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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
Disclosure
Nothing to disclose
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
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?
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
SUDEP: A Dual Phenotype of
Epilepsy and Cardiac Arrhythmia
October 14, 2009 Vol 1.
SUDEP1
Decrease in “cardiac“
potassium current
KCNQ1
Mice with human KvLQT1 mutations display brain expression and seizures
Both mutations cause loss of KvLQT1 current and LQT
T311I/+ A340E/+
KCNQ1 channels in brain
Mouse
Human
Goldman et al, 2009
Seizures
Monitored Sudep1 (KCNQ1) Terminal Event
EEG Seizure
EKG
End of Seizure
Sudden Bradycardia
Arrhythmias
Asystoles
Final Heart Beat Goldman et al, 2009
hours later
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
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%
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
SUDEP2 - Autonomic Channelopathy (not heart)
Temporal seizures, asystoles, sudden death
Vagal nodes of Ranvier
Brain + Vagus
expression Atropine blocks
arrhythmia
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
Cerrone 2011
The expanding ‘QT Syndrome’ Genome
Short
Brugada - V2 Normal
EKG phenotype
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
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
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.