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.

Epilepsy Society, UCL, and Congenica Join Forces in Genomic Study to Identify Causes of Unexpected Deaths in Epilepsy

Congenica announced a key partnership with the UK’s Epilepsy Society to study the genomics of sudden unexpected death in epilepsy (SUDEP). The new collaboration aims to improve the clinical understanding, prediction and treatment of the devastating and unpredictable condition, which affects approximately 1 in 1,000 adult and 1 in 4,500 pediatric patients with epilepsy every year.

SUDEP, which often occurs while epilepsy patients are asleep, is thought to be caused by a complex interaction of genetic factors rather than a single gene. As part of the partnership, an initial joint study will look at a cohort of 100 SUDEP clinical cases to better understand the condition’s underlying genetic causes. The multi-disciplinary research team will include scientists from the Epilepsy Society and members of Prof Sanjay Sisodiya’s clinical research team at UCL (University College London), alongside Congenica’s clinical scientists.

Acid Reflux Induced Laryngospasm as a Potential Mechanism of Sudden Death in Epilepsy

Objective: Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve.

Approach: We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long?Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter.

Main results: In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls.

Significance: The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans.

SUDEP and Seizure Safety Communication: Assessing if People Hear and Act

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death among people with chronic epilepsy. People with intellectual disability (ID) are overrepresented in this population. The SUDEP and Seizure Safety Checklist (“Checklist”) is a tool to discuss risk factors influencing seizures and the risk of SUDEP. It includes questions about the availability of nocturnal monitoring. In Cornwall UK, people with epilepsy and ID and their relatives and carers are routinely advised to consider nocturnal surveillance to reduce harm from potential nocturnal seizures. We assessed the retention of advice provided on nocturnal monitoring and if there were differences between those in residential care and those living with their families.

METHODS: A postal questionnaire was sent to carers of all people with epilepsy and ID in Cornwall followed by the adult specialist ID epilepsy service. All those who were contacted had received the same advice on SUDEP and nocturnal monitoring at least once in the past year. Each person was categorized into living in a residential setting or with their family group. Intergroup differences were compared using Fisher’s exact test.

RESULTS: Carers for 170 people were contacted and 121 responded (71%). The family group had statistically more nocturnal seizures than the residential group. While there was no difference in the awareness of SUDEP, the groups differed in their recollection of the person-centered discussion of risk with carers in residential setting being less aware. Where nocturnal monitoring advice was given, it was followed, and previously unknown seizures were identified in 75%.

CONCLUSIONS: Carers in residential settings are less likely to recall specific person-centered discussion of risks to the individual they support as compared with those living with families, although general awareness of SUDEP and implementing advice such as nocturnal monitoring is present equally in both groups. In improving detection of nocturnal seizures, audio monitoring may be a useful strategy to reduce risk of harm for people with intellectual disability.