMay be more common following grand

mal/generalized tonic-clonic seizuresProne position (face down) may increase risk—akin

to positioning influence in sudden infant death syndrome (SIDS)

Pathophysiologic Mechanisms

Epilepsia 2009 (5):916-920 Epilepsia 2010 (11):2344-2347

Genetic FactorsIncreased incidence of SUDEP in Dravet Syndrome,

an epilepsy syndrome caused by a sodium channel mutation2% of Dravet pts died from SUDEP based on IDEA

League report (cohort of 833 individuals) Epilepsia 2010 (5):1915-1918

Identification of SCN5A mutation in SUDEP case Seizure 2009 (2):158-160

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

Animal Model StudiesAdenosine 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):465-468

Animal Model StudiesDBA/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

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

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 toodetails of such cases may prove helpful in understanding

potential risk factors, but broad generalization of individual observations is VERY challenging

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

Future directions

Work with medical advisory board members and other specialist consultant to create specific guidelines for AHC patientsDiagnostic workup including laboratory and genetic

evaluationsStandard 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

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