Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Is adenotonsillectomy effective in improving central apnea events in patients with obstructive sleep apnea? A systematic review and meta-analysis.

PURPOSE: To evaluate the effects of adenotonsillectomy on improving central sleep apnea events in children with obstructive sleep apnea (OSA). METHODS: We searched four online databases for relevant articles published from inception until October 2022. We included studies that measured the number of central apnea events per sleep and central apnea-hypopnea index (CAHI) or central apnea index (CAI) scores in children with OSA before and after adenotonsillectomy. Our primary outcomes were changes in CAI scores, the number of central apnea events per sleep, and CAHI scores after surgery. Our secondary outcomes were changes in total and mixed apnea events, improvement of sleep outcomes, and differences in oxygen or carbon dioxide saturation during sleep. We performed meta-analyses by pooling the mean changes of all included studies with a 95% confidence interval using Stata 17. Subsequently, we performed subgroup analyses based on the presence of comorbidities. RESULTS: We included 22 studies comprising 1287 patients. Central and total sleep apnea parameters, except for CAHI and mixed apnea index scores, showed significant improvements after surgery. In addition, all respiratory parameters and second and third stages of non-rapid eye movement sleep showed significant postsurgical improvements. Patients with comorbidities showed significant improvements only in the total apnea-hypopnea index, oxygen desaturation index, and minimal oxygen saturation. CONCLUSION: Adenotonsillectomy improves central apnea events in patients with OSA but not in those with comorbidities.

Sex-related Differences in Loop Gain during High-Altitude Sleep-disordered Breathing.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

Design of the remede System Therapy (reST) study: A prospective non-randomized post-market study collecting clinical data on safety and effectiveness of the remede system for the treatment of central sleep apnea.

BACKGROUND: Central sleep apnea (CSA) is a disorder defined by lack of respiratory drive from the brain stem on breathing efforts. There is a lack of established therapies for CSA and most available therapies are limited by poor patient adherence, limited randomized controlled studies, and potentially adverse cardiovascular effects. The remede System (ZOLL Respicardia, Inc., Minnetonka, Minnesota) uses transvenous phrenic nerve stimulation to stimulate the diaphragm, thereby restoring a more normal breathing pattern throughout the sleep period. METHODS: The remede System Therapy (reST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remede System in the post-market setting. Up to 500 adult patients with moderate to severe CSA will be enrolled and followed up to 5 years at approximately 50 sites in the United States and Europe. Safety objectives include evaluation of adverse events related to the implant procedure, device or delivered therapy, death, and hospitalizations. Effectiveness endpoints include assessment of changes in sleep-disordered breathing metrics from polysomnograms and home sleep tests, changes in daytime sleepiness using the Epworth Sleepiness Scale, and changes in QoL using the PROMIS-29 and Patient Global Assessment questionnaires. The subgroup of patients with heart failure will undergo additional assessments including echocardiography to assess cardiac reverse remodeling, 6-min walk distance, QoL assessment by Kansas City Cardiomyopathy Questionnaire and measurement of biomarkers. CONCLUSION: This will be the largest prospective study evaluating long-term safety and effectiveness of transvenous phrenic nerve stimulation for the treatment of moderate to severe CSA in adult patients.

Evaluation and Treatment of Central Sleep Apnea in Patients with Heart Failure.

Sleep-disordered breathing (SDB) is a common comorbidity in patients with heart failure (HF). Prevalence of the most common subtypes of SDB, central sleep apnea (CSA) and obstructive sleep apnea (OSA), is increasing, which is concerning due to the association of SDB with increased mortality in patients with HF. Despite an increasing burden of CSA in HF, it is difficult to detect using current diagnostic tools and the treatment modalities are limited by variable efficacy and patient adherence. Though positive airway pressure therapies remain the cornerstone of OSA treatment, the management of CSA in the setting of HF continues to evolve. The association of the presence of CSA with worse prognosis in HF patients warrants the need for routine screening for signs and symptoms of CSA in this population. In this review, we examine the connection between CSA and HF, and highlight advancements in timely diagnostics, treatment modalities, and strategies to promote facilitation of compliance in this high-risk cohort.

