Spectrum of sleep-disordered breathing and quality of sleep in adolescent and adult patients with spinal muscular atrophy.

Sleep-disordered breathing is common among children with spinal muscular atrophy, but has been hardly studied among adult subjects. Little is known about sleep quality in spinal muscular atrophy. The aims of this study were to evaluate occurrence and characteristics of sleep-disordered breathing and subjective sleep quality among adolescent and adult patients with spinal muscular atrophy type 2 or 3. Twenty patients aged 33.9 ± 15.2 years were studied. They underwent nocturnal cardiorespiratory monitoring, lung and muscular function evaluation, and were administered the Pittsburgh Sleep Quality Index questionnaire. Nineteen patients showed sleep-disordered breathing, with obstructive events in seven subjects and non-obstructive events in the remaining 12. In the latter group, 10 patients showed pseudo-obstructive hypopneas. Patients with non-obstructive sleep-disordered breathing were younger (p = 0.042), had a lower body mass index (p = 0.0001), were more often affected by spinal muscular atrophy type 2 (p = 0.001), and showed worse impairment of respiratory function than patients with obstructive sleep-disordered breathing. Ten patients were classified as poor sleepers and 10 patients good sleepers. In the whole sample, sniff nasal inspiratory pressure proved to be the only independent predictor of sleep quality (p = 0.009). In conclusion, sleep-disordered breathing is common even among adult patients with spinal muscular atrophy type 2 and 3, and may show either obstructive or different types on non-obstructive features. A worse respiratory muscle function is associated to non-obstructive sleep-disordered breathing and poorer sleep quality. Sleep quality should receive greater attention especially in patients with spinal muscular atrophy type 2, who have a poorer respiratory muscle function, as it could affect their quality of life.

Comorbidity in myasthenia gravis: multicentric, hospital-based, and controlled study of 178 Italian patients.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder with fluctuating weakness that causes significant disability and morbidity. Comorbidities may influence the course of MG, particularly in specific subgroups. The aim of this study is to investigate the frequency of comorbidities in MG patients compared to healthy controls (HC) and to evaluate their distribution according to age at disease onset, sex, and disease severity. METHODS: MG patients attending the University Hospital "Paolo Giaccone" in Palermo and "SS Annunziata" Hospital in Chieti were enrolled; HC were enrolled from the general population. Non-parametric statistics and logistic regression were used to assess the association of specific comorbidities according to age at disease onset, sex, disease subtypes, and severity of the disease. RESULTS: A total of 356 subjects were included in the study: 178 MG patients (46% F; median age 60 years [51-71]) and 178 sex- and age-matched HC (46% F, median age 59 years [50-66]). Overall, 86% of MG patients and 76% of HC suffered from comorbidities, and MG patients had a higher number of comorbidities compared to HC. Patients with late-onset suffered from more comorbidities than those with early-onset MG. Hypertension was more common in male patients with MG, while thymic hyperplasia, osteoporosis, and autoimmune diseases were more common in females. Respiratory disorders and thymoma were more common in patients with more severe disease (p < 0.05 for all comparisons). CONCLUSION: MG patients, particularly those with late onset, showed a higher prevalence of comorbidities than HC. Assessment of comorbidities in MG is an essential issue to identify the appropriate treatment and achieve the best management.

Safety outcomes and patients' preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond.

BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Age Related Burden of Swallowing in Adult Patients Affected by Duchenne Muscular Dystrophy.

