Checklist and Inventory

Past studies have highlighted the possible role of 17 factors associated with increased risk of SUDEP, some of which are potentially modifiable. These form the background of the seizure and SUDEP safety checklist. This is a 10-minute risk assessment tool which can be used in daily practice in epilepsy clinics for screening patients who are at high risk of developing SUDEP. These checklists are also available on mobile applications. ^{Reference Shankar, Newman, McLean, Anderson and Obe18–20} However, no critical analysis of checklists and inventories is available till date.

These factors include sleeping in prone position, unclear treatment history, primary generalized epilepsy, increasing seizure frequency, compliance issues, alcohol problem, subtherapeutic antiepileptic drug (AED) levels, lack of night surveillance, duration >15 years, early-onset epilepsy, frequent AED changes, use of anxiolytic medication, intellectual disability (ID), male gender, patients on antidepressants and on carbamazepine, and increasing seizure severity. ^{Reference Shankar, Newman, McLean, Anderson and Obe18–20}

Of the 17 risk factors, 7 are potentially modifiable. These are unclear treatment history, poor adherence to medication, subtherapeutic medication levels, alcohol misuse, no night surveillance, sleeping in the prone position, and increasing seizure frequency (p < 0.001). Non-modifiable risk factors included duration of epilepsy and the presence of GTCSs. ^{Reference Shankar, Walker and McLean21}

In a study on the association between SUDEP-7 inventory and HRV, the SUDEP-7 score was found to be inversely and significantly associated with HRV. The results suggest that older age, longer duration of epilepsy, and the presence of ID may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. ^{Reference Novak, Miller, Markovic, Meymandi and DeGiorgio22,Reference DeGiorgio, Miller and Meymandi23}

Genetic Factors

Understanding the genetic basis for SUDEP is important in identifying patients and family members at risk. In a recent study, an exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes was performed in 61 patients with SUDEP. ^{Reference Bagnall, Crompton and Petrovski24} De novo mutations were identified in 28/61 cases (46%). Four patients (7%) had mutations in common genes responsible for long QT syndrome, 9 (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes, and 15 (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis. DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes identified. ^{Reference Bagnall, Crompton and Petrovski24}

EEG Markers

Postictal generalized EEG suppression (PGES) is the term used for diffuse EEG “flattening” after seizure cessation. It is defined as postictal unilateral or bilateral EEG suppression of >1-second duration occurring immediately or within 30 seconds of seizure cessation with an amplitude of <10 mV. ^{Reference Lhatoo, Faulkner, Dembny, Trippick, Johnson and Bird25} PGES is usually seen after GTCS. In a retrospective study of 48 epilepsy cases, 27% (13) of those who had GTCS had PGES followed by postictal slowing. ^{Reference Seyal, Bateman and Li26} The reported occurrence of PGES after convulsive seizures is 40%–60% in patients with generalized convulsive seizures as compared to 1%–2% in cases with focal seizures. ^{Reference Lhatoo, Faulkner, Dembny, Trippick, Johnson and Bird25,Reference Urges, Strzelczyk, Scott, Walker and Sander27}

In some SUDEP patients, EEG recordings after terminal seizures had demonstrated PGES. ^{Reference Donner, Camfield, Brooks, Buchhalter, Camfield and Loddenkemper3,Reference Pensel, Nass, Taubøll, Aurlien and Surges7} These findings have initiated the debate over its potential role as a predictor of future SUDEP risk and also in the pathophysiology of SUDEP, wherein the initiating event is considered as “electrocerebral shutdown.”

Longer duration (> 50 seconds) PGES are associated with increased risk of SUDEP. ^{Reference Novak, Miller, Markovic, Meymandi and DeGiorgio22,Reference Urges, Strzelczyk, Scott, Walker and Sander27} Children with PGES had higher SUDEP-7 scores than children without PGES. ^{Reference Lhatoo, Faulkner, Dembny, Trippick, Johnson and Bird25} Increased risk of PGES in children has been noted in sleep, with shorter duration of clonic phase, symmetric tonic extension posturing, and terminal burst suppression after seizure. ^{Reference Donner, Camfield, Brooks, Buchhalter, Camfield and Loddenkemper3}

Nocturnal Supervision

Past studies have highlighted the role of nocturnal supervision for detecting seizures and reported it to be protective. ^{Reference Pensel, Nass, Taubøll, Aurlien and Surges7,Reference Langan, Nashef and Sander35,Reference Nashef, Fish, Garner, Sander and Shorvon36} Combined use of nocturnal supervision with seizure detection devices may enable more effective seizure detection, but evidence to prevent SUDEP is lacking.

