Start, switch and stop (triple-S) criteria for enzyme replacement therapy of late-onset Pompe disease: European Pompe Consortium recommendation update 2024.

BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.

Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

BACKGROUND AND OBJECTIVES: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. METHODS: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. RESULTS: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. DISCUSSION: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.

Determinants of diaphragm inspiratory motion, diaphragm thickening, and its performance for predicting respiratory restrictive pattern in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD. METHODS: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests. RESULTS: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001). DISCUSSION: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

AIMS: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results. CONCLUSION: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Impact of a medication reconciliation care bundle at hospital discharge on continuity of care: A randomised controlled trial.

OBJECTIVE: To compare the impact of a care bundle including medication reconciliation at discharge by a pharmacist versus standard of care, on continuity of therapeutic changes between hospital and primary care and outcome of patients, within 1 month after discharge. METHODS: Randomised controlled trial in 120 adult patients with at least one chronic disease and three current medications before admission, hospitalised in an infectious disease department of a tertiary hospital and discharged home. Patients were randomly assigned (1:1) to receive a discharge care bundle including medication reconciliation, counselling session and documentation transfer to primary care physician (PCP) (intervention group) or standard of care (control group). Primary outcome was the proportion of in-hospital prescription changes, not maintained by the PCP, 1 month after discharge. Secondary outcome measures included the proportion of patients experiencing early PCP's consultation, hospital readmissions or adverse reactions within 1-month postdischarge and cost of discharge prescriptions. RESULTS: Baseline characteristics were comparable between the two groups. One month after discharge, the proportion of in-hospital prescription changes, not maintained by the PCP, was 11% in the intervention group versus 24% in the control group (P = .007). The median delay before PCP's consultation was longer in the intervention group (30.5 vs 19.5 days, P = .013), there were fewer patients readmitted to hospital (3.4% vs 20.7%, P = .009, odds ratio (OR) = 0.13 [0.02-0.53]) and fewer patients who suffered from adverse drug reaction (7.0% vs 22.8%, P = .04, OR = 0.26 [0.07-0.78]). CONCLUSION: This care bundle resulted in the reduction of treatment changes between hospital discharge and primary care.

Expiratory obstruction in patients with Duchenne muscular dystrophy under non-invasive ventilation: A step-by-step analysis of a new obstructive pattern.

PURPOSE: Non-invasive ventilation (NIV) is the reference standard for managing chronic hypoventilation in patients with Duchenne muscular dystrophy (DMD). In these patients, upper airway obstruction under NIV may compromise efficacy and adherence. We aim to describe a novel pattern of expiratory obstructive events occurring during nocturnal barometric NIV. METHODS: We retrospectively included all patients with DMD who underwent full-night polygraphy during NIV as part of their usual follow-up between May 2018 and July 2019. RESULTS: We provide a step-by-step description of this previously undescribed pattern of obstruction. Expiratory obstructions lead to end-inspiratory breath-holding and impossibility to take another inspiratory breath with a barometric mode until expiration occurs. These events were observed in 4 (36%) of 11 DMD patients under barometric NIV. CONCLUSION: Expiratory obstructions may be common in DMD patients receiving NIV and should be sought out routinely. This previously undescribed variant of obstructive event must be identified.

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.

Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. RECENT FINDINGS: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. SUMMARY: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.

Peak Cough Flow Fails to Detect Upper Airway Collapse During Negative Pressure Titration for Cough-Assist.

OBJECTIVE: To study the ability of peak cough flow (PCF) and effective cough volume, defined as the volume exsufflated >3 L/s, to detect upper airway collapse during mechanical insufflation-exsufflation (MI-E) titration in neuromuscular patients. DESIGN: Prospective observational study. SETTING: Rehabilitation hospital. PARTICIPANTS: Patients (N=27) with neuromuscular disease causing significant impairment of chest wall and/or diaphragmatic movement. INTERVENTIONS: The lowest insufflation pressure producing the highest inspiratory capacity was used. Exsufflation pressure was decreased from -20 cm H2O to -60/-70 cm H2O, in 10-cm H2O decrements, until upper airway collapse was detected using the reference standard of flow-volume curve analysis (after PCF, abrupt flattening or flow decrease vs previous less negative exsufflation pressure). MAIN OUTCOME MEASURES: PCF and effective cough volume profiles during expiration with MI-E. RESULTS: Upper airway collapse occurred in 10 patients during titration. Effective cough volume increased with decreasing expiratory pressure then decreased upon upper airway collapse occurrence. PCF continued to increase after upper airway collapse occurrence. In 5 other patients, upper airway collapse occurred at the initial -20 cm H2O exsufflation pressure, and during titration, PCF increased and effective cough volume remained unchanged at <200 mL. PCF had 0% sensitivity for upper airway collapse, whereas effective cough volume had 100% sensitivity and specificity. CONCLUSION: Of 27 patients, 15 experienced upper airway collapse during MI-E titration. Upper airway collapse was associated with an effective cough volume decrease or plateau and with increasing PCF. Accordingly, effective cough volume, but not PCF, can detect upper airway collapse.

