[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

Atractylon treatment prevents sleep-disordered breathing-induced cognitive dysfunction by suppression of chronic intermittent hypoxia-induced M1 microglial activation.

Chronic intermittent hypoxia (CIH) induced by sleep-disordered breathing (SDB) is a key factor involved in cognitive dysfunction (CD). Increasing evidence has shown that atractylon (ATR) has anti-inflammatory effects. However, it remains unclear if ATR has a protective effect against SDB-induced nerve cell injury and CD. So, in the present study, CIH-exposed mice and CIH-induced BV2 cells were used to mimic SDB. The results showed that ATR treatment decreased CIH-induced CD and the expression of inflammatory factors in the hippocampal region by suppression of M1 microglial activation and promotion of M2 microglial activation. Also, ATR treatment promoted sirtuin 3 (SIRT3) expression. Down-regulation of SIRT3 decreased the protective effect of ATR against CIH-induced microglial cell injury. Furthermore, in vitro detection found that SIRT3 silencing suppressed ATR-induced M2 microglial activation after exposure to CIH conditions. Taken together, these results indicate that ATR treatment prevents SDB-induced CD by inhibiting CIH-induced M1 microglial activation, which is mediated by SIRT3 activation.

Role of Zinc Supplementation on Ischemia/Reperfusion Injury in Various Organs.

Ischemia-reperfusion (I/R) injury is a serious condition which is associated with myocardial infarction, stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea and can lead to high morbidity and mortality. Salts of zinc (Zn) are commonly used by humans and have protective effects against gastric, renal, hepatic, muscle, myocardial, or neuronal ischemic injury. The present review evaluates molecular mechanisms underlying the protective effects of Zn supplement against I/R injury. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1991 to 2019. Zn supplementation increased the decreased parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), metallothionein (MT), protein sulfhydryl (P-SH), and nuclear factor-erythroid 2-related factor-2 (Nrf2) expression and decreased the increased elements such as endoplasmic reticulum (ER) stress, mitochondrial permeability transition pore (mPTP) opening, malondialdehyde (MDA), serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and microRNAs-(122 and 34a), apoptotic factors, and histopathological changes. Zn also increases phosphatidylinositol 3-kinase (PI3K)/Akt and glycogen synthase kinase-3ß (GSK-3ß) phosphorylation and preserves protein kinase C isoforms. It is suggested that Zn can be administered before elective surgeries for prevention of side effects of I/R injury.

Impact of sacubitril-valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO-SAS study design.

AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. METHODS AND RESULTS: The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. CONCLUSIONS: In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients.

Novel Approaches to the Management of Sleep-Disordered Breathing.

In the last several years, a variety of novel approaches to the treatment of sleep-disordered breathing have emerged. This new technology holds promise in serving to re-engage with patients who have previously been lost to follow-up due to continuous positive airway pressure intolerance. With more tools at our disposal, in turn more options can be offered to patients' growing demand for alternatives that are tailored to their individual needs. The key to proper deployment of alternative therapies will often depend on identification of certain phenotypic traits that trend toward a reasonable response to a given therapy.

Cost-Effectiveness of a Community Pharmacist-Led Sleep Apnea Screening Program - A Markov Model.

BACKGROUND: Despite the high prevalence and major public health ramifications, obstructive sleep apnea syndrome (OSAS) remains underdiagnosed. In many developed countries, because community pharmacists (CP) are easily accessible, they have been developing additional clinical services that integrate the services of and collaborate with other healthcare providers (general practitioners (GPs), nurses, etc.). Alternative strategies for primary care screening programs for OSAS involving the CP are discussed. OBJECTIVE: To estimate the quality of life, costs, and cost-effectiveness of three screening strategies among patients who are at risk of having moderate to severe OSAS in primary care. DESIGN: Markov decision model. DATA SOURCES: Published data. TARGET POPULATION: Hypothetical cohort of 50-year-old male patients with symptoms highly evocative of OSAS. TIME HORIZON: The 5 years after initial evaluation for OSAS. PERSPECTIVE: Societal. INTERVENTIONS: Screening strategy with CP (CP-GP collaboration), screening strategy without CP (GP alone) and no screening. OUTCOMES MEASURES: Quality of life, survival and costs for each screening strategy. RESULTS OF BASE-CASE ANALYSIS: Under almost all modeled conditions, the involvement of CPs in OSAS screening was cost effective. The maximal incremental cost for "screening strategy with CP" was about 455€ per QALY gained. RESULTS OF SENSITIVITY ANALYSIS: Our results were robust but primarily sensitive to the treatment costs by continuous positive airway pressure, and the costs of untreated OSAS. The probabilistic sensitivity analysis showed that the "screening strategy with CP" was dominant in 80% of cases. It was more effective and less costly in 47% of cases, and within the cost-effective range (maximum incremental cost effectiveness ratio at €6186.67/QALY) in 33% of cases. CONCLUSIONS: CP involvement in OSAS screening is a cost-effective strategy. This proposal is consistent with the trend in Europe and the United States to extend the practices and responsibilities of the pharmacist in primary care.