BACKGROUND: In Duchenne muscular dystrophy (DMD), dysphagia is a common but often overlooked symptom, which may affect quality of life (QoL). Its possible causes are progressive deterioration of muscle groups involved in swallowing function (oropharyngeal, inspiratory muscles) or impairment of autonomic function. OBJECTIVES: In adult patients with DMD, we aimed to identify predictors of swallowing-related QoL and to compare swallowing-related QoL at different ages. METHODS: Forty-eight patients aged 30.0±6.6 years were enrolled. Questionnaires were administered: the Swallowing Quality of Life questionnaire (SWAL-QOL) for swallowing-related QoL assessment, and the Compass 31 for autonomic symptoms assessment. The Brooke Upper Extremity Scale was used for upper limbs muscular function assessment. Respiratory and muscle function tests were performed, including spirometry, arterial blood gases, polysomnography, maximal inspiratory pressure (MIP), maximal expiratory pressure and sniff nasal inspiratory pressure. RESULTS: An abnormal composite SWAL-QOL score (≤86) was found in 33 patients. Autonomic symptoms were mild, while a severe impairment was shown by the Brooke Upper Extremity Scale. Spirometry and muscle strength tests demonstrated severe alterations, while diurnal and nocturnal blood gases were normal, due to effective use of noninvasive ventilation. Independent predictors of the composite SWAL-QOL score were age, MIP and Compass 31. A MIP < 22 had an accuracy of 92% in predicting altered swallowing-related QoL. The composite SWAL-QOL score was worse in subjects > 30 years old than in younger patients (64.5±19.2 vs 76.6±16.3, p < 0.02), due to worse scores in items pertinent to mental and social functioning; scores in domains pertinent to the physical function were similar in both groups. CONCLUSIONS: In adult DMD, swallowing-related QoL, which is altered in most patients, can be predicted by age, inspiratory muscles strength and autonomic dysfunction symptoms. While swallowing function is already altered in young patients, swallowing-related QoL can progressively worsen with advancing age due to psychological and social factors.

Cardiovascular autonomic control during application of different modes of noninvasive ventilation in patients affected by amyotrophic lateral sclerosis.

BACKGROUND: Cardiovascular events commonly cause death in amyotrophic lateral sclerosis (ALS) even in patients treated by noninvasive ventilation (NIV). OBJECTIVES: to evaluate autonomic function with the assessment of heart rate variability (HRV) in ALS patients treated by assist pressure control ventilation (APCV) and assist control ventilation (ACV) during sleep. METHODS: Consecutive ALS patients underwent one polysomnography during APCV and one during ACV. HRV was analyzed both in the total sleep period (from first stage N1 to last awakening) and in a 5-minute period of stable stage N2. Time domain, frequency domain and nonlinear indexes of HRV were measured. RESULTS: Nineteen patients (age 62.0 ± 8.7, 9F/10 M) were studied. The analysis did not reveal differences in blood gasses between NIV modalities, but a longer expiratory time (3.01±0.6 vs 2.8 ± 0.6 s, respectively APCV vs ACV, p = 0.001) and a lower arousal index (17.5 ± 9.1 vs 23.1 ± 13.9, p = 0.02) during APCV. HRV was indicative of higher vagal activity during APCV, especially in the 5-minute periods. In the total sleep periods, the HRV time domain indexes reflecting parasympathetic activity were positively correlated with the expiratory time and negatively with the inspiratory/expiratory time ratio. Low frequencies were positively, and high frequencies negatively, correlated with inspiratory time. HRV and sleep structure parameters were not correlated, except very low frequencies that were correlated to the arousal index. CONCLUSIONS: Respiratory influences on autonomic control can be preserved in ALS. The slower breathing pattern during APCV may help to maintain a higher vagal activity. Through this mechanism, in the long-term APCV could more beneficial to ALS patients than ACV.

Bioimpedance Phase Angle as a Prognostic Tool in Late-Onset Pompe Disease: A Single-Centre Prospective Study With a 15-year Follow-Up.

