Recurrent cerebellar ischemic infarctions and stereotyped peri-ictal sympathetic responses in a near-SUDEP patient with cardiovascular risk factors

Highlights • Troponin and leukocyte elevations could signal SUDEP risk in some epilepsy patients.• Inpatient neurologists may be necessary to discern near-SUDEP cases from sudden cardiac arrests.• Epileptic convulsions may exhibit patient-specific stereotypical sympathetic responses.• SUDEP pathophysiology may affect the posterior cerebral vasculature.


Introduction
A sudden unexpected death in epilepsy (SUDEP) diagnosis is typically assigned postmortem when a patient with known epilepsy dies suddenly and unexpectedly following one or more epileptic seizures and there are no alternative explanations, such as trauma, drowning, status epilepticus, or myocardial infarction, to explain his or her demise. [1] Most inpatient physicians are unaware of SUDEP, not only because of its retrospective and complex diagnostic criteria, but also because SUDEP victims are typically brought to the attention of pathologists, not clinicians. Yet, a diagnosis of ''near-SUDEP," [1] also called ''resuscitated SUDEP," [2] should be given when epilepsy patients who experience cardiac arrest immediately after a seizure are resuscitated and survive at least one hour. As this clinical scenario invariably requires intensive care unit (ICU) management, inpatient physicians are probably exposed to near-SUDEP victims much more frequently than they might expect. A timely recognition of such patients not only allows for an accurate diagnosis, but also presents a unique opportunity to investigate the pathophysiological clues that terminal seizures [3] might leave behind on imaging studies and blood tests. The present manuscript describes a patient with a history of cardiovascular disease who experienced a cardiac arrest immediately after a witnessed unknown onset bilateral tonic clonic seizure (GTCS). A near-SUDEP diagnosis was not reached until a neurology consultant uncovered what amounted to a history of untreated epilepsy. The subsequent workup and chart review suggest that the patient's cardiac arrest was precipitated by a combination of cardiovascular risk factors and a semiological, or stereotyped, peri-ictal sympathetic response.

