Respiratory Disorders in Parkinson’s Disease

INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disease firstly described in 1817 [1], characterized by a progressive degeneration of substantia nigra neurons, resulting in striatal dopamine depletion [2, 3]. The most prevalent PD symptoms are motor function impairments, such as bradykinesia, muscular rigidity, rest tremor and postural instability [4]. Moreover, secondary disorders can be observed, such as gait impairment and falls [5], leading to a loss of independence in activities of daily living [6]. However, when the first motor symptoms are clinically identified, 60% of dopaminergic neurons located in the substantia nigra have already been lost [7].

The non motor characteristics of PD have attracted attention, as they can significantly affect functionality and quality of life [8]. Moreover, these symptoms can present early, or in advancing disease, and largely do not improve on dopaminergic treatment. According to Braak’s model of PD staging, symptoms such as sleep behavior disorders [9, 10], olfactory loss [11], and depression [12] can start before motor impairments [13] and could play a crucial role in an early diagnosis [14]. Furthermore, other non-motor symptoms can increase throughout the progression of the disease, such as dementia, urinary incontinence, constipation, pain, fatigue, and respiratory disorders [15–18].

Several assessments are used to quantify respiratory dysfunctions in adults, focused on the evaluation of subjective symptoms, such as dyspnea, tachypnea, or other self-reported clinical features [19], or objective signs, including pulmonary function [20, 21], respiratory muscle strength [22], and functional capacity [23].

Compromised respiratory function in PD represents a risk for developing other pneumo-functional comorbidities [24], increasing the risk of hospitalization [25]. A review by Macleod et al. showed that the mortality index in PD is 50% higher than the control mortality, and there is a decrease in survival of 5% per year of follow up [26], in which pneumonia is the most common cause of death in PD patients [27–29]. Despite these epidemiology data about PD’s complications and its comorbid disorders, respiratory impairments, its mechanisms and evolution are poorly understood. Therefore, the aim of this systematic review is to synthesize evidence regarding respiratory disorders in PD throughout the progression of the disease, and to identify the gaps in the literature regarding this subject to guide future research.

METHODS

RESULTS

Search strategy

The electronic search resulted in 601 references in English or Portuguese. The selection process was carried out through consensus between two independent reviewers, resulting in 17 selected studies. A manual search was performed based on the analysis of reference lists of the selected studies resulting in the selection of 16 additional papers, of which three studies matched the inclusion criteria. The final selection process resulted in the inclusion of 19 studies (Fig. 1).

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Fig. 1

Trial flow diagram of the study's selection process.

DISCUSSION

In this systematic review, nineteen included studies used different methodologies to evaluate pulmonary function, respiratory muscle strength, and the physical capacity of 677 subjects with mild, moderate or severe PD. Eleven studies evaluated the respiratory muscle strength of PD patients through maximal expiratory pressure (MEP) and maximal inspiratory pressure (MIP) measurements. Eight of them showed lower MIP and MEP values in PD patients compared to age-matched CG or predicted normal values [34, 52]. These results show evidence of a respiratory muscle weakness, which starts in the very early stages of PD [34, 51], and increases throughout the progression of the disease [39, 52]. Only three studies did not observe any difference between PD patients and a CG [38, 50], and PD and predicted normal values [37]. In a study conducted by Canning et al. (1997), 13 out of 16 patients related that they regularly performed aerobic exercises, such as walking or cycling, which could explain the good outcome of the PD patients [37].

The respiratory muscles consist of two types of muscular fibers—type I and II—which are categorized according to its type of metabolism and contractile characteristics [53]. Wrede et al. (2012) showed that PD patients often present myopathological changes, such as hypertrophy of type I fibers, combined with a loss of type II fibers, leading to a decreased activation of fast-twitch fibers. The cause of this myopathy is unknown but could be a mechanism behind the respiratory muscle dysfunction observed in this review [54].

We believe that the reduction of the respiratory muscle strength observed in PD could be responsible for secondary respiratory disorders, such as changes in pulmonary function. This affirmation is supported by a review study by van de Wetering-van Dongen [55] that showed that respiratory training presents positive effects on pulmonary function and quality of life of PD patients.

