Literature Review Shows There is a Lack of Understanding of SUDEP for People with Epilepsy and Their Relations

People with epilepsy (PWE) have a two- to threefold increased chance of premature death due to the condition. Interested in exploring the first-person perspective on this topic, researchers conducted a narrative synthesis to present the qualitative insight of PWE, their family, friends, and healthcare providers (HCPs) in relation to epilepsy-related death.

A comprehensive electronic search of all peer-reviewed qualitative studies was conducted through databases using relevant keywords and Medical Subject Headings (MeSH) terms. Handsearching and exploration of pertinent gray literature was conducted thereafter. After a comprehensive literature search, the decisions of inclusion of literature were discussed and confirmed between the two authors. A total of 20 peer-reviewed papers were included. Within this, 17 were qualitative or mixed methods studies, and three were gray literature and guidelines/recommendations in discussing sudden unexpected death in epilepsy (SUDEP) with PWE and their families. The resultant main categories were the following: a) understanding of SUDEP and b) discussion of SUDEP.

Findings show that there is an overall lack of understanding of unexpected epilepsy-related death for people with epilepsy and their relations. The literature focused on the education of PWE and their family in relation to SUDEP, and therefore, there is a lack of discussion on the general topic of epilepsy-related death. Findings show the conflicting perceptions, feelings, and thought processes that occur in learning about and deciding to discuss SUDEP as a healthcare provider, person with epilepsy, or family/friend of a person with epilepsy. The literature suggests that it would be appropriate and necessary to discuss the topic of SUDEP with patients and their family members upon diagnosis.

Sudden Unexpected Death in Epilepsy Associated with Tissue Loss in Brain Areas Important in Cardiorespiratory Recovery

Objective: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Methods: Researchers retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.

Results: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.

Significance: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

CURE Discovery: Potential Genetic Link Between Epilepsy and Sudden Unexpected Death in Children

A potential link between epilepsy- and SUDEP-associated SCN1A gene variants and Sudden Infant Death Syndrome (SIDS) has been discovered by CURE Grantee Dr. Annapurna Poduri of Boston Children’s Hospital.1 Her work, generously supported by the Isaiah Stone Foundation, may provide insight into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. In Dr. Poduri’s analysis of 10 infants who died of SIDS, two children were found to have disease-associated variants in the SCN1A gene. Despite finding variants in an epilepsy-related gene and hippocampal lesions that are commonly associated with temporal lobe epilepsy, these children had no history of seizures or epilepsy.

SIDS occurs when a seemingly healthy baby dies suddenly. The sudden death of a child is a tragic occurrence and even more distressing when there is no known cause. There are several categories of this type of death: SIDS if the child is less than one year old; Sudden Unexplained Death in Childhood (SUDC) if the child is greater than one year old; and Sudden Unexpected Death in Epilepsy (SUDEP) if the child has epilepsy.

These types of childhood death are traditionally thought of as separate entities and the causes behind them are largely unknown. However, by finding a link between SIDS and SCN1A mutations,2,3 Dr. Poduri and her colleagues have deepened our understanding of the potential genetic factors behind sudden death in children. This research also suggests epilepsy genes may be more widely important in cases of sudden death in children than originally thought.

In fact, as an integral part of her CURE-funded work, Dr. Poduri and her colleagues in Robert’s Program on Sudden Death in Childhood set out to understand the genetic basis of these sudden childhood deaths, with the hypothesis that there may be a common mechanism between some cases of SIDS, SUDC, SUDEP, and epilepsy. This hypothesis is based on neuropathological abnormalities seen in the hippocampal region of approximately 40% of cases with SIDS and SUDC.4

Although typically considered rare, more children die each year from Sudden Unexplained Death in Pediatrics (SUDP), a category that includes SIDS and SUDC, than from childhood cancer or heart disease.5 Understanding the reasons behind these types of death is important in understanding how to prevent them.

Besides finding variants in the SCN1A gene in two children who died of SIDS, Dr. Poduri and her colleagues also found variants in the epilepsy-related SCN1B gene in two siblings who died suddenly and unexpectedly.6 These important findings identify additional epilepsy-related genes which may underlie some cases of sudden death in children, supporting the team’s idea that there are shared mechanisms between SIDS, SUDC, and epilepsy.

