CO2 Chemosensitivity Testing for SUDEP Risk in Epilepsy

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Iowa

Must not be taking: Opioids

Disqualifiers: Uncontrolled cardiac, pulmonary, hepatic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

335 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude people who are currently using opioids.

What data supports the effectiveness of this treatment for SUDEP risk in epilepsy?

The research suggests that abnormal chemosensing of carbon dioxide (CO2) in the brainstem may be linked to SUDEP risk in epilepsy. Testing CO2 sensitivity could help identify patients at higher risk, although direct evidence of the treatment's effectiveness in reducing SUDEP risk is not provided. ^{1 2 3 4 5}

Is the 6% CO2/50% O2/N2 gas mixture safe for humans?

The 5% carbon dioxide/95% oxygen mixture has been found to be safe in children with epilepsy, although its effectiveness was limited. However, high levels of oxygen can cause seizures in some people, especially if they have other health issues or are taking certain medications. ^{2 4 5 6 7}

How does CO2 chemosensitivity testing differ from other treatments for SUDEP risk in epilepsy?

CO2 chemosensitivity testing is unique because it focuses on measuring the body's response to increased carbon dioxide levels to identify patients at higher risk for SUDEP, rather than treating epilepsy directly. This approach is novel as it aims to find biomarkers for SUDEP risk, which currently has no standard treatment. ^{2 3 8 9 10}

What is the purpose of this trial?

The purpose of this research study is to better understand what causes Sudden Unexpected Death in Epilepsy (SUDEP). This study will enroll subjects from the University of Iowa Hospitals and Clinics (UIHC) Epilepsy Monitoring Unit (EMU) and Epilepsy Clinics. The investigators will analyze the effects of seizures on breathing, on the cardiovascular system, and on arousal. The investigators are studying these effects because some cases of SUDEP might be due, in part, to an inability to wake up or sense elevated carbon dioxide (CO2) levels when breathing is impaired. Subjects will be followed for ten years after enrollment to monitor their health.

Research Team

Brian Gehlbach, MD

Principal Investigator

University of Iowa

George Richerson, MD, PhD

Principal Investigator

University of Iowa

Eligibility Criteria

This trial is for adults aged 18-99 with confirmed or suspected epilepsy, either admitted to the Epilepsy Monitoring Unit (EMU) or receiving care at the University of Iowa Health Care Epilepsy Clinic. It's not suitable for those with uncontrolled heart, lung, liver diseases, progressive neurological conditions not related to epilepsy, current opioid users, pregnant women or those who could become pregnant without effective birth control.

Inclusion Criteria

Admission to the EMU for spell characterization (EMU group) or undergoing care in the University of Iowa Health Care Epilepsy Clinic

I have epilepsy.

Exclusion Criteria

I am a woman who could become pregnant and have not used effective birth control recently.

I do not have any uncontrolled heart, lung, or liver diseases.

I have difficulty making decisions and do not have someone to help me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Hospital Admission and Initial Testing

Participants undergo continuous VideoEEG, ECG, and noninvasive cardiorespiratory monitoring during their stay in the Epilepsy Monitoring Unit (EMU) to correlate heart rate and breathing patterns with EEG patterns related to seizures.

5 days

Inpatient stay

Outpatient Testing

Participants undergo repeat HCVR testing up to 4 times over 2 years, with some tests occurring 30 minutes, 2 hours, and 18 hours after seizures.

2 years

4 visits (in-person)

Long-term Follow-up

Participants are monitored annually for ten years through interviews and questionnaires to assess health and ascertain any occurrences of SUDEP.

10 years

Annual interviews (in-person or virtual)

Treatment Details

Interventions

• 6% Carbon dioxide/50% oxygen/balance nitrogen mixture

Trial Overview The study aims to understand what causes Sudden Unexpected Death in Epilepsy (SUDEP) by examining how seizures affect breathing and arousal. Participants will inhale a special gas mixture containing carbon dioxide and oxygen while their health is monitored over ten years.

Participant Groups

Group I: Respiratory physiology testing Experimental Treatment 1 Intervention

Subjects will wear a nosepiece and breathe through a Y-valve that allows switching from room air to two 5-liter rebreathing bags pre-filled with 50% O2, 6% CO2, and balance N2. Ventilation and respiratory gases will be measured using a pneumotachograph and rapid gas analyzers (Ultima PFX pulmonary function/stress testing system, Medical Graphics Corp). In subjects who experience clinical seizure-like activity, we will repeat the HCVR. This repeat test will occur 2 or more hours after a generalized convulsive seizure (GCS). We will repeat the HCVR at least 30 minutes after a non-GCS. Finally, we may repeat the HCVR at least 18 hours after the last seizure (GCS or non-GCS). It is anticipated that some subjects may exhibit frequent seizures that necessitate the adjustment of this schedule. Subjects may also be asked to sniff, hold their breath, and breathe through tubes of different sizes.

Who Is Running the Clinical Trial?

University of Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

Findings from Research

A case study of a patient with temporal lobe epilepsy revealed that focal seizures can lead to significant central apnea and oxygen desaturation, highlighting a potential risk factor for sudden unexpected death in epilepsy (SUDEP).

The patient's death from SUDEP occurred without any convulsive activity, suggesting that ictal hypoxia can happen in non-convulsive seizures, emphasizing the need for awareness of this risk in epilepsy management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ictal central apnea as a predictor for sudden unexpected death in epilepsy. Schuele, SU., Afshari, M., Afshari, ZS., et al.[2011]

Individuals with epilepsy (PWE) showed greater brainstem BOLD activations during hypercapnic breathing challenges compared to healthy controls (HC), particularly in the dorsal raphe, suggesting abnormal chemosensing related to respiratory control.

