Epilepsy is associated with significant risks of morbidity and death-Orrin Devinsky MD N Engl J Med 2011;365:1801-11.

It pays to have a cardiologist as a friend. They talk to you about those life and death matters-the real killer. The term is ‘sudden death’, it’s a chilling phrase, more specifically it’s now termed, ‘sudden, unexpected, seizure-induced death.’ Last Saturday a close cardiologist friend tells me about this article in the new England Journal of Medicine, just recently published this year in November 10 issue volume 365 on pages 1801-1811. The essence of the article is a summation of what I have been trying to teach myself over the past dozen years or so. Did you read my blog post about the three visits to Toronto to Dr. Duncan Stewart whose lab I worked in during my first sabbatical., twelve years ago? I will quickly recapitulate. On the first visit I made a fool of my self to the Head of Cardiology at the University of Toronto, the same Dr Duncan Stewart, trying to push the then undocumented idea that epilepsy is linked to possible cardiac-pulmonary failure occurring with excess seizure activities. Basically Dr Stewart kicked me out of his office, with the admonishment of, “You have no evidence to make such rash claims !” I felt chastened, since I have neither formal training in neurology nor cardiology but here I was advocating a neurocardiac link with epilepsy. The word neurocardiac was not even being used twelve years ago, imagine my impetuosity !

Before my second Toronto visit I spent the night up in the Royal York with all my PubMed research papers trying to get the link in my head about how if you are completely starved if you have epilepsy, the starvation state will stop the seizures. Incredibly this knowledge is even mentioned in the Bible! So I was trying to make sense of the link between stopping seizures with the state of the heart at the time of the imposed starvation. I kept pacing in that hotel room when I got one of those amazing epiphany insights: anorexia causes some heart problems, that are called QT elongation by the cardiologists that I found on PubMed in the early hours that morning. So when I paid my second visit to Dr Stewart I pretended I had not made any progress on my brain-heart link trying to fathom the novel approach of epilepsy affecting the heart. As he was about to explode at me in his office, basically wasting his time, I slid a few anorexia-heart anomaly PubMed papers across his desk, “Here read these you’re a cardiologist, what do you think ?” I asked. The silence hit me, as I thought , ‘I think I just got his attention.’ “What’s this all about he?” he grimaced with clenched teeth at me. I started to make my point, “Dr Stewart if it’s true that epilepsy can have the seizures stopped by complete starvation what happens to the heart at the same time as starvation?” I explained that’s what happens when usually young girls arrive at a hospital Emerg ER with a bad EKG tracing until they get some good nutrition going with apparently no harmful after affects on their hearts. Until they do it again.

Basically the point I was making is that despite stopping a seizure with starvation the heart is dragged into the issue, as an observation. “Mike I think you are onto the beginning of something, check it out.”

My final third visit with Dr Stewart in Toronto was  showing him a clinical paper describing a lady who visited the Emerg of a Paris Hopital presenting with a bad bunch of seizures. She was hooked up to an EKG machine just as she experienced one of her seizures. Her EKG was going arrhythmic, BINGO I finally had some solid brain-heart/neurocardiac evidence of the heart pacing decoupling during the start of a seizure. I think I had opened Dr Stewart’s eyes to the fact that Nature drags the heart into the disease of epilepsy.

So to read today this New England Journal opf medicine paper that states the kind of observation that I have been working on over the last twelve years is, well gratifying. I mean I’ve been trying to to see if there is this brain-heart link or failed link happening with each seizure which seems to be the current concept conclusion of Dr. Orrin Devinsky.

Now as readers of my blog what have I been suggesting about where these brain-heart controlled anomalies are located? Let me quote Dr Devinsky now. His first comment is how poorly the magnitude of this brain-heart problem with seizure is, ” The magnitude of the problem of sudden, unexpected death in epilepsy is unrecognized in the medical and lay communities. In a population-based cohort of children with epilepsy who were followed for 40 years, sudden, unexpected death occurred in 9% of patients and accounted for 38% of all deaths.” Despite millions of hours of video EEG, (electroencephalogram) ambulatory recordings of epilepsy patients, not one witnessed death has occurred while being recorded.

“Respiratory Factors
The concept of impaired respiration as a cause of death is supported by data from studies in animals and evidence from most witnessed and recorded  instances of sudden, unexpected death in epilepsy (Table 2).27,28-33 Seizure-induced respiratory changes can be lethal and may involve pulmonary dysfunction and suppression of brainstem respiratory and arousal centers.40 In sheep, prolonged seizures cause elevated pressure in the left atrial and pulmonary arteries, pulmonary edema, tachycardia, and death from hypoventilation. 42 Serotonergic neurons that modulate breathing and arousal may be involved in sudden, unexpected death in epilepsy, as is the case with sudden infant death syndrome.40,43 Some serotonergic neurons stimulate respiratory nuclei in the brain stem, whereas others, activated by hypercapnia, contribute to the ascending arousal system.44 Postictal depression of serotonergic activity can impair respiration and reflexive repositioning if the mouth and nose are obstructed by bedding. In some mouse strains, sound-induced seizure arrests respiration — an effect that is reduced by selective serotoninreuptake inhibitors (SSRIs) and 5-HT2C–receptor agonists.45 Among patients with epilepsy, use of an SSRI is associated with reduced oxygen desaturation during partial seizure but not during tonic– clonic seizure.46″

I’ve taken the liberty to quote entirely from Dr Devinsky’s article, notice he has specifically zoomed in on arousal centers, breathing control centers both located in and near the brain stem, specifically what i have referred to as the medulla. Looks to me like I got the observation right way back when now these other guys are catching up to the neurocardiac point of  exposing a brain-heart decoupling with each seizure.

