Mechanisms and prevention of acid reflux induced laryngospasm in seizing rats

Budde, Ryan; Pederson, Daniel J.; Biggs, Ethan N.; Jefferys, John G. R.; Irazoqui, Pedro P.

doi:10.1016/j.yebeh.2020.107188

Cited by 13 publications

(18 citation statements)

References 69 publications

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“…As seen in Figure 3c-e seizure activity increases over a period of 60 min after KA injection, with increasing power of high frequency EEG signals. Similar to previous studies[20,21,37] we observe that KA can significantly change breathing patterns (Figure 3f). We see an increase in respiration rate from baseline (80.6 ± 20.8 breaths/min) to a rapid, irregular rate (140.5 ± 67.6/min).…”

Section: Resultssupporting

confidence: 92%

“…MRI scans also revealed that for surviving rats, there was no detectable stomach fluid in the esophagus (6 out of 11 animals). This further strengthens the hypothesis of acid reflux having a causal relationship with sudden deaths and aligns well with our previous observations[20,37].…”

Section: Discussionsupporting

confidence: 93%

“…The Stewart group and other researchers established previous data linking seizure physiological markers to laryngospasm, respiratory distress, and sudden death in this model [16,20,21,34,37,73]. The results in this experiment are mostly concordant, but there are a few .…”

Section: Accordance and Disagreements With Previous Resultssupporting

confidence: 61%

“…Previous studies in an acute kainic acid (KA) model of seizure activity in rats revealed sudden death might originate from laryngospasm due to gastric acid reflux [20,37]. Additionally, it was observed that blocking of acid reflux (esophageal blocking with balloon catheter, gastric vagotomy, or fasting) eliminated sudden death.…”

Section: Introductionmentioning

confidence: 99%

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Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

Mandal¹,

Budde²,

Lawlor³

et al. 2021

Preprint

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Sudden death in epilepsy, or SUDEP, is a fatal condition that accounts for more than 4000 deaths each year. Limited clinical and preclinical data on sudden death suggests critical contributions from autonomic, cardiac, and respiratory pathways. Recent animal (rat) studies on kainic acid induced seizure models explored a potential mechanism for such sudden and severe cardiorespiratory dysregulation being linked to acid reflux induced laryngospasm. Here, we expand on those previous investigations and utilize a multimodal approach to provide visual evidence of acid reflux-initiated laryngospasm and subsequent fatal cardiorespiratory distress in seizing rats.We used systemic kainic acid to acutely induce seizure activity in Long Evans rats, under urethane anesthesia. We recorded electroencephalography (EEG), electrocardiography (ECG), chest plethysmography and esophageal pH signals during simultaneous fast MRI scans of the rat stomach and esophagus. MRI images, in conjunction with electrophysiology data were used to identify seizure progression, stomach acid movement up the esophagus, cardiorespiratory changes, and sudden death.In all cases of sudden death, esophageal pH recordings alongside MRI images visualized stomach acid movement up the esophagus. Severe cardiac (ST segment elevation), respiratory (intermittent apnea) and brain activity (EEG narrowing due to hypoxia) changes were observed only after acid reached the larynx, which strongly suggests onset of laryngospasm following acid reflux. Additionally, absence of stomach acid in the esophagus of animals that survived acute seizure, provided evidence of a causal relationship between acid reflux and sudden death. The complimentary information coming from electrophysiology and fast MRI scans provided insight into the mechanism of esophageal reflux, laryngospasm, obstructive apnea, and subsequent sudden death in seizing animals. The results carry clinical significance as they outline a potential mechanism that may be relevant to SUDEP in humans.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 93%

Section: Accordance and Disagreements With Previous Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

Mandal¹,

Budde²,

Lawlor³

et al. 2021

Preprint

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show abstract

“…For all calculations and analysis, t = 0 was set at the start of the mist. In a procedure similar to prior work, 38 chemoreflex rats were mounted supine in a stereotaxic frame with a 3D printed feeding tube inserted into the mouth. A laryngoscope mounted on a GoPro camera modified by the company BackBone visualized the larynx.…”