[Treatment-Emergent Central Sleep Apnea - Detection and Treatment]. / Treatment-emergent zentrale Schlafapnoe erkennen und behandeln.

Treatment-Emergent Central Sleep Apnea - Detection and Treatment Abstract. In treatment-emergent central sleep apnea (TECSA), affected patients with obstructive sleep apnea newly develop central sleep apnea (AHI central ≥5/h) under therapy with positive pressure ventilation which cannot be explained by other causes. The pathophysiology of TECSA is incompletely understood. PaCO2 and the associated apnea threshold seem to play a central role. The incidence of TECSA varies (1.8-20%), and in about 2/3 of cases it is self-limiting in the course of the therapy. If persistence or new onset occurs later in the course of positive pressure therapy, a further evaluation (e.g., echocardiography, neurologic examination, medication history) is indicated. Effective treatment options include a change in ventilation therapy (adaptive servoventilation or bilevel ventilation with back-up frequency) or additional nocturnal oxygen supplementation; these options should be decided case by case.

Altitude-Induced Sleep Apnea Is Highly Dependent on Ethnic Background (Sherpa Vs. Tamang).

Heiniger, Grégory, Simon Walbaum, Claudio Sartori, Alban Lovis, Marco Sazzini, Andrew Wellman, and Raphael Heinzer. Altitude-Induced Sleep Apnea Is Highly Dependent on Ethnic Background (Sherpa Vs. Tamang). High Alt Med Biol. 23:165-172, 2022. Rationale: High altitude-induced hypocapnic alkalosis generates central sleep apnea (CSA). In Nepal, two ethnic groups live at medium-to-high altitude: Tamangs originate from low-altitude Tibeto-Burman populations, whereas Sherpas descend from high-altitude Tibetans. Objective: To compare apnea severity at low and high altitude between Sherpas and Tamangs. Methods: Polygraphy recordings, including airflow and oxygen saturation, were performed in Nepal at "low" (2,030 m) and "high" (4,380 m) altitudes. Resting ventilation (V̇E) and mixed-exhaled CO2 (FECO2) were also measured at the same altitudes. Differences in apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and % of nocturnal periodic breathing (NPB) at the two altitudes were compared between ethnicities. Measurements and Main Results: Twenty Sherpas and 20 Tamangs were included (males, median [interquartile range] age: 24.5 [21.5-27.8] years vs. 26.0 [21.5-39.8] years, body mass index: 23.9 [22.1-26.1] kg/m2 vs. 25.21 [20.6-27.6] kg/m2). Compared with Tamangs, Sherpas showed a lower increase in AHI (+7.5 [2.6-17.2]/h vs. +31.5 [18.2-57.3]/h, p < 0.001), ODI (+13.8 [5.5-28.2]/h vs. +42.0 [22.6-77.6]/h, p < 0.001), and NPB proportion (+0.9 [0-3.5]% vs. +12.8 [3.1-27.4]%, p < 0.001) from low to high altitude. Resting V̇E was higher in Sherpas versus Tamangs at both low (8.45 [6.89-10.70] l/min vs. 6.3 [4.9-8.3] l/min, p = 0.005) and high (9.7 [8.5-11] l/min vs. 8.74 [7.39-9.73] l/min, p = 0.020) altitudes, whereas the mean ± standard deviation FECO2 decrease between low and high altitude was greater in Tamangs versus Sherpas (-0.50% ± 0.44% vs. -0.80% ± 0.33%, p < 0.023). Conclusion: Overall, altitude-adapted Sherpas showed a 3.2-times smaller increase in sleep-disordered breathing between low and high altitude compared with Tamangs, and higher ventilation and a smaller drop in FECO2 at high altitude. These data suggest that genetic differences in breathing control can be protective against CSA.

