Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia.

OBJECTIVE: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia-telangiectasia and explore genotype-phenotype correlations. METHODS: Cross-sectional data were collected retrospectively. Patients were classified as variant ataxia-telangiectasia based on retained ATM kinase activity. RESULTS: The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations. INTERPRETATION: Individuals with variant ataxia-telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis- or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein levels in some individuals. Missense mutations are associated with milder neurological presentations, but a particularly high malignancy risk, and it is important for clinicians to be aware of these phenotypes. ANN NEUROL 2019;85:170-180.

Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial.

Importance: Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death. Objective: To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation. Design, Setting, and Participants: A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible. Interventions: There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min [interquartile range {IQR}, 0.5-2.0 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min [IQR, 0.5-1.5 L/min]). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute. Main Outcomes and Measures: Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI. Results: A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 21.6 [IQR, 18.2-26.1], mean [SD] forced expiratory volume in the first second of expiration of 0.6 L [0.2 L], and mean [SD] Paco2 while breathing room air of 59 [7] mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group. Conclusions and Relevance: Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months. Trial Registration: clinicaltrials.gov Identifier: NCT00990132.

A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).

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 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 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.

Continuous Positive Airway Pressure plus Mandibular Advancement Therapy (PAPMAT): study protocol for an adaptive randomised crossover trial comparing the benefits and costs of combining two established treatments for obstructive sleep apnoea.

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.

Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

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 p = 0.018). 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.

Weaning from prolonged invasive ventilation in motor neuron disease: analysis of outcomes and survival.

INTRODUCTION: Non-invasive ventilation (NIV) improves prognosis in patients with motor neuron disease (MND) in the absence of major bulbar involvement. However, some experience a rapid and unexpected decline in respiratory function and may undergo emergency tracheal intubation. Weaning from invasive ventilation can be difficult, and reported independence from invasive ventilation is uncommon with poor prognosis. The outcomes of patients with MND referred to a specialist weaning service following emergency tracheal intubation were examined and compared with MND patients electively initiating NIV. METHODS: A case note review was performed on all patients with MND invasively ventilated and referred to a specialist weaning service between 1992 and 2007. Outcomes were compared with those electively commenced on NIV during the same period. RESULTS: Thirty patients were referred for weaning from invasive ventilation which was started in 17 before MND was diagnosed. Fourteen patients (47%) were weaned from invasive ventilation but still required NIV, 13 failed to wean, and three died. Seventeen were discharged home from hospital. The median survival from tracheal intubation was 13.7 months (95% CI 0 to 30.8) for those previously diagnosed and 7.2 months (95% CI 5.1 to 9.4) for those not previously known to have MND. Comparison with patients initiated electively on NIV demonstrated similar survival estimates to that from emergency intubation (median 9.4 (95% CI 6.9 to 12.0) vs 7.8 (95% CI 2.6 to 12.9) months respectively). CONCLUSION: The prognosis in MND following acute respiratory failure and intubation is not always complete ventilator dependence if patients are offered a comprehensive weaning programme.

A bench test to confirm the core features of volume-assured non-invasive ventilation.

UNLABELLED: Volume-assured non-invasive ventilation (NIV) theoretically guarantees minute ventilation with circuit leak compensation unlike other modes of NIV. Bench testing demonstrated that minute ventilation was maintained with varying lung compliance and resistance with minimal effect from circuit leak, confirming for the first time the core features of volume-assured NIV. BACKGROUND AND OBJECTIVE: Volume-assured non-invasive positive pressure ventilation (va-NIPPV) is a novel mode designed to adapt pressure support (PS) to achieve a target minute ventilation (TgV). This may optimize ventilation; however, no data confirm that va-NIPPV compensates appropriately for the changes in pulmonary mechanics and circuit leak seen in clinical practice. Bench testing assessed these principles. METHODS: A ventilator featuring a va-NIPPV mode was studied. A test lung with varying compliance and resistance, and pneumotachograph were used. Eight lung model settings were chosen: (i) low resistance and high compliance; (ii) low resistance and low compliance; (iii) high resistance and high compliance; and (iv) high resistance and low compliance, all with and without additional circuit leak. An expiration valve, respiratory rate of 15, inspiratory time of 1 s and PS between 3 and 21 cm H2O were used. Va-NIPPV was tested with varying TgV after establishing the range of minute ventilation possible in a pressure preset mode. RESULTS: At a TgV of 10 L/min, va-NIPPV delivered minute ventilation of (median (interquartile range) ): 11 (10.9-11, 10.2 (10.2-10.3), 12.4 (12.4-12.4) and 11.2 (10.9-11.2) L/min in test lung settings 1, 2, 3 and 4, respectively. Additional leak between 8-33 L/min had little effect. Similar results were seen at other TgV, within the ventilator's PS capabilities. CONCLUSIONS: These data confirm that va-NIPPV is able to approximate a preset TgV with varying lung compliance and resistance, and that additional circuit leak has little effect on the delivered minute ventilation.

Long-term non-invasive ventilation to manage persistent ventilatory failure after COPD exacerbation.