PWE exhibited increased connectivity between brainstem structures during hypercapnia, indicating potential dysfunction in respiratory regulation that could contribute to the risk of sudden unexpected death in epilepsy (SUDEP).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy. Hampson, JP., Lacuey, N., Rani, MS., et al.[2023]

The study measured the hypercapnic ventilatory response (HCVR) in 68 epilepsy patients, finding that a low HCVR is associated with a higher risk of prolonged postictal hypercapnia after generalized convulsive seizures (GCSs), which may increase the risk of severe respiratory depression and sudden unexpected death in epilepsy (SUDEP).

The HCVR measurement was safe and well-tolerated, indicating it can be a useful bedside tool in epilepsy monitoring units to identify patients at greater risk for respiratory complications following seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ventilatory response to CO2 in patients with epilepsy. Sainju, RK., Dragon, DN., Winnike, HB., et al.[2021]

In a study involving rats with implanted EEG electrodes, carbamazepine showed a dose-related protective effect against seizures induced by hyperbaric oxygen exposure, while ethosuximide did not provide any protection.

The findings suggest that carbamazepine could be an effective preventive treatment for oxygen-induced seizures during hyperbaric oxygen therapy, highlighting its potential role in enhancing safety during such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of carbamazepine and ethosuximide on hyperoxic seizures. Reshef, A., Bitterman, N., Kerem, D.[2019]

A case study of a combat diving candidate revealed unexpected symptoms of central nervous system oxygen toxicity (CNS-OT) while breathing pure oxygen with elevated carbon dioxide levels, highlighting the risks associated with hypercapnia during diving.

Despite the candidate exhibiting signs like severe headache, nausea, and facial muscle twitching, further medical examinations showed no neurological abnormalities, indicating that CNS-OT can occur even under controlled conditions, which has not been previously documented in literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptoms of central nervous system oxygen toxicity during 100% oxygen breathing at normobaric pressure with increasing inspired levels of carbon dioxide: a case report. Eynan, M., Arieli, Y., Taran, B., et al.[2021]

Inhaled 5% carbon dioxide/95% oxygen was well tolerated by all six children with non-convulsive status epilepticus (NCSE) during a 120-second treatment, with no significant adverse effects or changes in blood gas levels observed.

Despite being well tolerated, the treatment showed limited and transient effects on EEG normalization and did not result in any clinical improvements, indicating that its efficacy as an anticonvulsant in this context is questionable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5% Carbon Dioxide is safe but of limited efficacy as a treatment for paediatric non-convulsive status epilepticus: An open label observational study. Forsyth, R., Martland, T., Lai, M., et al.[2018]

In a review of seven seizure cases among five patients undergoing hyperbaric oxygen therapy, all patients had pre-existing medical conditions or were on medications that could lower their seizure threshold, such as chronic obstructive pulmonary disease and narcotic withdrawal.

The findings suggest that patients with certain risk factors, including specific medications and medical comorbidities, may be more susceptible to oxygen toxicity seizures during hyperbaric oxygen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions. Seidel, R., Carroll, C., Thompson, D., et al.[2013]

In a study involving 20 female Long-Evans rats, the activation of oxygen-conserving reflexes (OCRs) during seizures led to sudden death in 18 of the rats, mimicking physiological conditions observed in human cases of sudden unexpected death in epilepsy (SUDEP).

The study found that terminal central apnea and significant drops in mean arterial pressure preceded death, indicating that the induced reflexes during seizures can cause fatal outcomes, while nonseizing control rats did not experience fatal effects from similar reflex activations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ictal activation of oxygen-conserving reflexes as a mechanism for sudden death in epilepsy. Biggs, EN., Budde, R., Jefferys, JGR., et al.[2023]

In a study of 33 patients with localization-related epilepsy, significant increases in end-tidal CO₂ (ETCO₂) were observed during and after seizures, indicating severe respiratory disturbances that could contribute to the risk of sudden unexpected death in epilepsy (SUDEP).

The study found that while there were prolonged increases in ETCO₂ levels, postictal respiratory effort was not impaired, suggesting that ictal hypoxemia may be linked to ventilation-perfusion mismatch rather than direct respiratory failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory changes with seizures in localization-related epilepsy: analysis of periictal hypercapnia and airflow patterns. Seyal, M., Bateman, LM., Albertson, TE., et al.[2010]

Postconvulsive central apnea (PCCA) was observed in 22.1% of generalized convulsive seizures (GCS) and may serve as a clinical biomarker for sudden unexpected death in epilepsy (SUDEP), particularly since it was present in cases of near-SUDEP and one probable SUDEP case.

Postictal hypoxemia occurred in 86% of GCS, but early administration of oxygen significantly improved recovery of oxygen saturation levels, highlighting the importance of timely oxygen therapy in managing postictal hypoxemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers for SUDEP: Are We There Yet? King-Stephens, D.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ictal central apnea as a predictor for sudden unexpected death in epilepsy. [2011]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Ventilatory response to CO2 in patients with epilepsy. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The effect of carbamazepine and ethosuximide on hyperoxic seizures. [2019]

5. Australia pubmed.ncbi.nlm.nih.gov

Symptoms of central nervous system oxygen toxicity during 100% oxygen breathing at normobaric pressure with increasing inspired levels of carbon dioxide: a case report. [2021]

6. England pubmed.ncbi.nlm.nih.gov

5% Carbon Dioxide is safe but of limited efficacy as a treatment for paediatric non-convulsive status epilepticus: An open label observational study. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Ictal activation of oxygen-conserving reflexes as a mechanism for sudden death in epilepsy. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Respiratory changes with seizures in localization-related epilepsy: analysis of periictal hypercapnia and airflow patterns. [2010]

10. United States pubmed.ncbi.nlm.nih.gov

Biomarkers for SUDEP: Are We There Yet? [2020]