Flow and airway pressure analysis for detecting ineffective effort during mechanical ventilation in neuromuscular patients.

Ineffective efforts (IEs) are among the most common types of patient-ventilator asynchrony. The objective of this study is to validate IE detection during expiration using pressure and flow signals, with respiratory effort detection by esophageal pressure (Pes) measurement as the reference, in patients with neuromuscular diseases (NMDs). We included 10 patients diagnosed with chronic respiratory failure related to NMD. Twenty-eight 5-minute recordings of daytime ventilation were studied for IE detection. Standard formulas were used to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of IE detection using pressure and flow signals compared to Pes measurement. Mean sensitivity and specificity of flow and pressure signal-based IE detection versus Pes measurement were 97.5% ± 5.3% and 91.4% ± 13.7%, respectively. NPV was 98.1% ± 8.2% and PPV was 67.6% ± 33.8%. Spearman's rank correlation coefficient indicated a moderately significant correlation between frequencies of IEs and controlled cycles ( ρ = 0.50 and p = 0.01). Among respiratory cycles, 311 (11.2%) were false-positive IEs overall. Separating false-positive IEs according to their mechanisms, we observed premature cycling in 1.2% of cycles, delayed ventilator triggering in 0.1%, cardiac contraction in 9.2%, and upper airway instability during expiration in 0.3%. Using flow and pressure signals to detect IEs is a simple and rapid method that produces adequate data to support clinical decisions.

Effect and impact of mechanical ventilation in myotonic dystrophy type 1: a prospective cohort study.

Few studies have assessed the impact of home ventilation in patients with myotonic dystrophy type 1 (DM1) and no specific recommendations are available. We assessed the survival associated with category of home ventilation adherence of patients with DM1 followed up at a home ventilation unit using a Cox proportional hazards model. 218 patients were included; those who refused or delayed their acceptance of non-invasive ventilation were at higher risk for severe events (invasive ventilation or death) (P=0.03). Risk of death was associated with orthopnoea (HR 2.37; 95% CI 1.17 to 4.80; P<0.02) and adherence category (100 to 90% vs >75%: HR 3.26; 95% CI 1.32 to 8.04; P<0.03). Failure to use home ventilation as prescribed may be associated with increased mortality in patients with DM1.

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.

Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease.

BACKGROUND: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. METHODS: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared. RESULTS: Twelve patients (7 males) were identified. Median age at symptom onset was 24years [IQR=15.5; 36.0]. At baseline ventilation was invasive in 11 patients and noninvasive in one, with a median ventilation time of 24h [IQR=21.88; 24.00] (min 20; max 24). ERT was initiated at a median age of 52.5years [IQR=35.75; 66.50]. Median treatment duration was 55months [IQR=39.5; 81.0]. During observational period no adverse reaction to ERT was recorded, five patients (41.67%) died, three decreased their ventilation time by 30, 60 and 90min and two increased their assisted walking distance, by 80 and 20m. CONCLUSION: Some patients at a very advanced stage of Pompe disease may show a mild benefit from ERT, in terms of increased time of autonomous ventilation and of enlarged distance in assisted walk. ERT can be initiated in these patients in order to retain their current level of independence and ability to perform daily life activities.

Invasive versus non-invasive ventilation for acute respiratory failure in neuromuscular disease and chest wall disorders.

