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BACKGROUND: Obstructive sleep apnoea (OSA) involves repeated breathing pauses during sleep due to upper airway obstruction. It causes excessive daytime sleepiness and has other health impacts. Continuous positive airway pressure (CPAP) therapy is effective first line treatment for moderate to severe OSA. Unfortunately, many patients have difficulty tolerating CPAP and pressure intolerance is probably an important contributing factor. Mandibular advancement devices (MAD) are an alternative to CPAP. They are worn in the mouth during sleep to reduce airway obstruction. There is some evidence that, when used in combination with CPAP, MADs improve airway anatomy enough to reduce the CPAP pressure required to treat OSA and that this combination therapy could improve CPAP adherence. METHODS: Consecutive patients starting on CPAP for moderate to severe OSA will be recruited at a regional NHS sleep service. Patients with high CPAP pressure requirements after initial titration, who satisfy all entry criteria and consent to participate, will undertake a 2-arm randomised crossover trial. The arms will be (i) standalone CPAP and (ii) CPAP + MAD therapy. Each arm will last 12 weeks, including 2 weeks acclimatisation. CPAP machines will be auto-titrating and with facility for data download, so the impact of MAD on CPAP pressure requirements and CPAP adherence can be easily measured. The primary outcome will be CPAP adherence. Secondary outcomes will include measures of OSA severity, patient-reported outcome measures including subjective daytime sleepiness, quality of life, and treatment preference at the trial exit and health service use. Cost-effectiveness analyses will be undertaken. DISCUSSION: If the intervention is shown to be effective and cost-effective in improving adherence in this standard CPAP-eligible OSA patient population it would be relatively straightforward to introduce into existing OSA treatment pathways, within the wider NHS and more widely. Both MAD and CPAP are already used by sleep services so their combination would require only minor adjustments to existing clinical pathways. It would be straightforward to disseminate the results of the study through regional, national, and international respiratory meetings. The health economics analysis would provide cost-effectiveness data to inform service planning and clinical guidelines through policy briefing papers, including those by NICE and SIGN. TRIAL REGISTRATION: PAPMAT was registered with ISRCTN prior to recruitment beginning (ISRCTN Registry 2021): https://www.isrctn.com/ISRCTN33966032 . Registered on 17th November 2021.
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Obstrução das Vias Respiratórias , Avanço Mandibular , Apneia Obstrutiva do Sono , Humanos , Pressão Positiva Contínua nas Vias Aéreas , Análise Custo-Benefício , Estudos Cross-Over , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Accurate arterial blood gas (ABG) analysis is essential in the management of patients with hypercapnic respiratory failure, but repeated sampling requires technical expertise and is painful. Missed sampling is common and has a negative impact on patient care. A newer venous to arterial conversion method (v-TAC, Roche) uses mathematical models of acid-base chemistry, a venous blood gas sample and peripheral blood oxygen saturation to calculate arterial acid-base status. It has the potential to replace routine ABG sampling for selected patient cohorts. The aim of this study was to compare v-TAC with ABG, capillary and venous sampling in a patient cohort referred to start non-invasive ventilation (NIV). METHODS: Recruited patients underwent near simultaneous ABG, capillary blood gas (CBG) and venous blood gas (VBG) sampling at day 0, and up to two further occasions (day 1 NIV and discharge). The primary outcome was the reliability of v-TAC sampling compared with ABG, via Bland-Altman analysis, to identify respiratory failure (via PaCO2) and to detect changes in PaCO2 in response to NIV. Secondary outcomes included agreements with pH, sampling success rates and pain. RESULTS: The agreement between ABG and v-TAC/venous PaCO2 was assessed for 119 matched sampling episodes and 105 between ABG and CBG. Close agreement was shown for v-TAC (mean difference (SD) 0.01 (0.5) kPa), but not for CBG (-0.75 (0.69) kPa) or VBG (+1.00 (0.90) kPa). Longitudinal data for 32 patients started on NIV showed the closest agreement for ABG and v-TAC (R2=0.61). v-TAC sampling had the highest first-time success rate (88%) and was less painful than arterial (p<0.0001). CONCLUSION: Mathematical arterialisation of venous samples was easier to obtain and less painful than ABG sampling. Results showed close agreement for PaCO2 and pH and tracked well longitudinally such that the v-TAC method could replace routine ABG testing to recognise and monitor patients with hypercapnic respiratory failure. TRIAL REGISTRATION NUMBER: NCT04072848; www. CLINICALTRIALS: gov.
