Training, detraining, and retraining: Two 12-week respiratory muscle training regimens in a child with infantile-onset Pompe disease.

BACKGROUND: Respiratory muscle weakness is a primary cause of morbidity and mortality in patients with Pompe disease. We previously described the effects of our 12-week respiratory muscle training (RMT) regimen in 8 adults with late-onset Pompe disease [1] and 2 children with infantile-onset Pompe disease [2]. CASE REPORT: Here we describe repeat enrollment by one of the pediatric participants who completed a second 12-week RMT regimen after 7 months of detraining. We investigated the effects of two 12-week RMT regimens (RMT #1, RMT #2) using a single-participant A-B-A experimental design. Primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function. RELEVANCE: From pretest to posttest, RMT #2 was associated with a 25% increase in MIP and a 22% increase in MEP, corresponding with very large effect sizes (d= 2.92 and d= 2.65, respectively). Following two 12-week RMT regimens over 16 months, MIP increased by 69% and MEP increased by 97%, corresponding with very large effect sizes (d= 3.57 and d= 5.10, respectively). MIP and MEP were largely stable over 7 months of detraining between regimens. Magnitude of change was greater for RMT #1 relative to RMT #2.

Adapted physical activity and therapeutic exercise in late-onset Pompe disease (LOPD): a two-step rehabilitative approach.

Aerobic exercise, training to sustain motor ability, and respiratory rehabilitation may improve general functioning and quality of life (QoL) in neuromuscular disorders. Patients with late-onset Pompe disease (LOPD) typically show progressive muscle weakness, respiratory dysfunction and minor cardiac involvement. Characteristics and modalities of motor and respiratory rehabilitation in LOPD are not well defined and specific guidelines are lacking. Therefore, we evaluated the role of physical activity, therapeutic exercise, and pulmonary rehabilitation programs in order to promote an appropriate management of motor and respiratory dysfunctions and improve QoL in patients with LOPD. We propose two operational protocols: one for an adapted physical activity (APA) plan and the other for an individual rehabilitation plan, particularly focused on therapeutic exercise (TE) and respiratory rehabilitation.

The role of rehabilitation in the management of late-onset Pompe disease: a narrative review of the level of evidence.

Late-onset Pompe disease (LOPD) is characterized by progressive muscle weakness, respiratory muscle dysfunction, and minor cardiac involvement. Although in LOPD, as in other neuromuscular diseases, controlled low impact sub-maximal aerobic exercise and functional ability exercise can improve general functioning and quality of life, as well as respiratory rehabilitation, the bulk of evidence on that is weak and guidelines are lacking. To date, there is no specific focus on rehabilitation issues in clinical recommendations for the care of patients with Pompe disease, and standard practice predominantly follows general recommendation guidelines for neuromuscular diseases. The Italian Association of Myology, the Italian Association of Pulmonologists, the Italian Society of Neurorehabilitation, and the Italian Society of Physical Medicine and Rehabilitation, have endorsed a project to formulate recommendations on practical, technical, and, whenever possible, disease-specific guidance on rehabilitation procedures in LOPD, with specific reference to the Italian scenario. In this first paper, we review available evidence on the role of rehabilitation in LOPD patients, particularly addressing the unmet needs in the management of motor and respiratory function for these patients.

Diaphragm Pacing as a Rehabilitative Tool for Patients With Pompe Disease Who Are Ventilator-Dependent: Case Series.

BACKGROUND AND PURPOSE: Pompe disease is an inherited disorder notable for severe, progressive ventilatory compromise. Although ventilatory failure has been attributed to myofiber dysfunction secondary to diaphragmatic glycogen accumulation, neural involvement of the phrenic motor system is also a prominent feature. Direct diaphragm pacing supplements respiratory function in other disorders of the phrenic motor system. Accordingly, it is hypothesized that augmented neuromuscular activity via diaphragm pacing would promote weaning from mechanical ventilation in patients with Pompe disease who are unresponsive to conventional, muscle-directed treatments. CASE DESCRIPTION: Three patients with Pompe disease developed diaphragm paresis that resulted in chronic mechanical ventilation dependence. After preoperative inspiratory muscle strengthening exercises failed to improve function, fine-wire pacing electrodes were laparoscopically implanted into the diaphragm. Diaphragm conditioning was initiated the first postoperative week and consisted of gradual increases in stimulation parameters, lengthening of stimulation sessions, and ventilator weaning. Ventilation and intramuscular electromyographic activity were recorded periodically during conditioning to quantify diaphragm neuromuscular function. OUTCOMES: During paced breathing without mechanical ventilation, tidal volumes increased, and 2 patients were weaned from daytime ventilator dependence within the first 3 months of pacing, which has been sustained over the long-term. A third patient reduced reliance on daytime ventilation, but weaning was delayed by malacia of the large airways. In all patients, pacing appeared to facilitate spontaneous phrenic motor unit activity during independent breathing without ventilator or pacer support. DISCUSSION: The findings are consistent with the view that diaphragm pacing has potential rehabilitative value to reduce reliance on mechanical ventilation in people with Pompe disease, but further study is needed. Diaphragm pacing represents a paradigm shift in the management of respiratory insufficiency for Pompe disease that warrants further controlled examination.