Case presentation
A 60-year-old woman with a past medical history of paroxysmal atrial fibrillation (PAF), hypertension, hyperlipidemia, and obesity, (BMI 40.5 kg/m 2 ) but no known history of sleep apnea suffered a GTCS during which copious pink froth dripped from her mouth. A close friend who had spent the morning with her, and who had witnessed the seizure, activated emergency medical services (EMS) and reported that she had acted normally until the onset of her seizure. Upon arrival, emergency medical technicians (EMTs) observed postictal combativeness followed by cyanosis, and by a pulseless electrical activity (PEA) cardiac arrest that required five minutes of cardiopulmonary resuscitation (CPR) until the return of spontaneous circulation (ROSC). Because an attempt to intubate in the field failed, she was ventilated via bag-valve mask during transport to the ED where endotracheal intubation was successful. Soon after, she experienced a ventricular fibrillation cardiac arrest which transitioned to PEA and required six minutes of CPR, defibrillation, and two rounds of intravenous epinephrine until ROSC. She was started on vasopressors and transferred to the ICU. Her physical examination at that point demonstrated cyanosis, diffuse rhonchi and wheezes on auscultation and complete unresponsiveness to voice and pain. Her pupils were equal but non-reactive to light and her tone was flaccid. The initial chest X-ray showed severe bilateral pulmonary edema ( Fig. 1A), while serial bloodwork showed transient elevations of both troponin I (Fig. 2) and peripheral leukocytes (Table 1.). Collateral information obtained by a neurology consultant on the second hospital day uncovered a years-long history of frequent stereotyped episodes of unresponsive staring followed by several minutes of confusion and difficulty speaking. She had never sought medical attention for these episodes, which had become more frequent in recent months. A brain MRI performed four days after admission revealed global cerebral anoxic injury ( Fig. 1 B-C) and a punctate right cerebellar ischemic infarction ( Fig. 1 D-E). Faced with a dismal prognosis, her family opted to withdraw artificial life sustaining measures. An autopsy was not performed.
A subsequent chart review showed that sixteen months earlier she had been transported to the ED after coworkers heard a yelp and uninterpretable noises emanating from the office bathroom. After forcing the door open, EMTs found her on the floor, appearing combative and unable to speak or to follow commands. She was tachycardic, hypertensive and tachypneic. Her coworkers reported that she had acted normally that morning around the office. Given her sudden symptoms, she was triaged as a code stroke, but her mental status and language ability improved en route to the hospital where a stroke neurologist documented an initial score of zero on the National Institutes of Health Stroke Scale. She had no recollection of the event. Curiously, at that time, too, her workup demonstrated mild troponin I (Fig. 2) and peripheral leukocyte elevations ( Table 1) that closely resembled those of her current hospitalization. In addition, the MRI of the brain during that admission also demonstrated an acute right cerebellar ischemic infarction in the same vascular territory (Fig. 1 F-G). A cardiac event monitor placed at discharge demonstrated several runs of atrial fibrillation within ten days. She was prescribed apixaban for this condition, but she did not take it. There was no evidence of infection or myocardial ischemia during either hospitalization but a CT of the Fig. 1. Neurogenic pulmonary edema, anoxic brain injury and recurrent ischemic infarctions in a near SUDEP patient. A: Chest X-ray taken shortly after ED arrival following a witnessed GTCS that culminated in cardiac arrest. The image shows florid bilateral postictal neurogenic pulmonary edema. The letter R in the X-ray image refers to the patient's right side. B-G: Diffusion weighted imaging and apparent diffusion coefficient correlates demonstrating diffuse anoxic brain injury (B-C) and two small cerebellar ischemic infarctions, one diagnosed during the patient's near-SUDEP hospitalization (D-E) and one during an earlier hospitalization, sixteen months earlier, for a presumed GTCS (F-G). Note the adjacent location of the two ischemic infarctions within the same cerebellar vascular territory. Black and white arrows show the ischemic infarctions' DWI and ADC signals, respectively. chest and a CT angiogram of the head and neck, performed during her earlier hospitalization, showed diffuse coronary and carotid artery atherosclerosis (Table 1). Relevant data for both hospitalizations are shown in Table 1.

Discussion
To our knowledge, this is the first report of cerebellar ischemic infarctions occurring concurrently with GTCSs, one of which resulted in a near-SUDEP diagnosis. It is not possible to establish whether the patient's ischemic infarctions provoked her seizures, or vice versa, or whether the strokes occurred completely independently from the GTCSs. Unlike acute cortical infarctions, acute cerebellar infarctions are not considered triggers for early epileptic convulsions. [4] Given the PAF diagnosed after her earlier hospitalization, her ischemic infarctions could also be explained by cardioembolisms occurring before or during the GTCSs. Alternatively, the vascular territory affected could have been susceptible to infarction due to hypoxemia during the GCTSs, or due to hypoperfusion during her cardiac arrest. In the setting of her cardiovascular risk factors, such susceptibility could result from focal atherosclerosis, or, alternatively, from a predisposition to vasospasm in the affected vessels. The latter could be induced by catecholamines released into circulation during GTCSs, [5] as could her troponin I and leukocyte elevations. [6,7] Thus, the coexistence of acute ischemic infarction, troponin elevations and leukocytoses after each GTCS suggests that this patient experienced semiological, or stereotyped, ictal or peri-ictal sympathetic (i.e., catecholaminergic) responses, which might have played a role in her peri-ictal cardiac arrest.

Conclusion
This is the first report of apparently simultaneous and recurrent postictal cerebellar ischemic infarctions, troponin I elevations and mild leukocytoses in a near-SUDEP patient. Taken together, these findings suggest that stereotyped sympathetic responses might play a role in the pathophysiology of SUDEP, and that, in epilepsy patients with cardiovascular risk factors. postictal troponin I elevations and leukocytoses might signal an increased SUDEP risk.

Ethical Statement
All the authors mentioned in the manuscript have agreed to be authors, have read and approved the manuscript, and have given consent for submission and subsequent publication of the manuscript.