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Dióxido de Carbono , Insuficiência Respiratória , Humanos , Adulto , Estudos Longitudinais , Reprodutibilidade dos Testes , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Estudos de CoortesRESUMO
BACKGROUND: An unmet need remains for sensitive outcome measures in neuroprotective trials. The study aims to determine whether a composite clinical motor score, combining the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III motor examination score, Purdue Pegboard Test, and Timed Up and Go, provides greater sensitivity in detecting motor change in early disease than the MDS-UPDRS III alone. METHODS: The Oxford Discovery longitudinal cohort study involves individuals with isolated rapid eye movement sleep behaviour disorder (iRBD) (n=272, confirmed polysomnographically, median follow-up: 1.6 years), idiopathic Parkinson's disease (PD) (n=909, median follow-up: 3.5 years, baseline: <3.5 years disease duration) and controls (n=316, age-matched and sex-matched, without a first-degree family history of PD). Motor and non-motor assessments were performed at each in-person visit. RESULTS: Compared with the MDS-UPDRS III, the composite clinical motor score demonstrated a wider score distribution in iRBD and controls, lower coefficient of variation (37% vs 67%), and higher correlation coefficients with self-reported measures of motor severity (0.65 vs 0.61) and overall health status (-0.40 vs -0.33). Greater score range in mild to moderate PD, higher magnitude of longitudinal change in iRBD and longitudinal score linearity suggest better sensitivity in detecting subtle motor change. The composite clinical motor score was more accurate than the MDS-UPDRS III in predicting clinical outcomes, requiring 64% fewer participants with PD and 51% fewer participants with iRBD in sample size estimations for a hypothetical 18-month placebo-controlled clinical trial. CONCLUSION: The composite clinical motor score may offer greater consistency and sensitivity in detecting change than the MDS-UPDRS III.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Estudos Longitudinais , Testes de Estado Mental e Demência , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/diagnóstico , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Continuous positive airway pressure (CPAP) may be a useful treatment strategy for patients with severe COVID-19 pneumonia but its effectiveness in preventing mechanical ventilation is unknown. We aimed to evaluate the outcomes of COVID-19 patients treated with CPAP and determine predictors of CPAP response. DESIGN: This was a retrospective observational cohort study. SETTING: The study took place in the intensive care unit (ICU) at Royal Papworth Hospital (RPH) in Cambridge, UK. PATIENTS: We included all consecutive patients with confirmed COVID-19 pneumonia who were transferred from neighbouring hospitals between 14th March and 6th May, 2020 for consideration of ventilatory support. INTERVENTION: We instituted the use of CPAP for all patients who arrived in RPH not intubated and were not making satisfactory progress on supplemental oxygen alone. MEASUREMENTS AND MAIN RESULTS: Of 33 self-ventilating patients included in this study, 22 (66.7%) were male and the mean age was 54 ± 13.23 patients received CPAP. They were more hypoxaemic than those treated with oxygen alone (PaO2/FiO2 ratio; 84.3 ± 19.0 vs 170.0 ± 46.0 mmHg, p = 0.001). There was a significant improvement in PaO2/FiO2 ratio 1-2 hours after CPAP initiation (167.4 ± 49.0 from 84.3 ± 19.0 mmHg, p = 0.001). 14 (61%) patients responded to CPAP and 9 required intubation. There was no difference between these two groups in terms of the severity of baseline hypoxaemia (PaO2/FiO2 ratio; 84.5 ± 16.0 vs 83.9 ± 23.0 mmHg, p = 0.94) but CPAP responders had significantly lower C-reactive protein (CRP) (176 ± 83 vs 274 ± 63 mg/L, p = 0.007), interleukin-6 (IL-6) (30 ± 47 vs 139 ± 148 pg/mL, p = 0.037), and D-dimer (321 ± 267 vs 941 + 1990 ng/mL, p = 0.003). CT pulmonary angiogram was performed in 6 out of 9 intubated patients and demonstrated pulmonary emboli in 5 of them. All patients were discharged from ICU and there were no fatalities. CONCLUSIONS: In this cohort, CPAP was an effective treatment modality to improve hypoxaemia and prevent invasive ventilation in a substantial proportion of patients with severe respiratory failure. Accepting the small sample size, we also found raised biomarkers of inflammation (CRP and IL-6) and coagulopathy (D-Dimer) to be more useful predictors of CPAP responsiveness than the severity of hypoxaemia, and could help to guide intubation decisions in this clinical setting.