BACKGROUND AND OBJECTIVE: Patients with ventilatory failure at discharge from hospital following an exacerbation of COPD (ECOPD) have increased work of breathing and reduced inspiratory muscle strength compared with those with a normal arterial carbon dioxide tension (PaCO(2)). They also have a significantly worse prognosis. Long-term non-invasive positive pressure ventilation (NIPPV) may offer a treatment strategy but benefits have not been established. METHODS: We examined the outcomes of 35 patients, with a PaCO(2) >7.5 kPa and normal pH, following hospital admission with an ECOPD. Patients were initiated on long-term NIPPV. Our aims were to establish if NIPPV was tolerated and to describe the effects on ventilatory parameters. RESULTS: Daytime arterial blood gases and nocturnal ventilatory parameters improved significantly on NIPPV. Diurnal PaO(2), self-ventilating, rose from (mean (SD)) 7.3 (1.8) to 8.1 (0.9) kPa (P = 0.005) and PaCO(2) fell from 8.8 (1.3) to 7.3 (0.8) kPa (P

The effects of withdrawing long-term nocturnal non-invasive ventilation in COPD patients.

Patients with ventilatory failure due to chronic obstructive pulmonary disease (COPD) are increasingly managed with long-term non-invasive positive pressure ventilation (NIPPV) and this may improve survival. NIPPV can frequently be interrupted but there are few data detailing the short-term effects and none on the longer-term consequences of treatment withdrawal. Ten patients withdrew from NIPPV for 1 week and were randomised to restart NIPPV or to continued withdrawal for up to 6 months. Outcomes assessed included daytime blood gases, nocturnal ventilation, lung function, exercise capacity and health status. After 1 week of withdrawal PaO(2), PaCO(2), nocturnal oximetry, lung function and exercise capacity did not change, but mean nocturnal transcutaneous CO(2) (6.3 (1) vs. 7.6 (1.1) kPa p = 0.04) and daytime blood gas bicarbonate (30.3 (4.5) vs. 31.2 (3.9) mmol/L p = 0.04) rose. During a 6-month period of withdrawal of nocturnal NIPPV, daytime PaCO(2) (6 (1.1) vs. 7.5 (1.3) kPa p = 0.002) increased and health status (total St George's Respiratory Questionnaire score 55.5 (6.3) vs. 65.6 (10) p = 0.006) worsened. Three out of five patients met a priori criteria to restart NIPPV in the continued withdrawal group. Short interruptions to domiciliary NIPPV used to manage chronic ventilatory failure as a consequence of COPD do not cause a rapid clinical deterioration but nocturnal ventilation worsens and daytime bicarbonate levels increase following 1 week's cessation. Thereafter, daytime PaCO(2) rises and health status worsens, supporting the role of long-term NIPPV in the management of such patients.

A randomised crossover trial comparing volume assured and pressure preset noninvasive ventilation in stable hypercapnic COPD.

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.

The impact of changing people with sleep apnea using CPAP less than 4 h per night to a Bi-level device.

Pressure intolerance is a reason for poor acceptance and subsequent compliance in some patients starting treatment with continuous positive airway pressure (CPAP). In unselected populations initiating CPAP; different types of pressure generating device have not been found to improve compliance. We hypothesized that using Bi-level PAP for patients who reported pressure related discomfort as a cause for poor compliance with CPAP might increase their hours of treatment use. Patients using CPAP <4 h/night with symptoms to suggest pressure intolerance were randomized to receive either a Bi-level PAP device or a new CPAP for 4 weeks. Following a washout period of 2 weeks, they were crossed over to the other device for 4 weeks. Twenty eight volunteers completed the protocol. Compared to the baseline (mean 1.49 h per night), improvement in compliance was noticed when changed to a new CPAP (2.23 h, p = 0.006) or Bi-level PAP (2.73 h, p < 0.001). The trend suggesting superior compliance with a Bi-level PAP device compared to new CPAP was not significant (p = 0.059) and there were no differences in subjective or objective measures of sleepiness. The results of this study suggest that routine intervention with Bi-level PAP in this group of sub-optimally compliant individuals was not very effective in improving PAP usage. There is however a subgroup of patients who complains of difficulty with exhalation; where favorable trends towards improved compliance were observed on Bi-level PAP.

Volume assured versus pressure preset non-invasive ventilation for compensated ventilatory failure in COPD.

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.

Is there an alternative to pre-flight hypoxic challenge testing in scoliotic patients?

INTRODUCTION: Hypoxic challenge testing (HCT) is not readily available in all hospitals. It has recently been shown that resting oximetry does not reliably predict the results of HCT in patients with extrapulmonary restrictive lung disease. We assessed other clinical tests to see if they might be used as an alternative screen for HCT. METHODS: People with primary thoracic scoliosis were recruited. Resting SpO(2), arterial blood gases (ABG's), lung function and shuttle walking test (SWT) were measured. All subjects underwent HCT breathing an inhaled oxygen fraction of 15% for 20 min, or until SpO(2) fell below 85%, when ABG's were taken. RESULTS: Fourteen people (5 male) with thoracic scoliosis, Cobb angle 93 (31) degrees , aged 65 (8.5) years, FEV(1) 0.86 (0.4) L, FVC 1.2 (0.4)L were studied. The resting SpO(2) was 96 (2) %, PaO(2) 9.2 (1) kPa and PaCO(2) 6.1 (0.4) kPa. HCT was positive in 11 subjects (PaO(2) <6.6 kPa). Eight of 11 HCT positive subjects had a resting SpO(2) > 95%. Positive correlation was found between SpO(2) at SWT termination and PaO(2) following HCT (r = 0.56, p = 0.02). Those with saturations of 92% or under at SWT termination had positive HCT. CONCLUSIONS: Despite normal resting SpO(2) subjects with thoracic scoliosis may have positive HCT. Current recommendations for air travel do not accurately identify these people. Desaturation following a SWT may provide a useful screening tool, however a low threshold for performing HCT on people with thoracic scoliosis prior to air travel is warranted.