In the future, Dr. Poduri and her colleagues plan to continue their analysis of potential epilepsy-associated genetic variants, which may contribute to sudden childhood death, to better understand causes of these devastating occurrences. They are hopeful their findings will apply to children with and without epilepsy who may be at risk for sudden death. Their overall goal is to identify not only genetic risk factors for SIDS and SUDC, but also other means of identifying children at risk for sudden death. This work could lay the foundation for strategies which can be systematically implemented to prevent these deaths from occurring.

1 Brownstein CA et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018; 59(4):e56-e62.
2 Escayg A and Golding AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51(9):1650-1658.
3 Goldman AM. Mechanisms of sudden unexpected death in epilepsy. Curr Opin Neurol 2015; 28(2):166-174.
4 Kinney HC, Poduri A et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol 2016. 75(10):981-997.
6 Poduri, unpublished.

Low Interictal Hypercapnic Ventilatory Response May Increase the Risk of Severe Respiratory Depression and SUDEP After Generalized Convulsive Seizures

Featuring work by CURE Grantee Dr. Rup K. Sainju

Objective: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs).

Methods: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope for each subject was determined by linear regression. During the video–electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2, and capillary oxygen saturation (SPO2).

Results: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from 0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2. Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope.

Significance: Measurement of the hypercapnic ventilatory response is well tolerated and can be performed rapidly and safely at the bedside in the epilepsy monitoring unit. A subset of individuals has a very low sensitivity to CO2, and this group is more likely to have a prolonged increase in postictal CO2 after generalized convulsive seizures. Low interictal hypercapnic ventilatory response may increase the risk of severe respiratory depression and SUDEP after generalized convulsive seizures and warrants further study.

Low Ventilatory Response to CO2 May Increase the Risk of Severe Respiratory Depression and SUDEP After Generalized Convulsive Seizures

Study featuring the work of CURE Grantee Dr. Rup Sainju

Objective: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs).

Methods: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope for each subject was determined by linear regression. During the video–electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2, and capillary oxygen saturation (SPO2).

Results: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2. Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope.

Significance: Measurement of the hypercapnic ventilatory response [HCVR] is well tolerated and can be performed rapidly and safely at the bedside in the epilepsy monitoring unit. A subset of individuals has a very low sensitivity to CO2, and this group is more likely to have a prolonged increase in postictal CO2 after generalized convulsive seizures (GCS). Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

Brain Imaging in New SUDEP Model Reveals Map of Silenced Neural Activity After Seizure

Featuring the work of CURE Grantee Dr. Stuart Cain

In a paper published in the journal Brain, researchers have identified key aspects of fatal and non-fatal seizures. Building on CURE Epilepsy- and BC Epilepsy Society-funded research that Dr. Stuart Cain and Prof. Terrance Snutch began in 2014, the team has now identified regions of the brain that become inactive after seizures in mouse models.

Depolarization of neurons is part of the process by which signals in the brain are normally transmitted between nerve cells. However, following seizures or traumatic brain injury, a severe and long lasting “spreading depolarization” occurs which instead silences activity as it moves through specific brain regions. This new research confirms that if spreading depolarization engages the brainstem, the result is fatal.

Seizures and migraine can engage similar processes in the brain, and so the team took a model with a genetic mutation found in humans causing chronic migraines and severe seizures, then monitored brain cell swelling that occurs simultaneously with spreading depolarization in real time via diffusion-weighted magnetic resonance imaging (MRI). What they found was that during fatal seizure events, depolarization spread to the brainstem, first arresting breathing; cardiac arrest followed, leading to death within a minute of the seizure. The brainstem plays an important role in regulating cardiovascular and respiratory function. In non-fatal seizures, depolarization did not spread to the brainstem.

IT Startup Launches Software to Encourage Physician-Family Conversations About Epilepsy

Physicians can now be alerted to pediatric patients’ risk of sudden unexpected death in epilepsy, or SUDEP, during routine primary care visits by using software developed and commercialized by a researcher-entrepreneur at the Indiana University School of Medicine.

Digital Health Solutions LLC, founded by Dr. Stephen Downs, has created a module about SUDEP for its Child Health Improvement through Computer Automation, or CHICA, system. Families answer questions on an electronic tablet about several health topics, including epileptic seizures.

“For children who have seizures, CHICA asks follow-up questions about frequency, medication adherence and barriers to accessing care,” said Downs, who is the Jean and Jerry Bepko Professor of Pediatrics at the IU School of Medicine. “The program shares this information with the physician. It also makes a reminder, through the patient’s electronic health record, for the physician to discuss SUDEP with the family. The physician can document discussing SUDEP and provide computer-generated educational materials.”