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BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected pâ=â0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
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Doença de Parkinson , Transtorno do Comportamento do Sono REM , Saposinas/genética , Sinucleinopatias , Glucosilceramidase/genética , Humanos , Doença de Parkinson/complicações , Transtorno do Comportamento do Sono REM/diagnósticoRESUMO
BACKGROUND: Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older. METHODS/FINDINGS: Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4-19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5-11 years, and 119 were 12-19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30-2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44-12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers' catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded. CONCLUSIONS: In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1-8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.
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Narcolepsia/etiologia , Polissorbatos/efeitos adversos , Esqualeno/efeitos adversos , Vacinação/efeitos adversos , alfa-Tocoferol/efeitos adversos , Adolescente , Criança , Pré-Escolar , Combinação de Medicamentos , Inglaterra/epidemiologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/epidemiologia , Masculino , Narcolepsia/epidemiologia , Narcolepsia/imunologia , Razão de Chances , Pandemias , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Study Objectives: To evaluate adherence to sodium oxybate prescribing information for indication and dosage, patients' compliance with instructions for use, safety/tolerability in routine clinical practice, and abuse potential. Methods: A postauthorization, noninterventional surveillance study (NCT00244465) in patients who were prescribed sodium oxybate according to current practice by sleep disorders specialists. Patients were monitored for ≤18 months. Results: Overall, 749 patients were enrolled; 730 included in the intent-to-treat population (narcolepsy type 1 n = 670, other indications n = 60). We report on patients with narcolepsy type 1 (female 47.9%, mean age 39.4 years); 495/670 (73.9%) completed the study. Median dose: at start of study 4.5 g per night, 6 g per night throughout study, in two equal doses. According to the treatment compliance checklist, 35.5 per cent of patients consumed alcohol, 19.3 per cent took the medication <2 hr after food, and 27.1 per cent did not adhere to recommended time schedule, with few associated treatment-emergent adverse events (TEAEs). Incidences of higher-than-recommended doses, difficulty in preparing doses, and abuse were low. TEAEs were reported by 67.3 per cent, most frequently headache (11.6%) and nasopharyngitis (6.4%). Discontinuation due to TEAEs: 8.8 per cent. Serious TEAEs: 6.4 per cent. There were no reports of respiratory depression. No particular safety concerns were identified in pediatric or elderly patients, or those with underlying sleep apnea. Conclusions: In this large postauthorization safety study of sodium oxybate use, indication and dosage prescribing recommendations were generally followed, and most patients complied with instructions, with deviations around alcohol consumption, eating before dosing and timing. The overall safety profile was consistent with previous observations; incidence of abuse was low. Section: Neurological disorders. Clinical Trial: Postauthorization, noninterventional, surveillance, pharmacoepidemiology study to evaluate long-term safety, tolerability, and compliance in administration of Xyrem (sodium oxybate) oral solution in patients who receive treatment with this medication in regular clinical practice. https://clinicaltrials.gov/ct2/show/NCT00244465, ClinicalTrials.gov: NCT00244465.
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Anestésicos Intravenosos/uso terapêutico , Adesão à Medicação , Narcolepsia/tratamento farmacológico , Narcolepsia/epidemiologia , Vigilância da População , Oxibato de Sódio/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Narcolepsia/diagnóstico , Vigilância da População/métodos , Resultado do TratamentoRESUMO
Objectives: Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Methods: Clinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson's (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations. Results: Compared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson's Disease Rating Scale (UPDRS)-III, timed "get-up-and-go", Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson's compared to 0.3% (95% CI 0.009%, 2%) of controls. Conclusions: RBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions.