BACKGROUND: Acute respiratory failure is a common life-threatening complication of acute onset neuromuscular diseases, and may exacerbate chronic hypoventilation in patients with neuromuscular disease or chest wall disorders. Standard management includes oxygen supplementation, physiotherapy, cough assistance, and, whenever needed, antibiotics and intermittent positive pressure ventilation. Non-invasive mechanical ventilation (NIV) via nasal, buccal or full-face devices has become routine practice in many centres. OBJECTIVES: The primary objective of this review was to compare the efficacy of non-invasive ventilation with invasive ventilation in improving short-term survival in acute respiratory failure in people with neuromuscular disease and chest wall disorders. The secondary objectives were to compare the effects of NIV with those of invasive mechanical ventilation on improvement in arterial blood gas after 24 hours and lung function measurements after one month, incidence of barotrauma and ventilator-associated pneumonia, duration of mechanical ventilation, length of stay in the intensive care unit and length of hospital stay. SEARCH METHODS: We searched the following databases on 11 September 2017: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase. We also searched conference proceedings and clinical trials registries. SELECTION CRITERIA: We planned to include randomised or quasi-randomised trials with or without blinding. We planned to include trials performed in children or adults with acute onset neuromuscular diseases or chronic neuromuscular disease or chest wall disorders presenting with acute respiratory failure that compared the benefits and risks of invasive ventilation versus NIV. DATA COLLECTION AND ANALYSIS: Two review authors reviewed searches and independently selected studies for assessment. We planned to follow standard Cochrane methodology for data collection and analysis. MAIN RESULTS: We did not identify any trials eligible for inclusion in the review. AUTHORS' CONCLUSIONS: Acute respiratory failure is a life-threatening complication of acute onset neuromuscular disease and of chronic neuromuscular disease and chest wall disorders. We found no randomised trials on which to elaborate evidence-based practice for the use of non-invasive versus invasive mechanical ventilation. For researchers, there is a need to design and conduct new randomised trials to compare NIV with invasive ventilation in acute neuromuscular respiratory failure. These trials should anticipate variations in treatment responses according to disease condition (acute onset versus acute exacerbation on chronic neuromuscular diseases) and according to the presence or absence of bulbar dysfunction.

Short-term effect of volume recruitment-derecruitment manoeuvre on chest-wall motion in Duchenne muscular dystrophy.

Because progressive respiratory muscle weakness leads to decreased chest-wall motion with eventual ribcage stiffening, the purpose was to compare vital capacity (VC) and contributions of chest-wall compartments before and after volume recruitment-derecruitment manoeuvres (VRDM) in Duchenne muscular dystrophy (DMD). We studied nine patients with DMD and VC lower than 30% of predicted. VRDM was performed using 15 insufflations-exsufflations of +30 to -30 cmH2O. VC and three-dimensional chest-wall motion were measured, as well as oxygen saturation, transcutaneous partial pressure of carbon dioxide and the rapid shallow breathing index (respiratory rate/tidal volume) before (baseline) and immediately and 1 hour after VRDM. VC increased significantly immediately after VRDM (108% ± 7% of baseline, p = 0.018) but returned to baseline within 1 hour, and the rapid shallow breathing index increased significantly. The non-dominant side systematically increased immediately after VRDM ( p = 0.0077), and in the six patients with abnormal breathing asymmetry (difference >10% of VC) at baseline, this asymmetry was corrected immediately and/or 1 hour after VRDM. VRDM improved VC and reduced chest-wall motion asymmetry, but this beneficial effect waned rapidly with respiratory muscle fatigue, suggesting that VRDM may need to be repeated during the day to produce lasting benefits.

Nocturnal hypoventilation in neuromuscular disease: prevalence according to different definitions issued from the literature.

PURPOSE: Restrictive respiratory failure is a major cause of morbidity and mortality in neuromuscular diseases (NMD). Home mechanical ventilation (HMV) is used to treat hypoventilation, identified by daytime hypercapnia or nocturnal desaturation. Recently, transcutaneous measure of CO2 (TcCO2) has been increasingly used to detect hypoventilation, using different cut-offs. We aimed to compare the prevalence of hypoventilation in an unselected adult NMD population according to different definitions issued from the literature. METHODS: All consecutive nocturnal capno-oximetries performed between 2010 and 2014 in unventilated adult NMD patients were analysed retrospectively. Concomitant blood gas analysis and lung function data were collected. Patients on oxygen therapy were excluded. Hypoventilation was defined according to eight criteria, based on daytime PaCO2, daytime base excess, nocturnal SpO2 or TcCO2. RESULTS: Data from 232 patients were analysed (mean age 43.1 ± 15.4 years; 50.0 % women; vital capacity 59.2 ± 24.2 % of predicted). The hypoventilation prevalence was 10.3 to 61.2 %, depending on the used definition. The different definitions showed 49.1 to 94.8 % concordance (Cohen's kappa for agreement 0.115 to 0.763). Overall agreement between the eight definitions was poor (Light's kappa 0.267), and agreement between definitions based on nocturnal SpO2 and those based on TcCO2 was even lower (Light's kappa 0.204). CONCLUSIONS: We found large differences in hypoventilation prevalence according to the used definition. This has practical consequences, as HMV indication relies upon hypoventilation detection. We believe that capno-oximetry should be included in the diagnostic tools used to detect hypoventilation but this requires an update of consensus guidelines to agree upon the best definition.

Home monitoring of daytime mouthpiece ventilation effectiveness in patients with neuromuscular disease.