Background: Late-onset Pompe disease (LOPD) is an autosomal-recessive metabolic myopathy caused by deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA), leading to glycogen accumulation in proximal and axial muscles, and in the diaphragm. Enzyme Replacement Therapy (ERT) with recombinant GAA became available in 2006. Since then, several outcome measures have been investigated for the adequate follow-up of disease progression and treatment response, usually focusing on respiratory and motor function. Prognostic factors predicting outcome have not been identified till now. Methods: In this single Centre, prospective study, we evaluate the response to enzyme replacement therapy in 15 patients (7 males) with LOPD in different stages of disease, aged 49.4 ± 16.1, followed-up for 15 years. Treatment response was measured by the 6-min walking test, vital capacity in supine and upright position, respiratory muscle strength, muscle MRI, manual muscle testing. We investigated the usefulness of Body Impedance Vectorial Analysis for serial body composition assessment. Results: Although most patients with LOPD benefit from long-term treatment, some secondary decline may occur after the first 3-5 years. Some nutritional (lower body mass index, higher fat free mass, higher phase angle) and disease parameters (higher creatinine and shorter disease duration at the beginning of treatment) seem to predict a better motor outcome. Lower Phase Angle, possibly reflecting loss of integrity of skeletal muscle membranes and thus treatment mis-targeting, seems to correlate with worse treatment response on long-term follow-up. Conclusion: Body Impedance Vectorial Analysis is a fast, easily performed and cheap tool that may be able to predict long-term treatment response in patients with LOPD. Low Phase angle may serve as a marker of muscle quality and may be used to predict the response to a muscle-targeted intervention such as ERT, thus improving the identification of patients needing a closer follow-up due to higher fragility and risk of deterioration.

Emergencies cards for neuromuscular disorders 1st Consensus Meeting from UILDM - Italian Muscular Dystrophy Association Workshop report.

Acute hospitalisation may be required to support patients with Neuromuscular disorders (NMDs) mainly experiencing respiratory complications, swallowing difficulties, heart failure, urgent surgical procedures. As NMDs may need specific treatments, they should be ideally managed in specialized hospitals. Nevertheless, if urgent treatment is required, patients with NMD should be managed at the closest hospital site, which may not be a specialized centre where local emergency physicians have the adequate experience to manage these patients. Although NMDs are a group of conditions that can differ in terms of disease onset, progression, severity and involvement of other systems, many recommendations are transversal and apply to the most frequent NMDs. Emergency Cards (EC), which report the most common recommendations on respiratory and cardiac issues and provide indications for drugs/treatments to be used with caution, are actively used in some countries by patients with NMDs. In Italy, there is no consensus on the use of any EC, and a minority of patients adopt it regularly in case of emergency. In April 2022, 50 participants from different centres in Italy met in Milan, Italy, to agree on a minimum set of recommendations for urgent care management which can be extended to the vast majority of NMDs. The aim of the workshop was to agree on the most relevant information and recommendations regarding the main topics related to emergency care of patients with NMD in order to produce specific ECs for the 13 most frequent NMDs.

Polymorphism in exercise genes and respiratory function in late-onset Pompe disease.

Genetic polymorphisms influencing muscle structure and metabolism may affect the phenotype of metabolic myopathies. We here analyze the possible influence of a wide panel of "exercise genes" on the severity and progression of respiratory dysfunction in late-onset Pompe disease (LOPD). We stratified patients with comparable age and disease duration according to the severity of their respiratory phenotype, assessed by both upright FVC% and postural drop in FVC%. We included 43 patients with LOPD (25 males, age 50.8 ± 13.6 yr) with a 2-yr follow-up since the beginning of enzyme replacement therapy (ERT). Twenty-two patients showed a postural drop >25% T0, seven other patients developed it during the follow-up. We analyzed the relationship between the progression of respiratory dysfunction and genetic polymorphisms affecting muscle function and structure [angiotensin converting enzyme (ACE), α-actinin 3 (ACTN3), peroxisome proliferator-activated receptor α (PPR-α), angiotensin (AGT)], glycogen metabolism [glycogen synthase (GYS), glycogen synthase kinase-3 isoform ß (GSK3ß)], and autophagy [sirtuin 1 (SIRT1), autophagy-related gene 7 (ATG7)]. Individuals carrying two copies of the ACE D-allele shared a 24-fold increase in the risk of severe respiratory dysfunction and progression during the 2-yr follow-up. ACTN3-XX polymorphism was also associated with worse respiratory outcome. The study of exercise genes is of particular interest in respiratory muscles, due to their peculiar features, that is, continuous, low-intensity contraction and prominent recruitment of type I fibers. In line with previous observations on skeletal muscles, ACE-DD and ACTN3-XX genotypes were associated with indirect evidence of more severe respiratory phenotypes. On the contrary, polymorphisms related to autophagy and glycogen metabolism did not seem to influence respiratory muscles.NEW & NOTEWORTHY Previous reports evaluated the role of exercise genes in influencing skeletal muscle phenotype and response to ERT in LOPD. Here, we investigate the role of polymorphisms in several exercise gene, focusing on respiratory muscles. ACE-DD and ACTN3-XX polymorphisms, possibly influencing muscle properties and fiber composition, were associated with more severe respiratory phenotypes.