Pulmonary function tests (maximum inspiratory pressure, maximum expiratory pressure, vital capacity, forced vital capacity) predict ventilator use in late-onset Pompe disease.

In patients with Late-Onset Pompe Disease (LOPD), progressive respiratory muscle involvement leads to reduced pulmonary function, with respiratory failure the most common cause of mortality. Early disease manifestations include sleep-disordered breathing, which can be treated with non-invasive ventilation; however, progressive diurnal deficits can require invasive ventilation. To determine if pulmonary function tests (PFTs) predict the thresholds for ventilation and wheelchair use, a systematic literature review identified cross-sectional clinical patient data (N = 174) that was classified into ventilation and wheelchair cohorts. PFTs included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC), with vital capacities measured in the upright (-U) and supine (-S) positions. Receiver operating characteristic (ROC) curves were used to calculate cut-points (CP) and area under the curve (AUC). For all ventilation and mobility thresholds tested, ROC analyses demonstrated AUC values from 86-89% for MIP, 72-96% for MEP, and 74-96% for all vital capacity metrics. Thus, PFTs are useful in predicting the thresholds for nighttime ventilation, daytime ventilation, and wheelchair use, with MIP and VC-U having both high AUC values and consistency. The PFT mobility CPs were low (MIP CP = 0.9 kPa, MEP, CP = 2.6 kPa, VC-U CP = 19% predicted), suggesting an endurance component associated with wheelchair use.

Exercise training in adults with Pompe disease: the effects on pain, fatigue, and functioning.

OBJECTIVE: To assess if a 12-week exercise intervention to improve aerobic fitness, muscle strength, and core stability also had an impact on fatigue, pain, activity, and participation in adults with Pompe disease, an inherited neuromuscular disorder. DESIGN: Open-label trial. Change was assessed by the chi-square test and Wilcoxon signed-rank test. SETTING: Physiotherapy practices. PARTICIPANTS: Mildly affected adult patients with Pompe disease who were not dependent on ventilators and/or walking devices and were receiving enzyme replacement therapy. INTERVENTION: Patients participated in a 12-week exercise program, which included 36 sessions of standardized aerobic, resistance, and core stability exercises. MAIN OUTCOME MEASURES: Before and after the training program we evaluated fatigue (Fatigue Severity Scale), pain (yes/no), motor function (Quantitative Muscle Function Test, Rasch-built Pompe-specific Activity Scale), amount of physical activity (activity monitor), and health status (Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: Of the 25 patients enrolled, 23 completed the program. At the end of the program, levels of fatigue (median, 5.33 to 4.78, P=.01) and pain (56.5% to 21.7%, P=.04) improved. The quality of motor function and the amount of physical activity patients engaged in did not change. Changes in pain and fatigue were not related to improvements in aerobic fitness or muscle strength. CONCLUSIONS: This study in mildly affected adult patients with Pompe disease suggests that a combined training program aiming to increase aerobic fitness, muscle strength, and core stability also leads to improvements in fatigue and pain.

Effects of respiratory muscle training (RMT) in children with infantile-onset Pompe disease and respiratory muscle weakness.

PURPOSE: Respiratory muscle weakness is a primary therapeutic challenge for patients with infantile Pompe disease. We previously described the clinical implementation of a respiratory muscle training (RMT) regimen in two adults with late-onset Pompe disease; both demonstrated marked increases in inspiratory and expiratory muscle strength in response to RMT. However, the use of RMT in pediatric survivors of infantile Pompe disease has not been previously reported. METHOD: We report the effects of an intensive RMT program on maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using A-B-A (baseline-treatment-posttest) single subject experimental design in two pediatric survivors of infantile Pompe disease. Both subjects had persistent respiratory muscle weakness despite long-term treatment with alglucosidase alfa. RESULTS: Subject 1 demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d=0.25; 19% increase in MEP, d=0.87), while Subject 2 demonstrated very large increases in MIP/MEP (45% increase in MIP, d=2.38; 81% increase in MEP, d=4.31). Following three-month RMT withdrawal, both subjects maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up. CONCLUSION: Intensive RMT may be a beneficial treatment for respiratory muscle weakness in pediatric survivors of infantile Pompe disease.