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Doença de Parkinson/complicações , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/complicações , Idoso , Antidepressivos/farmacologia , Ansiedade , Apatia , Estudos de Casos e Controles , Depressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Obesidade , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Fenótipo , Qualidade de Vida , Transtorno do Comportamento do Sono REM/genética , Transtorno do Comportamento do Sono REM/fisiopatologia , Transtorno do Comportamento do Sono REM/psicologia , Medição de Risco , FumarRESUMO
SEE POSTUMA DOI101093/AWW131 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Resting state functional magnetic resonance imaging dysfunction within the basal ganglia network is a feature of early Parkinson's disease and may be a diagnostic biomarker of basal ganglia dysfunction. Currently, it is unclear whether these changes are present in so-called idiopathic rapid eye movement sleep behaviour disorder, a condition associated with a high rate of future conversion to Parkinson's disease. In this study, we explore the utility of resting state functional magnetic resonance imaging to detect basal ganglia network dysfunction in rapid eye movement sleep behaviour disorder. We compare these data to a set of healthy control subjects, and to a set of patients with established early Parkinson's disease. Furthermore, we explore the relationship between resting state functional magnetic resonance imaging basal ganglia network dysfunction and loss of dopaminergic neurons assessed with dopamine transporter single photon emission computerized tomography, and perform morphometric analyses to assess grey matter loss. Twenty-six patients with polysomnographically-established rapid eye movement sleep behaviour disorder, 48 patients with Parkinson's disease and 23 healthy control subjects were included in this study. Resting state networks were isolated from task-free functional magnetic resonance imaging data using dual regression with a template derived from a separate cohort of 80 elderly healthy control participants. Resting state functional magnetic resonance imaging parameter estimates were extracted from the study subjects in the basal ganglia network. In addition, eight patients with rapid eye movement sleep behaviour disorder, 10 with Parkinson's disease and 10 control subjects received (123)I-ioflupane single photon emission computerized tomography. We tested for reduction of basal ganglia network connectivity, and for loss of tracer uptake in rapid eye movement sleep behaviour disorder and Parkinson's disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson's disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson's disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson's disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson's disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder.
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Doenças dos Gânglios da Base , Neuroimagem Funcional/métodos , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Idoso , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/metabolismo , Transtorno do Comportamento do Sono REM/fisiopatologia , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness, impairs quality-of-life, and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure (CPAP) treatment and mandibular advancement devices (MAD) have been shown to be effective in individual trials but their effectiveness particularly relative to disease severity is unclear. A MEDLINE, Embase and Science Citation Index search updating two systematic reviews to August 2013 identified 77 RCTs in adult OSAH patients comparing: MAD with conservative management (CM); MAD with CPAP; or CPAP with CM. Overall MAD and CPAP significantly improved apnoea-hypopnoea index (AHI) (MAD -9.3/hr (p < 0.001), CPAP -25.4 (p < 0.001)). In direct comparisons mean AHI and Epworth sleepiness scale score were lower (7.0/hr (p < 0.001) and 0.67 (p = 0.093) respectively) for CPAP. There were no CPAP vs. MAD trials in mild OSAH but in comparisons with CM, MAD and CPAP reduced ESS similarly (MAD 2.01 (p < 0.001); CPAP 1.23 (p = 0.012). Both MAD and CPAP are clinically effective in the treatment of OSAH. Although CPAP has a greater treatment effect, MAD is an appropriate treatment for patients who are intolerant of CPAP and may be comparable to CPAP in mild disease.
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Pressão Positiva Contínua nas Vias Aéreas/métodos , Avanço Mandibular/instrumentação , Apneia Obstrutiva do Sono/terapia , Doenças Cardiovasculares/etiologia , Humanos , Avanço Mandibular/métodos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Individuals with REM sleep behaviour disorder are at significantly higher risk of developing Parkinson's disease. Here we examined visual short-term memory deficits--long associated with Parkinson's disease--in patients with REM sleep behaviour disorder without Parkinson's disease using a novel task that measures recall precision. Visual short-term memory for sequentially presented coloured bars of different orientation was assessed in 21 patients with polysomnography-proven idiopathic REM sleep behaviour disorder, 26 cases with early Parkinson's disease and 26 healthy controls. Three tasks using the same stimuli controlled for attentional filtering ability, sensorimotor and temporal decay factors. Both patients with REM sleep behaviour disorder and Parkinson's disease demonstrated a deficit in visual short-term memory, with recall precision significantly worse than in healthy controls with no deficit observed in any of the control tasks. Importantly, the pattern of memory deficit in both patient groups was specifically explained by an increase in random responses. These results demonstrate that it is possible to detect the signature of memory impairment associated with Parkinson's disease in individuals with REM sleep behaviour disorder, a condition associated with a high risk of developing Parkinson's disease. The pattern of visual short-term memory deficit potentially provides a cognitive marker of 'prodromal' Parkinson's disease that might be useful in tracking disease progression and for disease-modifying intervention trials.
