Tuesday, January 17, 2017

SUDEP mechanisms

Dlouhy BJ, Gehlbach BK, Richerson GB. Sudden unexpected death in epilepsy:basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry. 2016 Apr;87(4):402-13. 

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. The substantial lifetime risk of SUDEP and the lack of a clear pathophysiological connection between epilepsy itself and sudden death have fuelled increased attention to this phenomenon. Understanding the mechanisms underlying SUDEP is paramount to developing preventative strategies. In this review, we discuss SUDEP population studies, case-control studies, witnessed and monitored cases, as well as human seizure cardiorespiratory findings related to SUDEP, and SUDEP animal models. We integrate these data to suggest the most probable mechanisms underlying SUDEP. Understanding the modifiable risk factors and pathophysiology allows us to discuss potential preventative strategies.

From the manuscript 

SUDEP likely occurs through multiple mechanisms. However, evidence from witnessed and monitored EMU SUDEP cases suggests that a majority of patients have substantial respiratory dysfunction at the initial stages of the terminal event. Prolonged respiratory difficulty is often not an early symptom of sudden cardiac death, but is instead typically followed by an increase in ventilation and then gasping. Therefore, it is unlikely for SUDEP to be caused principally by a primary cardiac mechanism in which seizure-induced autonomic dysfunction of the heart leads to a lethal arrhythmia. Additionally, the fact that many patients are found prone in bed suggests that this position plays a role in the pathophysiology. The prone position where the face may be covered by pillows or blankets likely predisposes to worsening ventilation and oxygenation during respiratory dysfunction. This position also suggests a loss of arousal by patients, as they do not sense the alarm of rising CO2 levels. Therefore, we suggest SUDEP may commonly occur by seizure-induced hypoventilation and/or apnoea with oxygen desaturation and loss of arousal, where being prone worsens oxygenation, resulting in secondary autonomic cardiac dysfunction and lethal bradyarrhythmias. Although yet to be found, genetic mutations may predispose epilepsy patients to worsening oxygen desaturation during seizures. Additionally, cardiac arrhythmias and dysfunction may be more likely to occur during periods of seizure-induced oxygen desaturation in patients with congenital LQTS or other genetic mutations, including ion-channel mutations. Other causes of SUDEP may include primary cardiac arrhythmias from seizure activated autonomic pathways.

Prevention of respiratory changes

Preventing or minimising seizure-induced apnoea, hypoventilation and oxygen desaturation may preclude the secondary autonomic response, cardiac abnormalities and death. As discussed previously, fluoxetine and several other, but not all selective serotonin reuptake inhibit (SSRIs), reverse respiratory arrest in a mouse model of epilepsy. Translating this finding to humans, Bateman et al found that seizure-induced oxygen desaturation was significantly reduced in 87 seizures in 16 epilepsy patients taking SSRIs compared to 409 seizures in 57 epilepsy patients not taking SSRIs. Further study is needed to determine whether taking SSRIs is effective at preventing SUDEP. Supervision at night may be effective in decreasing SUDEP, presumably by allowing repositioning during seizures, inducing arousal and therefore stimulating breathing. In a retrospective study of 39 patients with  generalised convulsions, early peri-ictal nursing intervention was associated with a reduced duration of respiratory dysfunction and PGES. The institution of routine respiratory monitoring may prevent in-hospital deaths and ultimately lead to the identification of high-risk patients. Wearable and portable pulse oxygen saturation seizure alarms may provide a similar type of benefit, allowing family, friends or others to be alerted and to therefore reposition the patient for optimal breathing. The development of a diaphragmatic pacemaker  that becomes activated during periods of prolonged apnoea or oxygen desaturation could also be of benefit. Treating obstructive sleep apnoea using a continuous positive airway pressure device or with an upper airway implantable stimulation device could also decrease SUDEP risks by mitigating a contributing SUDEP risk factor for epilepsy patients.

Prevention of cardiac changes

The events leading to cardiac arrhythmias, asystole and cardiac failure are uncertain, but as discussed previously, occur either secondary to respiratory dysfunction or from primary seizure-induced autonomic cardiac effects. Regardless, preventing the bradyarrhythmias, asystole or tachyarrhythmias associated with these autonomic changes, may prevent death. In patients presenting initially with concerns of seizures and possibly epilepsy, ECG evaluation is critical as syncopal episodes from LQTS can be misdiagnosed as seizures. Additionally, as noted, some patients with congenital LQTS have epilepsy as well. These patients may be at high risk for SUDEP. Treating the LQTS may prevent sudden death in these patients. Multiple case reports have implanted cardiac pacemakers after finding substantial periods of ictal asystole. However, no large study of epilepsy patients with an implanted automatic implantable cardioverter defibrillator (AICD) has been conducted demonstrating prevention of SUDEP. It would not be prudent to implant cardiac pacemakers and cardiac defibrillators in all epilepsy patients. Further knowledge is needed to refine which patients are at highest risk, as these patients may benefit from an AICD. However, if the initiating and primary event that leads to cardiac dysfunction is respiratory dysfunction, cardiac pacing or defibrillation will not correct the oxygen desaturation leading to autonomic changes. In these cases, if oxygen saturation is not improved, maintaining a normal heart rhythm may prove challenging. An on-demand diaphragmatic pacemaker may be an effective way to prevent the hypoventilation that can occur in some patients after a seizure.

Michalak Z, Obari D, Ellis M, Thom M, Sisodiya SM. Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia. Neurology. 2017 Jan 13. pii: 10.1212/WNL.0000000000003584. doi:10.1212/WNL.0000000000003584. [Epub ahead of print]

To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP.
Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen-antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers.
Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivity for inflammatory reaction, BBB leakage, and HIF-1α in SUDEP cases was not different from that seen in control groups.
This study represents a starting point to explore by immunohistochemistry the mechanisms underlying SUDEP in human brain tissue. Our approach highlights the potential and importance of considering immunohistochemical analysis to help identify biomarkers of SUDEP. Our results suggest that with the markers used, there is no clear immunohistochemical signature of SUDEP in human brain.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/01/17/sudden-unexpected-death-in-epilepsy-inflammation/7011143/?category=latest&page_id=2

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