Increased inspiratory and expiratory muscle strength following respiratory muscle strength training (RMST) in two patients with late-onset Pompe disease.

Respiratory muscle strength training (RMST) is an exercise-based intervention which targets respiratory muscle weakness. We implemented RMST in two patients with late-onset Pompe disease (LOPD), both who had received long-term enzyme replacement therapy and had severe respiratory weakness. Over 16-32 weeks, inspiratory muscle strength increased by 73-74%. Expiratory muscle strength increased 31-48% over 12-22 weeks. These findings suggest that RMST may increase respiratory muscle strength, even in the setting of LOPD and severe baseline weakness.

Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II.

OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII. METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months. RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8%) showed transient secondary events during ERT. CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment.

[Treatment of subcutaneous and mediastinal emphysema with cuirass ventilation in a patient with Pompe disease undergoing non-invasive positive pressure ventilation].

We report a case of subcutaneous and mediastinal emphysema in a 39-year-old woman with late-onset Pompe disease who was undergoing non-invasive positive pressure ventilation (NPPV). Although the patient had a history of pneumothorax, she did not present with pneumothorax at the time of admission. She had not undergone adequate respiratory rehabilitation, which resulted in decreased respiratory compliance. We speculated that the emphysema had been caused by an increase in the airway pressure due to NPPV. Decrease in inspiratory pressure of NPPV from 14 cm H2O to 9 cm H2O made the patient dyspneic and hypoxic. Cuirass ventilation by itself resulted in dyspnea and hypoxia. By using a combination of cuirass ventilation (control mode) and NPPV (assist/control mode), we were able to decrease the inspiratory pressure to 7 cm H2O. After 26 days of treatment, the patient recovered from subcutaneous and mediastinal emphysema. After the treatment, her maximum inspiratory capacity was increased from 400 ml to 600 ml, which indicates increased thoracic compliance. Thus, a combination of cuirass ventilation and NPPV is beneficial in managing barotrauma that may occur during NPPV in a respirator-dependent patient.

Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease.

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain-Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain-Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated.

Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients.

Late-onset Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is a slowly progressive myopathy caused by deficiency of acid alpha-glucosidase. Current developments in enzyme replacement therapy require detailed knowledge of the kind and severity of symptoms and the natural course of the disease in the patient population. A detailed questionnaire covering the patients' medical history and current situation was developed and information was gathered from 54 Dutch patients. The mean age of the participants was 48.6 +/- 15.6 years. The first complaints started at a mean age of 28.1 +/- 14.3 years and were mostly related to mobility problems and limb-girdle weakness. Fifty-eight percent of the adult patients indicated the presence of mild muscular symptoms during childhood. Twenty-eight percent of the patients waited >5 years for the final diagnosis after the first visit to a physician for disease-related complaints. At the time of questionnaire completion, 48% of the study population used a wheelchair and 37% used artificial ventilation. Movements such as rising from an armchair, taking stairs or getting upright after bending over were difficult or impossible for more than two-thirds of the respondents. The age at onset, the rate of disease progression and the sequence of respiratory and skeletal muscle involvement varied substantially between patients. Seventy-six percent of the participants indicated being troubled by fatigue and 46% by pain. This survey has mapped the age at onset, presenting symptoms, heterogeneity in progression and range of disease severity in a large group of Dutch patients. We conclude that early manifestations in childhood require proper attention to prevent unnecessary delay of the diagnosis. The follow-up of patients with late-onset Pompe's disease should focus on respiratory and limb-girdle muscle function, the capacity to perform daily activities, and the presentation of fatigue and pain.

Pompe disease and physical disability.

This study describes the physical disability of 30 children and adolescents with Pompe disease (23 males, 7 females; mean age 7 years 7 months, SD 5 years 6 months; range 6 months to 22 years 1 month) using a disease-specific functional instrument. Data were collected by telephone interview with parents using a modified version of the Pediatric Evaluation of Disability Inventory. The sample included mostly males of Caucasian origin, recruited from several countries. Disability profiles in mobility and self-care skills were heterogeneous because functional status was not related to chronological age. Most children had severe functional deficits: nearly two-thirds of the sample was non-ambulatory and could not perform age-expected self-care skills. Three-quarters of the children used a ventilator. Two children were able to participate in age-appropriate sports and peer activities. Although the mean chronological age of the sample was 7 years 7 months, the mean age-performance for self-care skills was under 2 years 6 months and under 1 year 6 months for mobility. Implications of physical disability findings for individuals with Pompe disease are discussed.