Mouthpiece ventilation (MPV) allows patients with neuromuscular disease to receive daytime support from a portable ventilator, which they can disconnect at will, for example, for speaking, eating, swallowing, and coughing. However, MPV carries a risk of underventilation. Our purpose here was to evaluate the effectiveness of daytime MPV under real-life conditions. Eight wheelchair-bound patients who used MPV underwent daytime polygraphy at home with recordings of airflow, mouthpiece pressure, thoracic and abdominal movements, peripheral capillary oxygen saturation (SpO2), and transcutaneous partial pressure of carbon dioxide (PtcCO2). Times and durations of tasks and activities were recorded. The Apnea-Hypopnea Index (AHI) was computed. Patient-ventilator disconnections ≥3 minutes and episodes of hypoventilation defined as PtcCO2>45 mmHg were counted. Patient-ventilator asynchrony events were analyzed. The AHI was >5 hour(-1) in two patients. Another patient experienced unexplained 3% drops in arterial oxygen saturations at a frequency of 70 hour(-1). Patient-ventilator disconnections ≥3 minutes occurred in seven of eight patients and were consistently associated with decreases in SpO2 and ≥5-mmHg increases in PtcCO2; PtcCO2 rose above 45 mmHg in two patients during these disconnections. The most common type of patient-ventilator asynchrony was ineffective effort. This study confirms that MPV can be effective as long as the patient remains connected to the mouthpiece. However, transient arterial oxygen desaturation and hypercapnia due to disconnection from the ventilator may occur, without inducing unpleasant sensations in the patients. Therefore, an external warning system based on a minimal acceptable value of minute ventilation would probably be useful.

Accuracy of tidal volume delivered by home mechanical ventilation during mouthpiece ventilation: A bench evaluation.

The aim of our study was to evaluate efficacy and reliability of currently available ventilators for mouthpiece ventilation (MPV). Five life-support home ventilators were assessed in a bench test using different settings simulating the specificities of MPV, such as intermittent circuit disconnection and presence of continuous leaks. The intermittent disconnection of the circuit caused relevant swings in the delivered tidal volume ( VT), showing a VT overshoot during the disconnection periods and a VT decrease when the interface was reconnected to the test lung. The five ventilators showed substantial differences in the number of respiratory cycles necessary to reach a stable VT in the volume-controlled setting, ranging from 1.3 ± 0.6 to 7.3 ± 1.2 cycles. These differences were less accentuated in the volume-assisted setting (MPV-dedicated mode, when available). Our data show large differences in the capacity of the different ventilators to deal with the rapidly changing respiratory load features that characterize MPV, which can be further accentuated according to the used ventilator setting. The dedicated MPV modes allow improvement in the performance of ventilators only in some defined situations. This has practical consequences for the choice of the ventilator to be used for MPV in a specific patient.

Electrophysiological diagnosis of Guillain-Barré syndrome subtype: could a single study suffice?

BACKGROUND: Serial electrophysiology has been suggested as essential for accurate diagnosis in Guillain-Barré syndrome (GBS). However, whether more adapted electrophysiological criteria may allow a single study to be sufficient is unknown. METHODS: We retrospectively reviewed records of 365 consecutive patients with GBS from Birmingham, U.K., and Garches, France, admitted between 1998 and 2013. Electrophysiology was analysed using existing criteria as well as a set of modified criteria, developed using sensitive and specific cut-off values for demyelination and incorporating new knowledge on electrophysiology of axonal GBS. We compared diagnostic rates and classification changes using modified criteria with published literature relating to serial studies. RESULTS: With existing criteria, we found similar proportions of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (71.5% vs. 72%; p=1), axonal GBS (17.5% vs. 14.7%; p=0.62) and equivocal forms (9.9% vs. 13.3%; p=0.41) to the previous studies considered. With modified criteria, we identified comparable rates of AIDP (56.2% vs. 58.7%; p=0.70), axonal GBS (35.1% vs. 36%; p=0.89) and equivocal forms (7.7% vs. 5.3%; p=0.63) with a single nerve conduction study as compared with when serial electrophysiology was used in previous analyses. We observed an identical diagnostic shift from AIDP to axonal GBS with modified criteria as that described with serial studies (21.5% vs. 18.5%; p=0.72). Classification changes with modified criteria correlated significantly with performing of electrophysiology ≤7 days after symptom onset (p=0.045), indicating their greater usefulness in earlier disease stages. CONCLUSIONS: A single electrophysiological study may suffice to establish the ultimate electrodiagnosis of GBS subtype if the proposed modified electrodiagnostic criteria are used.