Short-Term Effects of Pressure Controlled Versus Volume Controlled Noninvasive Ventilation in Subjects With Amyotrophic Lateral Sclerosis.

BACKGROUND: Comparison of the effects of pressure controlled and volume controlled noninvasive ventilations (NIV) has usually been limited to the degree of improvement in blood gases. We compared sleep quality, abnormal respiratory events, and patient-ventilator asynchronies during administration of pressure controlled continuous mandatory ventilation (PC-CMV) and volume controlled continuous mandatory ventilation (VC-CMV) in subjects with amyotrophic lateral sclerosis naive to NIV after titration aimed at maximally improving nocturnal arterial blood gases. METHODS: A crossover evaluation of PC-CMV and VC-CMV was performed in 27 subjects with amyotrophic lateral sclerosis. After baseline polysomnography, ventilators were set in random order so as to warrant similar and satisfactory oxygen saturation and transcutaneous [Formula: see text] in both NIV modalities during day and night. Soon after titration, polysomnography was repeated during administration of each type of NIV. RESULTS: With respect to the baseline night, non-rapid eye movement 3, and rapid eye movement sleep stages increased, and the arousal index decreased during PC-CMV (P = .005, P = .02, and P = .01, PC-CMV vs VC-CMV, respectively) but not during VC-CMV. The arousal index during NIV was correlated to the peak pressure delivered by the ventilators (ρ = 0.47, P < .001). Few abnormal respiratory events were observed in both NIV modes. Patient-ventilator asynchronies were more frequent during VC-CMV (median [IQR] 20.8 [0.0 - 22.0] vs 31.8 [30.1 - 34.0] no./h, PC-CMV vs VC-CMV; P = .002). Twenty-one subjects declared that they preferred PC-CMV therapy. CONCLUSIONS: In the short term, PC-CMV may be a preferred NIV modality to VC-CMV for patients with amyotrophic lateral sclerosis, even when both NIV modes are similarly effective in the correction of hypoventilation. Evaluation of the effectiveness of NIV should not be limited to the assessment of blood gas correction.

Heterogeneity of predictors of nocturnal hypoventilation in amyotrophic lateral sclerosis.