Disadvantages of nocturnal supervision include high false-positive or negative detection rates, effect on quality of life issues, and cultural acceptance. In addition, one must also be aware of the fact that the intervention by a witness does not necessarily preclude the occurrence of SUDEP. Though turning the patient from prone to recovery position after GTCS may reverse respiratory compromise, more effective resuscitation may be needed.

Seizure Detection Devices

A variety of seizure detection devices are currently available. Though these may be effective in detecting seizures, some are marketed as being helpful to prevent SUDEP though the evidence for the same is lacking. Use of these devices should be individualized according to patient preference, seizure profile (nocturnal, generalized, and frequency), and overall risk of SUDEP. More extensive clinical investigation and trials are needed to find out their appropriate role in the SUDEP prevention algorithm. ^{Reference Pensel, Nass, Taubøll, Aurlien and Surges7}

Prone Position and SUDEP

SUDEP cases are more often found prone, but extrapolating this observation to sleeping prone as a contributing factor has no supportive evidence. A recent systematic review and meta-analysis of 253 cases of SUDEP reported that approximately 73.3% of patients were found in prone position (95% confidence interval [CI] 5 65.7%, 80.9%, p < 0.001). Prone position was observed in 85.7% (95% CI 5 74.6%, 93.3%) of patients aged < 40 years of age (95% CI 5 74.6%, 93.3%). The likely possible mechanism suggested is that turning to prone position during GTCS followed by postictal apnea (commonly associated with PGES) leads to obstructive apnea. In addition, prone position is associated with impaired arousal. ^{Reference Liebenthal, Wu, Rose, Ebersole and Tao37} However, as the prone positioning occurs during the seizure, a “back-to-sleep campaign,” such as that for SIDS prevention, may not be very helpful. Most experts believe that individuals with epilepsy turn in their sleep or turn with a GTCS making the bedtime sleep position irrelevant.

For SUDEP prevention, if the seizure is witnessed, turning patient from prone to lateral recovery position and stimulating the patient may help.

Safety Pillows

Latex safety pillows (ventilated foam pillows) may reduce the contribution of prone position toward postictal cardiorespiratory distress and prevent obstructive apnea. ^{Reference Pensel, Nass, Taubøll, Aurlien and Surges7,Reference Devinsky38} However, no studies are available to support their role in SUDEP prevention.

Serotonergic Drugs – SSRI

Lower brainstem serotoninergic nuclei play an important role in the regulation of respiration. Serotonin neurons in the brainstem sense rising carbon dioxide and low pH, thereby stimulating breathing and arousal. ^{Reference Richter, Manzke, Wilken and Ponimaskin39} Abnormalities of serotonergic neurons have been previously reported in SIDS and in a mouse model of SUDEP, thereby highlighting possible role of selective serotonin receptor inhibitors (SSRIs) for SUDEP prevention. ^{Reference Pensel, Nass, Taubøll, Aurlien and Surges7,Reference Uteshev, Tupal, Mhaskar and Faingold40–Reference Faingold, Tupal and Randall42} Use of SSRIs may decrease the risk of potential apnea.

In animal studies, fluoxetine has been shown to prevent the occurrence of fatal seizure-induced apnea in SUDEP. ^{Reference Faingold, Randall, Mhaskar and Uteshev41–Reference Faingold, Randall, Zeng, Peng, Long and Feng44} . In a retrospective study, it was seen that postictal hypoxemia was significantly less frequent in patients with drug refractory partial epilepsy receiving SSRIs as compared to those who were not on SSRIs. ^{Reference Batemal, Li, Lin and Seyal45}

Two double-blind, randomized, placebo-controlled trials (NCT02569970, NCT02929667) are underway (results awaited) to assess the efficacy of Fluoxetine against seizure-induced central apnea.

Reduce Adenosine and Endogenous Opioid-Induced Brainstem Depression