Phrenic nerve stimulation experiences. A single centre, controlled, prospective study.

Patients with central apnoea may use electro ventilation, provided their phrenic nerves and diaphragm muscles are normal. A tendency towards better survival has been found, and both an improved quality of life and facilitated nursing have been claimed with electro ventilation compared to mechanical ventilation. The high investment for the device may form a hurdle for fund providers like our hospital administration board. We, therefore, from our first patient onwards, collected clinically meaningful data in a special register of all patients using electro ventilation and their controls on mechanical ventilation. Since 1988 172 patients left our institution dependent on a respiratory device. Of these, all 48 patients with preserved phrenic nerves chose phrenic nerve stimulation. A patient on mechanical ventilation who agreed to participate was chosen as a control (n = 44). All patients were seen at least once a year. 90 patients suffered high tetraplegia, and 2 suffered central apnoea for other reasons. There is a tendency towards better survival, and there is a lower frequency of decubital ulcers (0.02) and respiratory tract infections (p0.000) with electro than with mechanical ventilation. The frequency of respiratory infections turned out to be a better measure of the quality of respiratory care than survival. The resulting decrease in the need for airway nursing, and the reduced incidence of respiratory infections repaid the high investment in electro ventilation within one year in our setting. Informed patients prefer electro to mechanical ventilation; fund providers might also agree with this preference.

Sleep-disordered breathing in pediatric neurofibromatosis type 1.

The relationship between neurofibromatosis type 1 (NF1) and sleep-disordered breathing (SDB) has not been widely studied. The aim of the study was to analyze SDB in children with NF1 of the respiratory system. All children with NF1 followed between September 2008 and July 2020 who had a respiratory polygraphy (RP) were included. The clinical charts, cerebral and cervical magnetic resonance imaging (MRI), and RP were analyzed. Twenty-two patients (11 girls, median age at RP 8.3 [0.2-18.2] years) were included in the study. Nine patients (41%) had a NF1 involvement of the upper airways, 13 (59%) patients of the central nervous system (CNS), the cranial nerves (CN) and/or medulla, and 17 (77%) patients had a hypertrophy of the adenoids and/or tonsils. Five patients were treated with Continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) before their first evaluation because of severe obstructive sleep apnea (OSA). Accordingly, 10 (45%) patients had no OSA, one (5%) mild OSA, 2 (9%) moderate OSA, and nine (41%) severe OSA. None of the patients had central sleep apnea. Despite upper airway surgery, three patients required CPAP, two could be weaned and one died after a switch to tracheostomy. None of the patients treated with CPAP/NIV could be weaned, one patient required tracheostomy. Neither the clinical nor the MRI findings were able to predict OSA on a RP. The prevalence of OSA in NF1 is high, regardless of the nature of airway obstruction and the clinical and MRI findings, underlining the value of a systematic RP. CPAP may reduce the need of tracheostomy.

Obese Patients Experience More Severe CSA than Non-Obese Patients.

OBJECTIVE: To investigate whether central sleep apnea (CSA) is associated with an increased risk of obesity. MATERIALS AND METHODS: From 1 January 2000 to 31 December 2015, we screened 24,363 obese patients from the 2005 longitudinal health insurance database, which is part of the Taiwan National Health Insurance Research Database. From the same database, 97,452 non-obese patients were also screened out. Age, gender, and index dates were matched. Multiple logistic regression was used to analyze the previous exposure risk of obese and CSA patients. A p-value of <0.05 was considered significant. RESULTS: Obese patients were more likely to be exposed to CSA than non-obese patients would (AOR = 2.234, 95% CI = 1.483-4.380, p < 0.001). In addition, the closeness of the exposure time to the index time is positively correlated with the severity of obesity and has a dose-response effect (CSA exposure < 1 year, AOR = 2.386; CSA exposure ≥ 1 year and <5 years, AOR = 1.725; CSA exposure time ≥ 5 years, AOR = 1.422). The CSA exposure time of obese patients was 1.693 times that of non-obese patients. Longer exposure time is associated with more severe obesity and has a dose-response effect (CSA exposure < 1 year, AOR = 1.420; CSA exposure ≥ 1 year and <5 years, AOR = 2.240; CSA ≥ 5 years, AOR = 2.863). CONCLUSIONS: In this case-control study, patients with CSA had a significantly increased risk of obesity. Long-term exposure to CSA and obesity is more likely and has a dose-response effect.