Section: Methodsmentioning

confidence: 99%

Ictal activation of oxygen‐conserving reflexes as a mechanism for sudden death in epilepsy

et al. 2021

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Objective To test the hypothesis that death with physiological parallels to human cases of sudden unexpected death in epilepsy (SUDEP) can be induced in seizing rats by ictal activation of oxygen‐conserving reflexes (OCRs). Methods Urethane‐anesthetized female Long‐Evans rats were implanted with electrodes for electrocardiography (ECG), electrocorticography (ECoG), and respiratory thermocouple; venous and arterial cannulas; and a laryngoscope guide and cannula or nasal cannula for activation of the laryngeal chemoreflex (LCR) or mammalian diving reflex (MDR), respectively. Kainic acid injection, either systemic or into the ventral hippocampus, induced prolonged acute seizures. Results Reflex challenges during seizures caused sudden death in 18 of 20 rats—all MDR rats (10) and all but two LCR rats (8) failed to recover from ictal activation of OCRs and died within minutes of the reflexes. By comparison, 4 of 4 control (ie, nonseizing) rats recovered from 64 induced diving reflexes (16 per rat), and 4 of 4 controls recovered from 64 induced chemoreflexes (16 per rat). Multiple measures were consistent with reports of human SUDEP. Terminal central apnea preceded terminal asystole in all cases. Heart and respiratory rate fluctuations that paralleled those seen in human SUDEP occurred during OCR‐induced sudden death, and mean arterial pressure (MAP) was predictive of death, showing a 17 or 15 mm Hg drop (MDR and LCR, respectively) in the 20 s window centered on the time of brain death. OCR activation was never fatal in nonseizing rats. Significance These results present a method of inducing sudden death in two seizure models that show pathophysiology consistent with that observed in human cases of SUDEP. This proposed mechanism directly informs previous findings by our group and others in the field; provides a repeatable, inducible animal model for the study of sudden death; and offers a potential explanation for observations made in cases of human SUDEP.

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Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study

et al. 2023

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BackgroundThe incidence of gastroesophageal reflux disease (GERD) has been shown to be elevated in individuals with epilepsy. Traditional observational studies have led to a limited understanding of the effects of GERD and BE on epilepsy due to the interference of reverse causation and potential confounders.MethodsWe conducted a bidirectional two‐sample Mendelian randomization (MR) analysis to determine whether GERD and BE can increase the risk of epilepsy. Genome‐wide association study data on epilepsy and its subgroups were obtained from the International League Against Epilepsy consortium for primary analysis using three MR approaches and the FinnGen consortium for replication and meta‑analysis. We calculated causal estimates between the two esophageal diseases and epilepsy using the inverse‐variance weighted method. Sensitivity analysis was conducted to detect heterogeneity and pleiotropy.ResultsWe found a potential effect of genetically predicted GERD on the risk of epilepsy (odds ratio [OR] = 1.078; 95% confidence interval [CI], 1.014–1.146, p = .016). Specifically, GERD showed an effect on the risk of generalized epilepsy (OR = 1.163; 95% CI, 1.048–1.290, p = .004) but not focal epilepsy (OR = 1.059, 95% CI, 0.992–1.131, p = .084). Notably, BE did not show a significant causal relationship with the risks of generalized and focal epilepsy.ConclusionsUnder MR assumptions, our findings suggest a potential risk‐increasing effect of GERD on epilepsy, especially generalized epilepsy. Considering the exploratory nature of our study, the association between GERD and epilepsy needs to be confirmed by future prospective studies.

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Mechanisms and prevention of acid reflux induced laryngospasm in seizing rats

Cited by 13 publications

References 69 publications

Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

Ictal activation of oxygen‐conserving reflexes as a mechanism for sudden death in epilepsy

Causal relationship between gastroesophageal reflux disease, Barrett's esophagus, and epilepsy: A bidirectional Mendelian randomization study

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