Study Suggests Risk of Sudden Unexpected Death in Epilepsy (SUDEP) May Decrease Over Time

In hopeful news for people with epilepsy, those at high risk for sudden unexpected death in epilepsy (SUDEP) may move to a lower-risk category over time while those at low risk tend to stay there, suggests first-of-its-kind research being presented at the American Epilepsy Society Annual Meeting.

The study is based on a database of more than 1.4 million seizures reported by 12,402 people with epilepsy using an electronic seizure diary, SeizureTracker.com. Results of the study suggest people with epilepsy who are at high risk for SUDEP and the doctors who treat them shouldn’t assume they will remain at that risk level, and that a yearly risk assessment is a good idea. Further, those at low risk can be comforted by knowing their risk is unlikely to change, researchers noted.

To study if the risk of SUDEP can change, researchers analyzed the database from SeizureTracker.com – one of the largest groups of patient-reported seizure diaries – and found that after three years, 27 percent of patients at high risk moved out of the high-risk category. In the medium-risk group, 32.5 percent changed categories, although the analysis didn’t determine if they moved to the high- or low-risk category. Of those in the low-risk category, only 7 percent moved to a higher-risk category.

CURE Discovery: Improving Sleep

CURE Discovery: Improving Sleep with Small Environmental Changes May Decrease Seizures

Relatively small changes in environmental factors which improve the ‘internal clock’ (otherwise known as the circadian rhythm) and the quality of sleep lead to decreases in seizures in mice with similarities to Dravet syndrome, a severe form of epilepsy. These promising results are the latest findings from the lab of CURE grantee Dr. Franck Kalume of Seattle Children’s Hospital, whose grant is generously supported through the BAND Foundation.

Individuals with Dravet syndrome have problems with their circadian rhythm and with regulating their sleep.1 Upon observing that mice with similarities to Dravet syndrome have similar sleep disturbances,2 Dr. Kalume and his team set out to determine if improving circadian rhythm and sleep patterns in these mice could reduce the occurrence of seizures.

To improve circadian rhythm in the mice, the team confined either meals or exercise to nighttime, when mice are typically active. The team limited these activities during the day, when mice typically sleep. As a result of these simple changes, the team found that the mice became more active at night and less active during the day, an indication of improved circadian rhythm. The mice also showed improvements in the quality of their sleep.

Significantly, restricting these activities to nighttime led to a decrease in the incidence of irregular brain activity that is characteristic of an epileptic brain, an indication that improvements in sleep practices may improve epilepsy.

Dr. Kalume and his team next plan to confine both exercise and meals to nighttime to see if this leads to an even greater reduction of seizures. They also plan to determine the effect of these changes on the risk of sudden death in these mice, as these mice and humans with Dravet syndrome are more susceptible to Sudden Unexpected Death in Epilepsy (SUDEP).

These important results contribute to our understanding of the relationship between sleep and epilepsy and provide hope for the development of new therapies to improve epilepsy outcomes. Dr. Kalume and his team hope these studies will lead to practical steps not involving medication that individuals with epilepsy can take to improve their circadian rhythm and sleep to reduce seizures and the risk of SUDEP.

1 Licheni SH et al. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol 2018; 60(2):192-198.
2 Kalume F et al. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis. 2015; 77: 141-54.

NightWatch

High-Tech Bracelet Detects Night-Time Epilepsy Seizures

A new high-tech bracelet, developed by scientists from the Netherlands, detects 85 percent of all severe night-time epilepsy seizures. That is a much better score than any other technology currently available.

The researchers involved think that this bracelet can reduce the worldwide number of unexpected night-time fatalities in epilepsy patients.

SUDEP, sudden unexpected death in epilepsy, is a major cause of mortality in epilepsy patients. People with an intellectual disability and severe therapy resistant epilepsy, may even have a 20 percent lifetime risk of dying from epilepsy.

For the sake of comparison, the current detection standard, a bed sensor that reacts to vibrations due to rhythmic jerks, was tested at the same time. This signaled only 21 percent of serious attacks. On average, the bed sensor therefore remained unduly silent once every four nights per patient.

The Nightwatch, on the other hand, only missed a serious attack per patient once every 25 nights on average. Furthermore, the patients did not experience much discomfort from the bracelet and the care staff were also positive about the use of the bracelet.