Sleep-disordered breathing in school-aged children with Prader-Willi syndrome.

STUDY OBJECTIVES: Studies of sleep-disordered breathing (SDB) in children with Prader-Willi syndrome (PWS) have focused on early childhood and growth hormone (GH)-naïve children, but little is known about older children, including those on long-term GH therapy. This study aimed to describe the nature and prevalence of SDB in school-aged children with PWS in the growth hormone era. METHODS: This retrospective single-center chart review included children aged 6-18 years with PWS who had overnight polysomnography not involving respiratory support over 5 years (2012-2017). The main outcome measures were the presence of obstructive sleep apnea, central sleep apnea, or hypoventilation defined by an elevated transcutaneous partial pressure of carbon dioxide (TcPCO2) as per standard pediatric criteria. RESULTS: Seventeen children (8 males; median age 11.6 years, range 6.6-16.1 years) were included. Fifteen demonstrated SDB of different types: central sleep apnea (18%), obstructive sleep apnea (24%), both obstructive and central sleep apnea (29%), or hypoventilation without obstructive or central sleep apnea (18%). Twelve (71%) children had evidence of hypoventilation. Those with hypoventilation had a higher central apnea-hypopnea index but no difference in the obstructive apnea-hypopnea index, age, sex, growth parameters, or the presence of scoliosis or sleep-related symptoms compared with those without hypoventilation. CONCLUSIONS: Sleep-related hypoventilation is common in school-aged children with PWS. The presence of central sleep apnea, including the quantification of central hypopneas, but not obstructive sleep apnea or clinical factors, predicted the presence of hypoventilation. Long-term polysomnography surveillance in children with PWS should include identification of central hypopneas and measurement of continuous pCO2. CITATION: Schaefer J, Davey MJ, Nixon GM. Sleep-disordered breathing in school-aged children with Prader-Willi syndrome. J Clin Sleep Med. 2022;18(4):1055-1061.

An 8-Month-Old Infant With Respiratory Failure After a Fall.

CASE PRESENTATION: An 8-month-old previously healthy, full-term girl presented with altered mental status after falling approximately 3 feet from a bed, landing on her head. In the ED, she had a CT scan of her head (Fig 1) and was intubated for airway protection. While in the PICU, initial chest radiography showed bilateral infiltrates that were consistent with ARDS, which subsequently resolved. Her respiratory status continued to improve, which allowed a trial on CPAP with invasive neurally adjusted ventilatory assist (NAVA) support, which she was unable to tolerate because of the need for increased support during sleep. On hospital day 8, she was extubated to noninvasive NAVA and was noted to have poor truncal tone and inability to lift or rotate her head. Repeat head CT scans were unchanged. Despite nasal CPAP and NAVA support, she experienced hypercapnia to 83 mm Hg that required reintubation. Brain MRI was completed on hospital day 10 (Fig 1). Lumbar puncture results were obtained, which were unremarkable. Extubation was attempted again on hospital days 15 and 22 with subsequent hypercapnia that required reintubation. She was able to gradually lengthen her CPAP trials but continued to have periods of hypercapnia and bradypnea.

Exertional and nocturnal periodic breathing after successful cardiac transplantation. A case report.

