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Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental Neurogenetics Laboratory Departments of Neurology, Neuroscience, Human and Molecular Genetics Baylor College of Medicine Partners Against Mortality in Epilepsy Conference June 21-24, 2012 Supported by: NIH, NINDS SUDEP Center Planning Grant Dana Foundation, Blue Bird Circle Foundation

Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

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Page 1: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Neurocardiac Mechanisms in SUDEP

June 24, 2012

Jeffrey Noebels, MD, PhD

Developmental Neurogenetics Laboratory

Departments of Neurology, Neuroscience,

Human and Molecular Genetics

Baylor College of Medicine

Partners Against Mortality in Epilepsy Conference – June 21-24, 2012

Supported by: NIH, NINDS SUDEP Center Planning Grant

Dana Foundation, Blue Bird Circle Foundation

Page 2: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Disclosure

Nothing to disclose

Page 3: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Learning Objectives

• Understand the forebrain cardiac representation and the neural bradycardia control pathway from brain to heart

• Define the search for SUDEP genes, i.e. single genes with a dual phenotype of epilepsy and sudden death

• Examine the mechanism of KVLQT1, the first validated

Lonq QT Syndrome gene for human cardiac SUDEP.

• Examine the mechanism of Kv1.1, a non-LQTS SUDEP gene

• Review the use of EKG and gene testing to predict SUD risk

Page 4: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

amygdala

cingulate

hippocampus

The ‘Neurobradycardia’ Pathway

DM n X

n.Amb XI

vagus

insula

Circuit of Papez

Why don’t all TLE cases show bradycardia?

Could it be due to a ‘second hit’?

Or a single ‘hit’ causing a dual phenotype

of seizures and sudden cardiac death?

Page 5: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Amygdala Entorhinal cortex

Brains Have ‘Heart Channels’

Scn5a

Can Ion Channel Defects Co-expressed in Heart and Brain Cause SUDEP?

Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain H.A. Hartmann, L.V. Colom, M.L. Sutherland & J.L. Noebels

Nature Neuroscience, 1999, 2:593-595

Page 6: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

SUDEP: A Dual Phenotype of

Epilepsy and Cardiac Arrhythmia

October 14, 2009 Vol 1.

SUDEP1

Decrease in “cardiac“

potassium current

KCNQ1

Page 8: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Monitored Sudep1 (KCNQ1) Terminal Event

EEG Seizure

EKG

End of Seizure

Sudden Bradycardia

Arrhythmias

Asystoles

Final Heart Beat Goldman et al, 2009

hours later

Page 9: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

KCNQ1 Potassium Channels in Vagal Nerve Nuclei

n. X

n.XI

Cortical Discharges Often Trigger “Lockstep” Cardiac Asystole

Goldman et al, 2009

EEG

EKG

~30% EEG spikes locked to asystole

~60% asystoles locked to EEG spike

Page 10: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Johnson et al, Neurology 2009 72:224-31

“Positive Seizure Phenotypes” in Genotyped LQT Syndrome Patients

98/343 (29%) of all LQT pts had a ‘seizure phenotype’

KVLQT1

25%

SCN5

25%

HERG

50%

Page 11: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

11 yr old male, no PMH, collapsed during light activity, brief seizure, recovered. Presented seizing at hospital. First EKG recorded: v fib. Unable to ressuscitate.

Case Report: KvLQT1 Molecular Autopsy

Channel Analysis: • T96R N terminus in KCNQ1

• father QTc .40; mother .45 failed to shorten with exercise. Mother also had T96R • Patch clamp of channel: unequivocal abnormal loss of function.

Clinical History:

Skinner et al. Heart Rhythm 2010

Page 12: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

SUDEP2 - Autonomic Channelopathy (not heart)

Temporal seizures, asystoles, sudden death

Vagal nodes of Ranvier

Brain + Vagus

expression Atropine blocks

arrhythmia

Page 13: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Kv1 Vagal Hyperexcitability is rescued by a KCNQ2 channel opener

In vitro axon afterdischarges

triggered

Mutant 5x more likely than +/+

Mouse vagus axons

flupirtine maleate

opens KCNQ2

analog of retigabine/ezogabine

flupirtine abolishes repetitive activity

Glasscock et al, 2012 J. Physiol.

Defect Rescue

Page 14: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Cerrone 2011

The expanding ‘QT Syndrome’ Genome

Short

Brugada - V2 Normal

EKG phenotype

Page 15: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

2/3 of cases with positive ECG not recognized in the community

96% of QT experts, but only <25% internists

correctly classify QT intervals as normal or prolonged

Our Problem:

100% not recognized in an epilepsy clinic when ECG is not done

12 lead ECG NOT ROUTINE after 1st sz or during the course of AED dose adjustment and add-on polytherapy

= large gray zone

LQTS Ascertainment may be difficult

Page 16: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Wilde et al 2002

Same patient over 1 week

V2 ST segment elevation in Brugada Syndrome is underdiagnosed

> 35% negative on 1st ECG

Do NOT expect to find it every time you look

Most important take home message:

Brugada Syndrome Ascertainment is difficult

Ikeda, 2006

Same patient over 15 minutes

Page 17: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental
Page 18: Neurocardiac Mechanisms in SUDEP - az9194.vo.msecnd.netaz9194.vo.msecnd.net/pdfs/120602/301.03.pdf · Neurocardiac Mechanisms in SUDEP June 24, 2012 Jeffrey Noebels, MD, PhD Developmental

Impact on Clinical Care and Practice

• A still unknown fraction of epilepsy patients are at risk

for cardiac arrhythmia and sudden unexpected death.

• Early recognition and treatment could decrease SUDEP

• Routine clinical evaluation of idiopathic epilepsy should

include a 12-lead ECG before, and probably after

medication change.