Analysis of motor and respiratory function in Duchenne muscular dystrophy patients
Introduction
Duchenne muscular dystrophy (DMD) is an inherited and X-linked disease that affects ˜1:3500 male newborns (Söderpalm et al., 2013; Machado et al., 2012). The deficiency in dystrophin protein production causes inadequate muscle responses to mechanical stretching and contraction, progressive degeneration in muscle fibers and fibrosis in the contractile tissue, causing progressive muscular dysfunction (Zhou and Lu, 2010).
Commonly, children with DMD aged between three to five years exhibit progressive muscle weakness that evolves to scapular girdle and other muscular groups, culminating with ambulation loss in age between nine to 12 years (Humbertclaude et al., 2012). Historically, cardiorespiratory issues lead to death (˜20 years old) Humbertclaude et al., 2012). However, when we consider DMD with all the interventions to date (Ricotti et al., 2015), over the past few years the survival for ages close to 20 years and beyond increased from 0 to close to 50% (Eagle et al., 2002).
After ambulation loss, numerous issues show major attention (Bach et al., 2010). Wheelchair restriction is associated with fastest scoliosis progression, spine and thoracic chest malformations, which impair the respiratory status, accelerating the evolution of respiratory insufficiency and the process of hypercapnia (Finder et al., 2004).
Although there are limitations in the DMD treatment, the management of motor and respiratory deterioration has improved in recent decades. Moreover, corticosteroids showed an improvement in the quality of life being a viable therapy (Guglieri et al., 2017; Ryder et al., 2017). Also, new treatments have emerged as the use of Eteplirsen in the DMD treatment. The Eteplirsen is a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants and it is applicable for ˜14% of patients with DMD mutations (Irwin and Herink, 2017; Lim et al., 2017; Aartsma-Rus and Krieg, 2017).
Nowadays, more children with DMD are transitioning into adulthood (Schrans et al., 2013). A randomized controlled trial demonstrated that dynamic training approach with low intensity (assisted bicycle training) is beneficial for motor maintenance (Jansen et al., 2013). However, in relation to the respiratory dysfunction management, the results of muscular training are controversial (Finder et al., 2004).
Lung volume recruitment and cough efficiency techniques have been studied to minimize the deterioration of lung function in DMD patients (Brito et al., 2009; McKim et al., 2012). The study performed by McKim et al. (2012) was conducted in Canada with 22 DMD patients, when one evaluated the long-term effect on measures of forced vital capacity (FVC) before and after the introduction of regular lung volume recruitment (LVR) maneuvers (breath stacking). The rate of FVC decline in DMD patients improved with initiation of regular LVR (McKim et al., 2012). Also, the study performed by Brito et al. (2009) evaluated cough efficiency using two manually-assisted cough techniques in 28 DMD patients. In the study, chest compression and air stacking techniques were efficient in increasing cough peak flow (CPF). Besides, the combination of these two techniques (chest compression and CPF) had additional effect (Brito et al., 2009).
After the DMD diagnosis, the loss of motor function was verified (Buckon et al., 2016; Nunes et al., 2016). Also, the loss of lung function showed association with loss of motor function (Mayer et al., 2015; Meier et al., 2017; Finder, 2015), once the respiratory dysfunction worsened slowly and progressively with age (Finder et al., 2004). In several circumstances, the DMD patient and/or their caregivers fail to notice the deterioration in lung function, but, everyone recognizes a deterioration in cough, and this fact should be highlighted as a marker for severity progression. Cough, which is initially a defense mechanism, becomes progressively insufficient over time until it becomes ineffective in eliminating airway secretions (Brito et al., 2009; McKim et al., 2012). According to Brito et al. (2009), in ˜90% cases of respiratory failure in DMD patients, there are accompanying episodes of pulmonary illnesses, mainly by bacterial pneumonias, and the ineffective cough worsen the severity of the pulmonary status (Brito et al., 2009). To verify the deterioration of motor and respiratory function, nowadays, we have a great number of tools for assessment of ventilatory and motor function in DMD (Buckon et al., 2016; Nunes et al., 2016; Diniz et al., 2012; de Lattre et al., 2013; de Carvalho et al., 2015; LoMauro et al., 2015).
For DMD patients to enjoy the therapeutic benefits, the health professional must be aware of motor and respiratory demands during disease progression. Empirically, these dysfunctions coexist in the DMD patient since very early. However, the approach to assessment and management is done systematically, professionals often do not think of how much the dysfunction in one system affects the other. Although not studied or evaluated together, they are seen in clinical practice quite frequently. In our study emerged the hypothesis about the high severity in DMD patients with non-ambulatory condition when compared with ambulatory patients for motor and respiratory function. Also, we have an early motor and respiratory function impairment in DMD patients when compared with control subjects. In this context, the study aimed at to establishing motor and respiratory function impairment in DMD patients by the analysis of numerous tools.
Section snippets
Methods
A cross-sectional study was conducted in a University Hospital and approved by the Research Ethics Committee (#500/2011). Written Informed consent was obtained from all individuals included in the study. During a 2-year study, 34 DMD patients were monitored. Twenty-three DMD patients, out of the 34 invited to join the study, have participated in the study (Fig. 1).
The DMD diagnostic criteria were: elevated serum creatine kinase levels; muscular biopsy tested via immunohistochemistry indicating
Clinical and demographic data
The DMD patients were classified into I-phase [ambulatory (n = 9)] or III-phase [non-ambulatory (n = 10)]. The classification per walking status showed association with patient’s age, at an arbitrary cutoff for 11 years old (p = 0.003).
A total of 16/19 DMD patients were using oral glucocorticoid medications (prednisone). The mean time of use of oral prednisone was 2.74 ± 1.94 years, median of 2.12 years (amplitude of 0.08–6.33 years). Two DMD patients suspended the treatment without medical
Discussion
A few studies have assessed motor and respiratory deterioration simultaneously to date. In our study, we observed that DMD patients have motor and respiratory deterioration when compared with healthy subjects, and between them, regarding different conditions (ambulatory and non-ambulatory status). Moreover, it is the first study to analyze the association between VCap and DMD severity.
Conclusion
The DMD patients presented motor and respiratory deterioration when compared with control subjects, mainly for MFM/6MWT and spirometry/VCap, respectively. Moreover, the non-ambulatory condition was associated with worse MFM and spirometry. The deterioration of motor and respiratory function showed correlation between each other. In this context, motor and respiratory deterioration may be evaluated by MFM, 6MWT, spirometry and VCap. The assessments should be performed on a routine basis.
Authors’ contribution
LCL conceived the study, carried out the collection, analysis and interpretation of data, performed statistical analysis and drafted the manuscript. CCBA participated in the design of the study, carried out the analysis and interpretation of data and drafted the manuscript. AADCT participated in the design of the study, carried out the analysis and interpretation of data and drafted the manuscript. AN conceived the study, participated in the collection of data and revised the manuscript
Conflict of interest
None of the authors has any conflict of interest to disclose.
Ethical publication statement
We have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Acknowledgements
Our study was funded by: LCL: Coordination for the Improvement of Higher Education Personnel (CAPES in the Portuguese acronym) and the author thanks for the master’s fellowship. FALM: Financial support from the following institutions: São Paulo Research Foundation (FAPESP in the Portuguese acronym), the author thanks the Foundation for sponsoring the researches #2011/12939-4; #2015/12183-8 and #2015/12858-5; Fund for the Support of Education, Research and Extension of the University of
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