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Transtornos da Memória/complicações , Transtornos da Memória/psicologia , Memória de Curto Prazo , Doença de Parkinson/psicologia , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/psicologia , Percepção Visual , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Rememoração Mental , Doença de Parkinson/complicações , Estimulação Luminosa , Polissonografia , Sintomas ProdrômicosRESUMO
The treatment options currently available for narcolepsy are often unsatisfactory due to suboptimal efficacy, troublesome side effects, development of drug tolerance, and inconvenience. Our understanding of the neurobiology of narcolepsy has greatly improved over the last decade. This knowledge has not yet translated into additional therapeutic options for patients, but progress is being made. Some compounds, such as histaminergic H3 receptor antagonists, may prove useful in symptom control of narcolepsy. The prospect of finding a cure still seems distant, but hypocretin replacement therapy offers some promise. In this narrative review, we describe these developments and others which may yield more effective narcolepsy treatments in the future.
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BACKGROUND: Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness (EDS), impairs quality of life (QoL) and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure (CPAP) treatment is clinically effective but undermined by intolerance, and its cost-effectiveness is borderline in milder cases. Mandibular advancement devices (MADs) are another option, but evidence is lacking regarding their clinical effectiveness and cost-effectiveness in milder disease. OBJECTIVES: (1) Conduct a randomised controlled trial (RCT) examining the clinical effectiveness and cost-effectiveness of MADs against no treatment in mild to moderate OSAH. (2) Update systematic reviews and an existing health economic decision model with data from the Trial of Oral Mandibular Advancement Devices for Obstructive sleep apnoea-hypopnoea (TOMADO) and newly published results to better inform long-term clinical effectiveness and cost-effectiveness of MADs and CPAP in mild to moderate OSAH. TOMADO: A crossover RCT comparing clinical effectiveness and cost-effectiveness of three MADs: self-moulded [SleepPro 1™ (SP1); Meditas Ltd, Winchester, UK]; semibespoke [SleepPro 2™ (SP2); Meditas Ltd, Winchester, UK]; and fully bespoke [bespoke MAD (bMAD); NHS Oral-Maxillofacial Laboratory, Addenbrooke's Hospital, Cambridge, UK] against no treatment, in 90 adults with mild to moderate OSAH. All devices improved primary outcome [apnoea-hypopnoea index (AHI)] compared with no treatment: relative risk 0.74 [95% confidence interval (CI) 0.62 to 0.89] for SP1; relative risk 0.67 (95% CI 0.59 to 0.76) for SP2; and relative risk 0.64 (95% CI 0.55 to 0.76) for bMAD (p < 0.001). Differences between MADs were not significant. Sleepiness [as measured by the Epworth Sleepiness Scale (ESS)] was scored 1.51 [95% CI 0.73 to 2.29 (SP1)] to 2.37 [95% CI 1.53 to 3.22 (bMAD)] lower than no treatment (p < 0.001), with SP2 and bMAD significantly better than SP1. All MADs improved disease-specific QoL. Compliance was lower for SP1, which was unpopular at trial exit. At 4 weeks, all devices were cost-effective at £20,000/quality-adjusted life-year (QALY), with SP2 the best value below £39,800/QALY. META-ANALYSIS: A MEDLINE, EMBASE and Science Citation Index search updating two existing systematic reviews (one from November 2006 and the other from June 2008) to August 2013 identified 77 RCTs in adult OSAH patients comparing MAD with conservative management (CM), MADs with CPAP or CPAP with CM. MADs and CPAP significantly improved AHI [MAD -9.3/hour (p < 0.001); CPAP -25.4/hour (p < 0.001)]. Effect difference between CPAP and MADs was 7.0/hour (p < 0.001), favouring CPAP. No trials compared CPAP with MADs in mild OSAH. MAD and CPAP reduced the ESS score similarly [MAD 1.6 (p < 0.001); CPAP 1.6 (p < 0.001)]. LONG-TERM COST-EFFECTIVENESS: An existing model assessed lifetime cost-utility of MAD and CPAP in mild to moderate OSAH, using the revised meta-analysis to update input values. The TOMADO provided utility estimates, mapping ESS score to European Quality of Life-5 Dimensions three-level version for device cost-utility. Using SP2 as the standard device, MADs produced higher mean costs and mean QALYs than CM [incremental cost-effectiveness ratio (ICER) £6687/QALY]. From a willingness to pay (WTP) of £15,367/QALY, CPAP is cost-effective, although the likelihood of MADs (p = 0.48) and CPAP (p = 0.49) being cost-effective is very similar. Both were better than CM, but there was much uncertainty in the choice between CPAP and MAD (at a WTP £20,000/QALY, the probability of being the most cost-effective was 47% for MAD and 52% for CPAP). When SP2 lifespan increased to 18 months, the ICER for CPAP compared with MAD became £44,066. The ICER for SP1 compared with CM was £1552, and for bMAD compared with