The evaluation of pulmonary function is commonly used to diagnose, monitor or evaluate pulmo-nary impairments [56], as well to determine the type of pulmonary dysfunction, such as obstructive, restrictive or a combination of both impairments [57]. The most relevant measurements include the forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), vital capacity (VC), and FEV₁/FVC ratio [58]. These parameters can provide important information to guide respiratory training, which has been proved clinically efficient in this population [59].

In this review, 18 studies assessed pulmonary function of PD patients. An obstructive pattern was identified in seven studies [35, 46], and a restrictive dysfunction was shown by four studies [38, 45]. In addition, one study identified that PD patients have both obstructive and restrictive dysfunctions [47]. Four studies did not observe any changes in the pulmonary function of PD patients [34, 51], however in this case only early-stage PD patients were evaluated.

Obstructive disorder is characterized by a greater reduction in FEV1 compared to FVC, resulting in a reduced FEV1/FVC ratio below the lower normality limit [60]. In PD, the reduction of the respiratory muscle strength, associated with laryngeal muscle dysfunction [61] and autonomic dysfunction [62] can lead to a reduced ventilatory capacity and upper airway obstruction, increasing respiratory work.

The restrictive pattern is marked by a reduced FVC in the absence of an obstructive pattern [63]. Restrictive disorders in PD can be caused by stiffness, chest wall deformity and respiratory muscle weakness, which decreases mobility thoracic, lung volumes and capacities [19, 65].

Furthermore, some of the included studies showed a correlation between the pulmonary impairments and the disease stage. It is known that the worsening of pulmonary function is associated with the severity of the disease, and it is expected that patients with a higher score on the HY scale will have significantly lower parameters compared to those in the early stages of PD [35, 46].

Ultimately, three studies assessed the influence of PD on physical capacity, through walk tests (six-minute walk and ten-meter walk tests) and cycle ergometer tests. Patients with PD presented a reduced walk distance when compared to an aged-matched control group during the 6MWT [36]. In addition, PD showed a lower velocity than the predicted normal values during the ten-meter walk test at fast speed [37], and a positive correlation between the PD subjects' performance and an increased values of mouth pressures at the cycle ergometer test [52] and 6MWT [36]. These results suggest that PD patients have physical capacity impairments, which could be a result of the characteristic respiratory dysfunction, resulting in impairments of their daily living functions.

Moreover, Canning et al. showed that PD patients present normal values during the cycle ergometer test and the ten-meter walk test at normal speed, and related that the regular exercise habits of the included subjects may have contributed to maintaining normal levels. The same study found differences in the test results between PD active and sedentary subjects [37].

In summary, this review presented common respiratory disorders in PD, which is extremely important to guide clinical practice. This systematic review revealed that the respiratory muscle weakness can be observed from early stages of PD, and that other dysfunction such as obstructive and restrictive patterns, and physical capacity impairments are mostly observed in moderate and advanced subjects.

With that in mind, we believe that the respiratory weakness is an important marker to be considered during patient care, and that early respiratory training could be effective in the treatment of respiratory dysfunctions, delaying the appearance of secondary disorders. There is some evidence showing that respiratory training can improve respiratory parameters in PD [55, 66], but we did not find any study that investigated its effects on preventing the progression of respiratory disorders in PD.

Future studies should investigate the cause of the observed respiratory symptoms, establishing the following: 1) what are the mechanisms behind the respiratory symptoms?; 2) is pulmonary dysfunction secondary to respiratory muscle weakness?; 3) is early respiratory training effective to prevent the appearance of pulmonary dysfunction?

CONCLUSION

In conclusion, this systematic review showed that respiratory disorders are a common feature in PD. Respiratory muscle weakness is observed from early PD stages and increases throughout the progression of the disease. The pulmonary dysfunction, such as obstructive and restrictive patterns, and the physical capacity impairments are mostly observed in moderate and advanced subjects, and we believe that it could be a direct result of the decreased muscle strength. Furthermore, larger studies should address the remaining questions discussed in this systematic review, by using standardized measurements and long-term follow up.