OBJECTIVE: In amyotrophic lateral sclerosis (ALS), early recognition of nocturnal hypoventilation (NH) is essential to start noninvasive ventilation (NIV), but nocturnal transcutaneous PCO2 (PtcCO2) is difficult to monitor. Usefulness of respiratory and muscular function test in the prediction of NH has been explored without distinguishing among ALS phenotypes. We evaluated cross-sectional relationships between functional tests and nocturnal PCO2, and the best predictors of NH, separately in patients with spinal and bulbar onset of ALS. Methods: ALS patients candidate to NIV were recruited. Diurnal respiratory and muscular function tests and nocturnal polysomnography with PtcCO2 monitoring were performed. NH was defined as peak PtcCO2 >49 mm Hg. Results: Thirty-six patients with spinal and 11 with bulbar onset ALS were included. Nocturnal oxygen saturation and PtcCO2, and proportion of subjects with NH were similar in each group (spinal: 50%; bulbar: 45.5%). Significant differences between groups were found in forced vital capacity (p = 0.03), maximal inspiratory pressure (p = 0.01) and sniff nasal inspiratory pressure (SNIP) (p = 0.007), but not in diurnal arterial blood gases. In the spinal group, SNIP and Base Excess (BE) independently predicted nocturnal PtcCO2 (R2 0.59, p < 0.0001). In the bulbar group only SNIP was correlated to PtcCO2, but it varied little in relationship to PtcCO2 changes. Conclusions: Respiratory and muscle function parameters are differently related to NH in ALS patients with spinal and bulbar presentation. SNIP and BE may be helpful to reveal NH in spinal patients, while in bulbar patients no respiratory or muscle function tests may reliably predict NH.

Subjective sleep quality in adult patients affected by Duchenne muscular dystrophy. Beyond nocturnal hypoventilation.

OBJECTIVE: In stable neuromuscular patients under long-term non-invasive ventilation (NIV), subjective sleep quality may be predicted by chronic hypoventilation, as assessed by base excess (BE), and %N3 sleep stage duration. In this study, we explored how other variables, closely associated with self-reported health complaints, contributed to subjective sleep quality in adult patients with Duchenne muscular dystrophy (DMD). METHODS: This is a secondary analysis of a quality of life study in 48 adult DMD patients under NIV therapy, with little evidence of residual hypoventilation. Subjective sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI). A PSQI score >5 was considered indicative of poor sleep quality. Several other symptoms were evaluated: sleepiness, by the Epworth Sleepiness Scale (ESS); depression and anxiety, by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D); autonomic symptoms, by the Composite Autonomic Symptom Score 31; pain, by the Numeric Pain Rating Scale (NPRS); and fatigue, by the Fatigue Severity Scale (FSS). RESULTS: Mean PSQI was 6.1 ± 2.9. Abnormal scores were found for NPRS in 40, for HADS-A in 10 and for FSS in 24 subjects. The NPRS, HADS-A and FSS scores and the N3 sleep stage, independently predicted PSQI (R2 = 0.47, p < 0.0001). CONCLUSIONS: In adult DMD patients, pain, fatigue and anxiety may have a prominent influence on subjective sleep quality. Improvement of sleep quality may be of utmost importance in DMD, as it may ameliorate quality of life and extend its benefits to cardiovascular morbidity and life expectancy.

Quality of life in long term ventilated adult patients with Duchenne muscular dystrophy.

The aim of this study was to evaluate quality of life (QoL) and its possible determinants in patients affected by Duchenne muscular dystrophy (DMD) in late stages of their disease, when non-invasive ventilation (NIV) is already established. Forty-eight DMD patients who were treated by NIV were enrolled. QoL was assessed by the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. By this questionnaire, different aspects of QoL were assessed on a scale from 0 (best) to 100 (worst). In addition, motor and respiratory function tests were performed. Dysautonomia symptoms, sleep quality, sleepiness, anxiety, and depression were evaluated by validated questionnaires. The global INQoL score was 42.8 ±â€¯19, reflecting a moderately altered QoL. The physical health domain was heavily impaired while the psychosocial domain was only mildly affected. Independence had the highest scores (81.1 ±â€¯21.2), proving to be the most affected item. On multivariate analysis, maximal inspiratory pressure and Pittsburgh Sleep Quality Index, but not daily duration of NIV therapy, predicted global INQoL score. Respiratory impairment and sleep quality were independent predictors of poor QoL in DMD patients under NIV. Sleep quality in DMD is often disregarded, while it should be carefully addressed to ensure a better QoL.