We present a case report of a heart failure patient who underwent cardiopulmonary exercise testing and sleep screening 12 months before and after heart transplantation (HTx). Severe Cheyne-Stokes respiration (CSR) with central sleep apnoea (CSA) was identified either before and after HTx, while periodic breathing during exercise vanished. We suggest that optimization of hemodynamics and medical therapy (low dose of diuretic) did not withdraw the central mechanisms underlying the diathesis for CSR-CSA. While periodic breathing during exercise reversal may support a closer link with an exertional central hemodynamic. This observation indirectly neglects the possible unifying mechanistic background of CSR and periodic breathing, during exercise, in this setting.

[Cellex in the therapy of patients with complex and central apnea in the early recovery period of ischemic stroke]. / Opyt primeneniya polipeptidnogo preparata Tselleks u patsientov s kompleksnym i tsentral'nym apnoe sna v rannem vosstanovitel'nom periode ishemicheskogo insul'ta.

A variety of structural and functional post-stroke disturbances demands an integrated clinical/diagnostic approach. Persistent hypoxemia due to disturbance of a saturation of blood oxygen in sleep can decrease the effectiveness of neurorehabilitation. In some cases of sleep apnea, the efficiency of continuous positive airway pressure therapy is insufficient and it should be combined with course neuroprotective therapy. Modern approaches to neuroprotective and neuroreparative therapy are considered as the independent direction for treatment of the central sleep apnea syndromes in patients with stroke consequences that is obviously important aspect of secondary prevention of a stroke.

The efficacy of neurosurgical intervention on sleep-disordered breathing in pediatric patients with Chiari malformation type I.

OBJECTIVE: Chiari malformation type I (CM-I) involves the herniation of the cerebellar tonsils through the foramen magnum. CM-I is associated with both obstructive sleep apnea (OSA) and central sleep apnea (CSA) in children. The primary management of symptomatic CM-I remains surgical decompression. There is, however, a paucity of data evaluating the efficacy of decompression surgery on outcomes related to sleep-disordered breathing (SDB). The objective of this study was to evaluate SDB outcomes, specifically the need for respiratory support following decompression in pediatric patients with CM-I. METHODS: This was a retrospective chart review of all children diagnosed with CM-I when younger than 18 years of age who had polysomnography (PSG) studies pre- and postsurgery, between January 2008 and October 2018 at the Hospital for Sick Children in Toronto. Patient demographics, symptoms, PSG data, ongoing respiratory support, and surgical notes were recorded. Differences in PSG studies obtained pre- and postsurgery were compared using the Wilcoxon test for paired samples. RESULTS: A total of 15 children with 15 interventions met inclusion criteria with pre- and postsurgery PSG studies and were considered for statistical analysis. Of the 15 subjects included for analysis, preoperative OSA was present in 2 (13.3%), CSA in 5 (33.3%), mixed SDB (both OSA and CSA) in 4 (26.7%), and no significant SDB in 4 (26.7%). Postoperatively, OSA was present in 3 (20.0%), CSA in 4 (26.7%), mixed SDB in 0 (0%), and no significant SDB in 8 (53.3%). The presence of severe OSA decreased from 4/15 (26.7%) to 2/15 (13.3%) postoperatively, and severe CSA decreased from 5/15 (33.3%) to 2/15 (13.3%) postoperatively. Following decompression surgery, 7/15 subjects (46.7%) required positive airway pressure for management of their SDB. Overall, significant improvements were observed in a number of respiratory parameters following decompression including the following: the total apnea-hypopnea index (AHI) (17.5 ± 48.2 vs 6.1 ± 32.7 events/hour; p = 0.001), obstructive AHI (2.1 ± 16.1 vs 1.0 ± 6.6 events/hour; p = 0.005), central AHI (6.3 ± 48.9 vs 2.7 ± 33.0 events/hour; p = 0.005), and the desaturation index (16.7 ± 49.6 vs 3.8 ± 25.3; p = 0.001). CONCLUSIONS: Although decompression surgery led to a significant reduction in obstructive and central events, many children continued to have persistent SDB and required additional positive airway pressure therapy. This information is important and relevant for anticipatory guidance around decompression surgery and the necessity for respiratory support for the management of SDB in pediatric patients with CM-I.