Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, with an estimated 35% lifetime risk in this patient population. There is a surprising ...lack of awareness among patients and physicians of this increased risk of sudden death: in a recent survey, only 33% of Canadian paediatricians who treated patients with epilepsy knew the term SUDEP. Controversy prevails over whether cardiac arrhythmia or respiratory arrest is more important as the primary cause of death. Effective preventive strategies in high-risk patients will rely on definition of the mechanisms that lead from seizures to death. Here, we summarize evidence for the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal period. We highlight potential cellular mechanisms underlying these abnormalities, such as a defect in the serotonergic system, ictal adenosine release, and changes in autonomic output. We discuss genetic mutations that cause Dravet and long QT syndromes, both of which are linked with increased risk of sudden death. We then highlight possible preventive interventions that are likely to decrease SUDEP incidence, including respiratory monitoring in epilepsy monitoring units and overnight supervision. Finally, we discuss treatments, such as selective serotonin reuptake inhibitors, that might be personalized to a specific genetic or pathological defect.
There is a long-standing controversy about the role of serotonin in sleep/wake control, with competing theories that it either promotes sleep or causes arousal. Here, we show that there is a marked ...increase in wakefulness when all serotonin neurons are genetically deleted in mice hemizygous for ePet1-Cre and homozygous for floxed Lmx1b ( Lmx1b f/f/p ). However, this only occurs at cool ambient temperatures and can be explained by a thermoregulatory defect that leads to an increase in motor activity to generate heat. Because some serotonin neurons are stimulated by CO 2 , and serotonin activates thalamocortical networks, we hypothesized that serotonin neurons cause arousal in response to hypercapnia. We found that Lmx1b f/f/p mice completely lacked any arousal response to inhalation of 10% CO 2 (with 21% O 2 in balance N 2 ) but had normal arousal responses to hypoxia, sound, and air puff. We propose that serotonin neurons mediate the potentially life-saving arousal response to hypercapnia. Impairment of this response may contribute to sudden unexpected death in epilepsy, sudden infant death syndrome, and sleep apnea.
Serotonergic neurons in the medulla have recently been shown to be sensors of carbon dioxide and pH. There is compelling evidence that the co-release of serotonin, substance P and ...thyrotropin-releasing hormone from these neurons stimulates the neural network that controls breathing at numerous sites using many different mechanisms. Serotonergic neurons in the midbrain are also chemosensitive, and might mediate non-respiratory responses to increased carbon dioxide, such as arousal. This role in control of pH homeostasis could provide a neurobiological explanation for the link between changes in the serotonin system and sudden infant death syndrome (SIDS).
Key points
Sudden unexpected death in epilepsy is the leading cause of death in patients with refractory epilepsy.
Respiratory and cardiac impairment induced by a seizure have been identified as ...possible causes of seizure‐related death, but which is more important has been the subject of debate.
Serotonin has been linked to seizure control, but whether it is primarily anti‐convulsant or proconvulsant remains controversial.
In this study we induced seizures in mice with a genetic deletion of serotonin neurones and their phenotypically normal littermates while recording EEG, EMG, ECG and breathing, and assessed the effects of seizures on breathing, cardiac activity and survival
Serotonin and serotonin neurones are involved in setting the seizure threshold, regulating seizure severity and preventing mortality, and death in at least one seizure model is due to respiratory arrest, which can be prevented with selective serotonin reuptake inhibitor treatment or 5‐HT2A receptor activation.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of SUDEP, and serotonin (5‐HT) system dysfunction may be involved. Here we examined the effect of 5‐HT neurone elimination or 5‐HT reduction on seizure risk and seizure‐induced mortality. Adult Lmx1bf/f/p mice, which lack >99% of 5‐HT neurones in the CNS, and littermate controls (Lmx1bf/f) were subjected to acute seizure induction by maximal electroshock (MES) or pilocarpine, variably including electroencephalography, electrocardiography, plethysmography, mechanical ventilation or pharmacological therapy. Lmx1bf/f/p mice had a lower seizure threshold and increased seizure‐induced mortality. Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by mechanical ventilation during the seizure or 5‐HT2A receptor agonist pretreatment. The selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1bf/f but not of Lmx1bf/f/p mice. In C57BL/6N mice, reduction of 5‐HT synthesis with para‐chlorophenylalanine increased MES‐induced seizure severity but not mortality. We conclude that 5‐HT neurones raise seizure threshold and decrease seizure‐related mortality. Death ensued from respiratory failure, followed by terminal asystole. Given that SUDEP often occurs in association with generalised seizures, some mechanisms causing death in our model might be shared with those leading to SUDEP. This model may help determine the relationship between seizures, 5‐HT system dysfunction, breathing and death, which may lead to novel ways to prevent SUDEP.
Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT) dysregulation are ...commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections—increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.
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•Functional specializations map to distinct 5HT neuron developmental lineages•Life-sustaining breathing reflex is specifically driven by Egr2-Pet1 5HT neurons•Egr2-Pet1 5HT neurons function as frontline PCO2/pH chemoreceptor•5HT neuronal system is found to have sensory and motor subdivisions
Brust et al. show that the life-sustaining respiratory CO2 chemoreflex is regulated by a specialized subtype of serotonergic neuron—the Egr2-Pet1 subtype—and reveal its unique physiological, biophysical, and hogological properties centered around chemosensory processing and likely specified by genetic lineage developmentally. Thus, specialized modules contribute to serotonergic functional breadth.
Physiological homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain ...serotonergic neurons in homeostasis, we used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein—coupled receptor Di), designed for cell type—specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO 2 ) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO 2 acidosis. Body thermoregulation at room temperature was also disrupted after CNO triggering of Di; core temperatures plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.
Aims
Increased chemosensitivity to carbon dioxide (CO2) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A ...receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in
HF.
Methods and results
The BREATH study was a randomized, double‐blind, placebo‐controlled, crossover study (EudraCT‐code 2015‐005383‐42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate‐severe CA nocturnal apnoea‐hypopnoea index (AHI) ≥15 events/h were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash‐out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention‐to‐treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14–73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone‐related serious adverse events.
Conclusions
Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with
HF.
The increased chemoreflex gain (CG), which causes central apnoeas in heart failure (A), is blunted by buspirone, which increases the difference between CO2 at the equilibrium setpoint (ES) and at apnoeic threshold (AT) and stabilizes breathing (B). Buspirone acts on the serotonergic system (C), linking to pre‐synaptic 5‐HT1A autoreceptors and decreasing the release of serotonin in the synaptic cleft (D). ETCO2, end‐tidal pressure of carbon dioxide; ETO2, end‐tidal pressure of oxygen; VENT, ventilation.
To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy.
This was a prospective, multicenter epilepsy monitoring study of autonomic ...and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed.
We studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy; 65 had focal epilepsy; 1 had both; and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 of 121 (40.4%) seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 of 140 (22.1%) seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1,000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP incidence rate 5.1 per 1,000 patient-years. No cases of laryngospasm were detected. Rhythmic muscle artifact synchronous with breathing was present in 75 of 147 seizures and related to stertorous breathing (odds ratio 3.856, 95% confidence interval 1.395-10.663,
= 0.009).
PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.
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