Is early detection of late-onset Pompe disease a pneumologist's affair? A lesson from an Italian screening study.

BACKGROUND: Late-onset Pompe disease (LOPD) is a recessive disease caused by α-glucosidase (GAA) deficiency, leading to progressive muscle weakness and/or respiratory failure in children and adults. Respiratory derangement can be the first indication of LOPD, but the diagnosis may be difficult for pneumologists. We hypothesize that assessing the GAA activity in suspected patients by a dried blood spot (DBS) may help the diagnosis of LOPD in the pneumological setting. POPULATION AND METHODS: We performed a multicenter DBS survey of patients with suspected LOPD according to a predefined clinical algorithm. From February 2015 to December 2017, 140 patients (57 ± 16 yrs., 80 males) were recruited in 19 Italian pneumological units. The DBS test was performed by a drop of blood collected on absorbent paper. Patients with GAA activity < 2.6 µmol/L/h were considered positive. A second DBS test was performed in the patients positive to the first assay. Patients testing positive at the re-test underwent a skeletal muscle biopsy to determine the GAA enzymatic activity. RESULTS: 75 recruited subjects had outpatient access, 65 subjects were admitted for an acute respiratory failure episode. Two patients tested positive in both the first and second DBS test (1.4% prevalence), and the LOPD diagnosis was confirmed through histology, with patients demonstrating a deficient GAA muscle activity (3.6 and 9.1 pmol/min/mg). A further five subjects were positive in the first DBS test but were not confirmed at re-test. The two positive cases were both diagnosed after hospitalization for acute respiratory failure and need of noninvasive ventilation. Most of the recruited patients had reduced maximal respiratory pressures (MIP 50 ± 27% and MEP 55 ± 27% predicted), restrictive pattern (FEV1/FVC 81.3 ± 13.6) and hypoxaemia (PaO2 70.9 ± 14.5 mmHg). Respiratory symptoms were present in all the patients, but only 48.6% of them showed muscle weakness in the pelvic girdle and/or in the scapular girdle (35.7%). CONCLUSIONS: DBS GAA activity test may be a powerful screening tool among pneumologists, particularly in the acute setting. A simple clinical algorithm may aid in the selection of patients on which to administer the DBS test.

Reliability of autonomic activations as surrogates of cortical arousals in ventilated patients affected by amyotrophic lateral sclerosis.

PURPOSE: The study aims to evaluate the performance of autonomic activations as a tool to assess sleep fragmentation and to recognize hypopneas in patients with amyotrophic lateral sclerosis (ALS) under non-invasive mechanical ventilation and secondarily, to evaluate, in patients with the same disease, the relationship between disruption of autonomic nervous system (ANS) activity and the usefulness of the autonomic activations as surrogates of cortical arousals. METHODS: Sixteen ALS patients underwent simultaneous polysomnography and portable cardiorespiratory monitoring (PM). On the polysomnography, standard rules were used for scoring arousals and respiratory events. On the PM, autonomic arousals were scored as ≥ 15% heart rate (HR) increase with a ≥ 35% pulse wave amplitude (PWA) reduction, HR increase ≥ 20%, or PWA decrease ≥ 40%. Nocturnal HR variability was analyzed in the ALS patients and in 11 control subjects as an index of ANS activity. RESULTS: Synchronized epoch by epoch analysis of the polysomnography and PM recordings showed that only 31.0 (22.5-58.7)% cortical and 36.1 (20.5-47.2)% autonomic arousals were associated with one another. Among hypopneas scored at polysomnography, 71.7% were associated with a cortical arousal but not with a desaturation. On average, HR variability in ALS showed signs of depressed ANS activity that was particularly evident in the patients where the cortical arousals exceeded the autonomic ones. CONCLUSIONS: In ventilated ALS patients, autonomic activations may hardly have a role as surrogates of cortical arousals for assessment of sleep fragmentation and for respiratory scoring. Depression of ANS activity may be related to their poor performance.