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We read with great interest the report by McLean and Wimalaratna . They describe the death during ambulatory EEG monitoring of an adult female epileptic patient. A significant finding was an abruptly “flat line” EEG,
and the authors suggested that the cerebral electrical shutdown may have been the cause of death.
We have been studying the autonomic and cardiovascular consequences of sei...
We have been studying the autonomic and cardiovascular consequences of seizure activity in rats and have observed this same phenomenon in animals that die. The mechanism for death in these animals is a profound bradyarrhythmia with mechanical cardiac dysfunction that results in
hypoperfusion of the brain, and ultimately hypoperfusion of the heart . These changes result from a massive combined activation of the parasympathetic and sympathetic divisions of the autonomic nervous system that is driven by the seizures and can be compounded by respiratory
obstruction. We have also shown that abrupt decreases in cerebral perfusion via transient carotid artery occlusion are sufficient to abort seizure activity and “flat line” the EEG .
Changing blood flow (e.g. carotid occlusion) and lowering blood oxygen content (e.g. respiratory obstruction) are both processes that can rapidly terminate seizure activity. Transient unilateral or bilateral carotid
occlusion terminated seizure activity in the ipsilateral hemisphere or bilaterally in seconds . Seizures combined with respiratory obstruction or re-breathing
air from a balloon caused cardiovascular dysfunction that terminated seizure activity on a timescale of many seconds to minutes . In either case, a flat line EEG was not the cause of death. Death resulted from acute cardiac
dysfunction caused by massive autonomic overactivity. Spontaneous breaths during flat line EEG and the reversibility of the brain state are additional evidence that the “core” brain functions are intact.
The Figure gives an example of an animal with seizures in a life-threatening condition that includes a period of flat line EEG. Recovery from the flat line EEG condition is emphasized by the return of seizure activity which occurs because of the presence of a systemic convulsant (kainic acid, 10 mg/kg ia). These experimental studies indicate that a flat line EEG signals a cardiac state wherein the brain is inadequately perfused. Shortly after
the onset of this state, the condition of the heart itself will be in jeopardy. The whole process takes seconds to minutes depending on the intensity of the seizure activity and associated conditions such as respiratory obstruction.
Is the flat line EEG a harbinger of death? The answer depends entirely on whether one has the ability to remove the conditions causing a flat line EEG.
In the case of transient carotid occlusion, once blood flow was restored, brain activity recovered in seconds. In the case of autonomic overactivity causing
cardiovascular dysfunction leading to hypoperfusion of the brain, the two sources of drive for the autonomic overactivity, the seizures themselves and any respiratory obstruction, need to be eliminated. In the animal model,
it is clear that the seizure activity is aborted by the processes that flat-line the EEG, but cardiovascular dysfunction continues in the face of respiratory
obstruction. If ventilation is restored, the EEG can be restored. If ventilation is not restored, the flat line EEG will signal imminent death from cardiac failure. In a mouse model of sudden death, exposure to an oxygen-rich
environment prevented death . If it is possible to maintain ventilation, or if ventilation is never compromised, one must address the seizure activity.
The fact is we have seen very few seizures that, by themselves, have the ability to cause cardiac failure, so preserving ventilation is arguably, by itself, sufficient
to prevent death.
“Flat line” EEG in a rat model of death during seizures. Urethane anesthetized rats receiving kainic acid as a convulsant have recurring limbic cortical seizures [2 3]. Intense seizure activity or seizures combined with
asphyxia produce a profound bradycardia and cardiac dilatation leading to hypoperfusion of the brain, the termination of ongoing seizure activity, and eventually a flat line EEG. The top panel shows the full experiment and specific times are highlighted below. The set of sweeps in each panel are, from top to bottom: arterial blood pressure, ECG, EEG, and a pressure transducer on the ventilator tubing. The output of the ventilator produces
upward deflections, and spontaneous “pulling” against the closed air system produces downward deflections. The horizontal bar at the bottom of the top panel shows the time during which the ventilator was stopped. This is
also apparent as the switch from positive to negative deflections on the ventilation record. The seizure continues for a short time after the ventilator has stopped (panel 2, bottom), but is arrested in less than 1 minute (panel 3,bottom), and the EEG is a flat line by panel 4. Bradycardia and AV block are evident in panel 4. As the force of the attempts to inspire increased
(larger negative deflections) there were larger movement artifacts in the ECG and EEG recordings (panel 4, bottom). The combination of restored ventilation and seizure suppression permitted recovery of cardiac performance and brain perfusion, with recovery of brain activity (in this case, additional seizures).
Calibrations are: BP, 20 mm Hg; ECG, 1 mV; EEG, 2 mV; ventilator, 20 mm Hg; and time, 5 sec. Data were collected together with Dr. Harumi Hotta of
the Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
1. McLean BN, Wimalaratna S. Sudden death in epilepsy recorded in ambulatory EEG. J Neurol Neurosurg Psychiatry 2007;78(12):1395-7.
2. Sakamoto K, Saito T, Orman R, Koizumi K, Lazar J, Salciccioli L, et al.
Autonomic consequences of kainic acid-induced limbic cortical seizures in rats: peripheral autonomic nerve activity, acute cardiovascular changes, and death. Epilepsia in press.
3. Saito T, Sakamoto K, Koizumi K, Stewart M. Repeatable focal seizure suppression: a rat preparation to study consequences of seizure activity based on urethane anesthesia and reversible carotid artery occlusion. J
Neurosci Methods 2006;155(2):241-50.
4. Venit EL, Shepard BD, Seyfried TN. Oxygenation Prevents Sudden Death in Seizure-prone Mice. Epilepsia 2004;45(8):993-6.