CM the ICER was £13,836. The ICER for CPAP compared with SP1 was £89,182, but CPAP produced lower mean costs and higher mean QALYs than bMAD. Differential compliance rates for CPAP reduces cost-effectiveness so MADs become less costly and more clinically effective with CPAP compliance 90% of SP2. CONCLUSIONS: Mandibular advancement devices are clinically effective and cost-effective in mild to moderate OSAH. A semi-bespoke MAD is the appropriate first choice in most patients in the short term. Future work should explore whether or not adjustable MADs give additional clinical and cost benefits. Further data on longer-term cardiovascular risk and its risk factors would reduce uncertainty in the health economic model and improve precision of effectiveness estimates. TRIAL REGISTRATION: This trial is registered as ISRCTN02309506. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 67. See the NIHR Journals Library website for further project information.
Assuntos
Doenças Cardiovasculares/etiologia , Pressão Positiva Contínua nas Vias Aéreas/instrumentação , Distúrbios do Sono por Sonolência Excessiva/etiologia , Avanço Mandibular/instrumentação , Apneia Obstrutiva do Sono/terapia , Adulto , Idoso , Doenças Cardiovasculares/economia , Comorbidade , Pressão Positiva Contínua nas Vias Aéreas/economia , Pressão Positiva Contínua nas Vias Aéreas/métodos , Análise Custo-Benefício , Estudos Cross-Over , Inglaterra , Feminino , Humanos , Masculino , Avanço Mandibular/economia , Avanço Mandibular/métodos , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Anos de Vida Ajustados por Qualidade de Vida , Análise de Regressão , Medição de Risco , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/economia , Medicina Estatal/economiaRESUMO
PURPOSE OF REVIEW: Although mandibular advancement devices (MADs) provide an alternative to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA), their effectiveness and role remain unclear. Several recent studies and an updated meta-analysis have attempted to address these uncertainties. This review examines their contribution to the existing evidence and discusses the future priorities for MAD research. RECENT FINDINGS: Recent work has examined the impact of MAD design on clinical and cost-effectiveness in milder disease. A robust comparison of CPAP and MADs in more severe OSA has reported equivalent improvements in several important health outcomes. Other notable contributions have examined compliance, definitions of treatment success and longer term outcomes of MAD therapy. SUMMARY: There is now a growing body of evidence suggesting that MADs are a clinically and cost-effective treatment for OSA; and in some cases, patient preference may make them a better option than CPAP. Further work needs to continue to refine MAD therapy in order to optimize treatment response and compliance, whilst retaining a pragmatic and cost-effective approach that is relevant to clinical practice and sustainable in the longer term.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Avanço Mandibular , Aparelhos Ortodônticos Removíveis , Apneia Obstrutiva do Sono/terapia , Pressão Positiva Contínua nas Vias Aéreas/instrumentação , Análise Custo-Benefício , Humanos , Avanço Mandibular/instrumentação , Cooperação do Paciente , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: The addition of domiciliary non-invasive ventilation (NIV) to standard therapy in chronic obstructive pulmonary disease (COPD) patients with compensated ventilatory failure (CVF) is reported to have beneficial effects. Compliance with NIV is an important factor. Volume assured NIV (va-NIV) may improve compliance and ventilation during sleep by automatically titrating ventilatory pressures. METHODS: A prospective single centre, randomised, parallel group trial comparing va-NIV and pressure preset NIV (pp-NIV) in COPD patients with CVF naïve to domiciliary NIV was performed (ISCRTN91892415). The primary outcomes were arterial blood gases, mean overnight oximetry (mSpO2) and compliance after three months. Secondary outcomes included pulmonary function, exercise capacity and health-related quality of life assessment. RESULTS: Forty patients were randomised in a 1:1 ratio. The va-NIV median target minute ventilation was 8.4 L/min and pp-NIV median inspiratory pressure was 28 cmH2O. There were no significant differences between groups in primary or secondary outcomes after three months. Mean (SD) PaO2 8.7 (1.7) versus 7.9 (1.7) kPa (p = 0.19), PaCO2 6.7 (0.5) versus 7.3 (1.1) kPa (p = 0.1), mSpO2 89.7 (4.2) versus 89.8 (3.9) % (p = 0.95), compliance 5.0 (3.1) versus 4.7 (3.2) hours (p = 0.8) in va-NIV versus pp-NIV respectively. Patients allocated va-NIV spent fewer days in hospital initiating therapy 3.3 (1.6) versus 5.2 (2.8) (p = 0.02). Both groups showed significant improvements in PaCO2 and mSpO2 after three months treatment. CONCLUSIONS: Domiciliary va-NIV and pp-NIV have similar effects on physiological outcomes in COPD patients with CVF and both are well tolerated.
