Perspectives on the basis of seizure-induced respiratory dysfunction

Mulkey, Daniel K.; Milla, Brenda M

doi:10.3389/fncir.2022.1033756

Cited by 4 publications

(4 citation statements)

References 131 publications

(163 reference statements)

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“…The definition of SUDEP is “sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence of a seizure, and excluding documented status epilepticus, where post-mortem examination does not reveal a toxicological or anatomical cause of death” (Nashef, 1997 ). Dysfunction of the cardiorespiratory autonomic system and sudden death are frequently associated with seizures in chronic epilepsy (Kloster and Engelskjøn, 1999 ; Langan et al, 2000 ; So et al, 2000 ; Opherk et al, 2002 ; Seyal et al, 2010 ; Mulkey and Milla, 2022 ). When patients with epilepsy and respiratory disorders experience hypoxic episodes, microglia-activated neuroinflammatory changes may trigger seizures and cause post-ictal respiratory arrest and SUDEP.…”

Section: Discussionmentioning

confidence: 99%

Minocycline prevents hypoxia-induced seizures

Fukushi

Ikeda

Takeda

et al. 2023

Front. Neural Circuits

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Severe hypoxia induces seizures, which reduces ventilation and worsens the ictal state. It is a health threat to patients, particularly those with underlying hypoxic respiratory pathologies, which may be conducive to a sudden unexpected death in epilepsy (SUDEP). Recent studies provide evidence that brain microglia are involved with both respiratory and ictal processes. Here, we investigated the hypothesis that microglia could interact with hypoxia-induced seizures. To this end, we recorded electroencephalogram (EEG) and acute ventilatory responses to hypoxia (5% O2 in N2) in conscious, spontaneously breathing adult mice. We compared control vehicle pre-treated animals with those pre-treated with minocycline, an inhibitory modulator of microglial activation. First, we histologically confirmed that hypoxia activates microglia and that pre-treatment with minocycline blocks hypoxia-induced microglial activation. Then, we analyzed the effects of minocycline pre-treatment on ventilatory responses to hypoxia by plethysmography. Minocycline alone failed to affect respiratory variables in room air or the initial respiratory augmentation in hypoxia. The comparative results showed that hypoxia caused seizures, which were accompanied by the late phase ventilatory suppression in all but one minocycline pre-treated mouse. Compared to the vehicle pre-treated, the minocycline pre-treated mice showed a delayed occurrence of seizures. Further, minocycline pre-treated mice tended to resist post-ictal respiratory arrest. These results suggest that microglia are conducive to seizure activity in severe hypoxia. Thus, inhibition of microglial activation may help suppress or prevent hypoxia-induced ictal episodes.

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Section: Discussionmentioning

confidence: 99%

Minocycline prevents hypoxia-induced seizures

Fukushi

Ikeda

Takeda

et al. 2023

Front. Neural Circuits

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“…In MORTEMUS, all nine patients for which peri-ictal cardiac and respiratory activity could be discerned experienced terminal apnoea prior to terminal asystole [48]. How seizures affect breathing has been a subject of intense study recently [20 ▪ ,49].…”

Section: Mechanisms For Sudden Unexpected Death In Epilepsymentioning

confidence: 99%

“…Recent studies in a hyperexcitable mouse model demonstrate that when SD reaches superior colliculus, it is more likely to be fatal [86,87 ▪ ,88]. In certain syndromic epilepsies, ion channel mutations could also be present in key control regions and directly impair cardiorespiratory function in this manner [49].…”

Section: Mechanisms For Sudden Unexpected Death In Epilepsymentioning

confidence: 99%

Sudden unexpected death in epilepsy

Buchanan

Maciel

Summerfield

2023

Current Opinion in Neurology

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Purpose of reviewSudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. This review highlights the recent literature regarding epidemiology on a global scale, putative mechanisms and thoughts towards intervention and prevention.Recent findingsRecently, numerous population-based studies have examined the incidence of SUDEP in many countries. Remarkably, incidence is quite consistent across these studies, and is commensurate with the recent estimates of about 1.2 per 1000 patient years. These studies further continue to support that incidence is similar across the ages and that comparable factors portend heightened risk for SUDEP. Fervent research in patients and animal studies continues to hone the understanding of potential mechanisms for SUDEP, especially those regarding seizure-induced respiratory dysregulation. Many of these studies and others have begun to lay out a path towards identification of improved treatment and prevention means. However, continued efforts are needed to educate medical professionals about SUDEP risk and the need to disclose this to patients.SummarySUDEP is a devastating potential outcome of epilepsy. More is continually learned about risk and mechanisms from clinical and preclinical studies. This knowledge can hopefully be leveraged into preventive measures in the near future.

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“…defect of respiratory rhythm generation in the brainstem, disturbance of phrenic output and diaphragm contraction, and airway obstruction (Blum, 2009). These respiratory failures are proposed as one of mechanisms for sudden unexplained death in epilepsy (SUDEP), although the detailed mechanisms of SUDEP are not well understood (Mulkey and Milla, 2022;Wenker et al, 2022). Brainstem-spinal cord preparation has been used for in vitro analyses of respiratory rhythm generation (Suzue, 1984;Ballanyi et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output

et al. 2023

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Seizure-like burst activities are induced by blockade of GABA A and/or glycine receptors in various spinal ventral roots of brainstem-spinal cord preparation from neonatal rodents. We found that this is not applicable to the phrenic nerve and that a new inhibitory descending pathway may suppress seizure-like activity in the phrenic nerve. Experiments were performed in brainstem-spinal cord preparation from newborn rats (age: 0-1 day). Left phrenic nerve and right C4 activities were recorded simultaneously. When GABA A and glycine receptors were blocked by 10 μM bicuculline and 10 μM strychnine (Bic+Str), seizure-like burst activities appeared in the fourth cervical ventral root (C4) but not the phrenic nerve. After making a transverse section at C1, the inspiratory burst activity disappeared from both C4 and the phrenic nerve, whereas seizure-like activity appeared in both nerves. We hypothesized that inhibitory descending pathways other than those via GABA A and/or glycine receptors (from the medulla to the spinal cord) work to avoid disturbance of regular respiratory-related diaphragm contraction by seizure-like activity. We found that cannabinoid receptor antagonist, AM251 was effective for the induction of seizure-like activity by Bic+Str in the phrenic nerve in brainstem-spinal cord preparation. Cannabinoid receptors may be involved in this descending inhibitory system.

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Perspectives on the basis of seizure-induced respiratory dysfunction

Cited by 4 publications

References 131 publications

Minocycline prevents hypoxia-induced seizures

Minocycline prevents hypoxia-induced seizures

Sudden unexpected death in epilepsy

Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output

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