Sudden Unexpected Death in Epilepsy - PowerPoint Presentation

Slide1

Sudden Unexpected Death in Epilepsy

Kathryn J. Swoboda, MD, FACMG

Matthew

Sweney

, MS, MD

AHCF International

Family Conference

San Francisco, CA

June 28

th

, 2012Slide2

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.Slide3

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

I

ndividuals 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 itSlide4

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, 1963Slide5

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

c

ensus data, which has its own host of problems

Taking confusion one step further…Slide6

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)Slide7

Epidemiology

Lancet

Neurol

2008 (

7

):1021-1031 Slide8

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 Slide9

Risk Factors (typically from an adult standpoint)

Epilepsy & Behavior 2009(14):280-287

Epilepsia

2011.

DOI: 10.1111/j.1528-1167.2010.02952.

xSlide10
Slide11

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):903-8Slide12

Pathophysiologic Mechanisms

Lancet 2008(7):1021-1032Slide13

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 Slide14

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 Slide15

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)

M

assive 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 Slide16

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)

:916-920

Epilepsia

2010 (11):2344-2347 Slide17

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):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 MechanismsSlide18

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):465-468 Slide19

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 Slide20

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 serotonin

ergic 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 Slide21
Slide22

What about SUDEP and AHC?

Support for diagnosis of

e

pilepsy

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 challengingSlide23

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 medicationsSlide24

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 Slide25

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