Assuntos
Tolerância ao Exercício/fisiologia , Hipercapnia/terapia , Ventilação não Invasiva/métodos , Doença Pulmonar Obstrutiva Crônica/terapia , Insuficiência Respiratória/terapia , Idoso , Gasometria , Feminino , Humanos , Hipercapnia/etiologia , Hipercapnia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oximetria , Respiração com Pressão Positiva/métodos , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Insuficiência Respiratória/etiologia , Resultado do TratamentoRESUMO
RATIONALE: Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. OBJECTIVES: To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. MEASUREMENTS AND METHODS: This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5-<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6â weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4â weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. MAIN RESULTS: 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20,000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39,800/QALY. CONCLUSIONS: Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. TRIAL REGISTRATION NUMBER: ISRCTN02309506.
Assuntos
Avanço Mandibular/instrumentação , Apneia Obstrutiva do Sono/terapia , Sono/fisiologia , Adulto , Idoso , Análise Custo-Benefício , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Avanço Mandibular/economia , Pessoa de Meia-Idade , Polissonografia , Qualidade de Vida , Estudos Retrospectivos , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/fisiopatologia , Resultado do TratamentoAssuntos
Estimulantes do Sistema Nervoso Central/uso terapêutico , Hipersonia Idiopática/tratamento farmacológico , Narcolepsia/tratamento farmacológico , Antidepressivos Tricíclicos/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Catalepsia/diagnóstico , Catalepsia/tratamento farmacológico , Dextroanfetamina/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/etiologia , Hipersonia Idiopática/fisiopatologia , Estilo de Vida , Metilfenidato/uso terapêutico , Modafinila , Narcolepsia/diagnóstico , Narcolepsia/etiologia , Narcolepsia/fisiopatologia , Polissonografia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Oxibato de Sódio/uso terapêutico , Resultado do TratamentoAssuntos
Apneia Obstrutiva do Sono/etiologia , Apneia Obstrutiva do Sono/terapia , Pressão Positiva Contínua nas Vias Aéreas , Doenças do Sistema Endócrino/complicações , Humanos , Síndrome Metabólica/complicações , Oxigenoterapia/métodos , Educação de Pacientes como Assunto , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Redução de PesoRESUMO
Recent randomised controlled trials suggest non-invasive ventilation may offer benefit in the long-term management of ventilatory failure in stable COPD. The best mode of ventilation is unknown and newer volume assured modes may offer advantages by optimising ventilation overnight when treatment is delivered. This study compares volume assured with pressure preset non-invasive ventilation. Randomised crossover trial including twenty five subjects previously established on long-term non-invasive ventilation to manage COPD with chronic ventilatory failure. Two 8-week treatment periods of volume assured and pressure preset non-invasive ventilation. The primary outcomes were daytime arterial blood gas tensions and mean nocturnal oxygen saturation. Secondary outcomes included lung function, exercise capacity, mean nocturnal transcutaneous carbon dioxide, health status and compliance. No significant differences were seen in primary or secondary outcomes following 8 weeks of treatment when comparing volume assured and pressure preset ventilation. Primary outcomes assessed: mean (standard deviation) PaO(2) 7.8 (1.2) vs 8.1(1) kPa, PaCO(2) 6.7 (1.1) vs 6.3 (1.2) kPa and mean nocturnal oxygenation 90 (4) vs 91 (3)% volume assured versus pressure preset, respectively. Volume assured and pressure preset non-invasive ventilation appear equally effective in the long-term management of ventilatory failure associated with stable COPD.