Clinical outcomes of traditional Chinese medicine compound formula in treating sleep-disordered breathing patients.

Sleep-disordered breathing (SDB) is a prevalent affliction, which can range from simple snoring to severely obstructive sleep apnea. Compared to current treatment options of SDB, traditional Chinese medicine (TCM) provides a noninvasive way to relieve SDB-related symptoms and deaths. The purpose of this retrospective study was to observe the progression of adult SDB patients who had taken compound formula SZ + NUH (concentrated herbal granules) for four weeks. Depending on subjects' individual needs, minor additions of formulas or single herbs were allowed. We found a significant amount of relief from snoring among the 118 enrolled subjects, according to before-after scores observed through the Snore Outcome Survey (SOS). Furthermore, as projected from the moderate linear correlation in before-after scores, we inferred that those cases with more severe snoring at baseline had greater improvement after treatment. Excessive daytime sleepiness was also significantly improved according to the results of the Epworth Sleepiness Scale (ESS). Assessment, using the SF-36 (Taiwanese version) revealed possible benefits of SZ + NUH in improving multiple facets of subjects' quality of life. During treatment, no significant side effects occurred. In conclusion, the TCM compound formula based on SZ + NUH could be a safe and effective option for SDB treatment.

Sleep apnea is induced by a high-fat diet and reversed and prevented by metformin in non-obese rats.

OBJECTIVE: We assessed the relationship between a high-fat (HF) diet and central apnea during rapid eye movement and non-rapid eye movement sleep stages by recording ventilatory parameters in 28 non-obese rats in which insulin resistance had been induced by an HF diet. We also studied whether metformin (an anti-hyperglycemic drug frequently used to treat insulin resistance) could reverse sleep apnea or prevent its occurrence in this experimental paradigm. RESEARCH METHODS AND PROCEDURES: Rats were fed with a standard diet (10 rats), an HF diet (8 rats), or an HF diet concomitantly with metformin treatment (10 rats). Each animal was instrumented for electroencephalographic and electromyographic recording. After 3 weeks, ventilatory parameters during sleep were recorded with a body plethysmograph. All rats were treated with metformin for 1 week, after which time the ventilatory measurements were measured again. RESULTS: Our results showed that the three groups of animals did not differ in terms of body growth over the entire experimental period. The HF diet did not modify sleep structure or minute ventilation in the different sleep stages. A great increase (+266 +/- 48%) in central apnea frequency was observed in insulin-resistant rats. This was explained by an increase in both post-sigh (+195 +/- 35%) and spontaneous apnea (+437 +/- 65%) in the different sleep stages. These increases were suppressed by metformin treatment. DISCUSSION: Insulin resistance induced by the HF diet could be the promoter of sleep apnea in non-obese rats. Metformin is an efficient curative and preventive treatment for sleep apnea, suggesting that insulin resistance modifies the ventilatory drive independently of obesity.

A case of sleep choking syndrome improved by the Kampo extract of Hange-koboku-to.

A case of sleep choking syndrome with typical symptoms is presented. A 44-year-old Japanese male suffered from multiple episodes of choking, which suddenly appeared with fear of impending death about 30 min after falling asleep almost every night. Overnight polysomnography showed an apnea index of 0.92 events/h, an apnea-hypopnea index of 2.77 events/h, and normal respiration during sleep with the exception of the episodes of apnea and hypopnea. No choking episode occurred in the sleep laboratory. The administration of 500 mg of acetazolamide was ineffective, but the choking episode improved after the administration of Kampo extract of Hange-koboku-to (Ban-xia-hou-pu-tang). Hange-koboku-to may be effective in treating choking sensation during sleep as well as during wakefulness.

Treatment of obstructive sleep apnea syndrome with a Kampo-formula, San'o-shashin-to: a case report.

The following describes a 76-year-old male with obstructive sleep apnea syndrome successfully treated with a Kampo-formula, San'o-shashin-to (Formula medicamentorum tres ad dispellendi cordis). Polysomnography, performed before and after administration of San'o-shashin-to, revealed that the apnea index decreased from 11.1 events/hour to 4.1 events/hour, and that the apnea plus hypopnea index decreased from 18.4 events/hour to 10.7 events/hour. The patient was normo-weight (body mass index: 20.4 kg/m2), and events of sleep apnea and hypopnea were mostly noted during a non-rapid eye movement sleep. It is possible that San'o-shashin-to has some alleviating effects on the upper airway resistance during sleep.