sudden unexpected death in epilepsy
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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 th , 2012. What is SUDEP?. - PowerPoint PPT PresentationTRANSCRIPT
Sudden Unexpected Death in Epilepsy
Kathryn J. Swoboda, MD, FACMGMatthew Sweney, MS, MD
AHCF International Family ConferenceSan 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 centuryPosed 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
EpidemiologyMortality (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…
EpidemiologySUDEP 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 childrenConsiderably less attention paidProbably less frequent, some estimate cases range 1-
2/10,000 patient years (roughly 1/10 of adult SUDEP)Rarity makes organized studies challengingEmphasis 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 FactorsAutonomic “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 FactorsLong-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 FactorsThe 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 FactorsCerebral 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):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 thisDr. Chugani’s work has demonstrated some involvement of
the serotonergic system in AHC
Pathophysiologic MechanismsEpilepsia 2006 (1):21-26
HypothesesHypothesis 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 patientsMany 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 directionsWork 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
AcknowledgementsPatients and Families with AHCMatthew 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