Now lets get to the guts of this sudden death event, what Dr Devinsky calls CEREBRAL SHUTDOWN, to what I call- the train wreck of a fatal seizure. “Seizure and the postictal state can affect brainstem respiratory centers. Central apneas or hypopneas complicate most seizures.38 In one study, patients with epilepsy who died suddenly had longer periods of postictal generalized EEG suppression than did patients with epilepsy who did not die suddenly.21 Respiration depends on brain-stem activity; prolonged suppression of activity stops respiration. Postictal shutdown of cerebral and brain-stem function may be related to the mechanisms that stop seizures. Postictal hypercapnia and hypoxemia can occur despite increased respiratory effort, possibly from ventilation–perfusion inequality, which is caused by right-to-left pulmonary shunting or neurogenic pulmonary edema.47 Sudden, unexpected death has been reported in a patient with epilepsy who had postictal pulmonary edema.36 Postictal hypercapnia can cause severe acidosis that is arrhythmogenic.48 The effects of prolonged postictal EEG suppression, apnea, pulmonary shunting and edema, suffocation in the prone position, impaired arousal to hypercapnia, laryngeal spasm, and respiratory acidosis probably combine and cascade with cardiac factors to cause many cases of sudden, unexpected death in patients with epilepsy.”

Next Dr Devinsky outlines the specific cardiac changes, here they are: ” Cardiac events are considered to be likely culprits in some instances of sudden, unexpected death in patients with epilepsy. 4,11,12,30,48,49 Seizure-induced arrhythmias occur in animals and humans,49,50 but in 13 case studies of near and actual sudden
death in patients with epilepsy, only 1 incident was clearly due to a cardiac event.30 Hypoxemia could lower the threshold for cardiac arrhythmias during seizure, especially in patients with channelopathies affecting both brain and cardiac tissue (e.g., long-QT syndrome type 2).51 Mice lacking the Kv1.1 potassium channel have severe seizures and die prematurely, possibly because of cardiac arrhythmias. 48 Interictal and ictal cardiovascular changes occur in patients with epilepsy,49,50 including prolongation of the QT interval corrected for heart rate (QTc) during the ictal and interictal periods and shortening of the QTc interval postictally. (This is my anorexia insight of QT elongation ) 52-54 Ictal asystole occurs during video EEG
in 0.1 to 0.4% of patients, but recurrence is rare after pacemaker implantation.49,55 Patients with epilepsy who die suddenly have rates of cardiac repolarization abnormalities and arrhythmias
that are similar to those among other patients with epilepsy,22,53 but sudden death is associated with more severe tachycardia during nocturnal seizures. 22 Intense seizures may cause greater activation of the sympathetic nervous system, possibly contributing to cardiopulmonary dysfunction56 and to prolonged suppression of brain activity,38 which can in turn cause apnea and impair arousal while the heart functions independently. Intense seizures may also trigger greater compensatory responses (e.g., elevated adenosine levels), and these responses may contribute to sudden death.57″

Notice Dr Devinsky is mentioning specific cardiac events although during the seizure the brain stem zones appear to be affected which has been exactly my point all along. The above part highlighted in bold is as if from a portion of our working hypothesis concerning our actual observation of neurocardiac decoupling implicating the tight deregulation, decoupling of the sympathetic/parasympathetic balance that appears to be controlled in the brain stem/medulla.

Dr Devinsky drwas attention to some other risk factors such as,” Since greater interictal autonomic changes occur in patients with chronic epilepsy than in those with recent-onset epilepsy,35 there may also be progressive changes in the brain-stem areas that regulate cardiorespiratory function and arousal. However, sudden death can occur early in the course of epilepsy and in patients who have seizures only rarely. It is not known why sudden death occurs
in some patients after only a few seizures, whereas others are spared despite a lifetime of tonic– clonic seizures. Genetic susceptibility (e.g., cardiac channelopathy), alcohol use, medication withdrawal, and fever may increase the risk of sudden death after a seizure, but these potential risk factors have not been adequately studied. Regarding genetic susceptibility, mutations in the ion channel genes expressed in brain and cardiac tissue may underlie susceptibility to epilepsy, brainstem autonomic dysfunction, and cardiac arrhythmias.”5

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Montreal Grandmother, Agnes Kent was saved by Raul Wallenberg from certain death, when he provided papers for her and her Mom to escape away from the Nazis. Today when asked what that escape meant, she replied,"Remind people, that while statesmen and whole countries remained silent and did nothing, a single individual chose to act, with ramifications that proved enormous. Similar choices confront us today. Write that simple truth she said, it can never be repeated often enough because the world keeps forgetting it."
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