Abnormal ventilatory control in Parkinson's disease—Further evidence for non-motor dysfunction

https://doi.org/10.1016/j.resp.2011.09.012Get rights and content

Abstract

There has been increasing recognition of pre-motor manifestations of Parkinson's disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO2. Arterial blood gases were taken at rest and following 20 min exposure to 15% O2. A linear correlation assessed associations between respiratory function and indices of PD severity.

19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function.

Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows.

Highlights

► Abnormal respiratory control is seen in mild-moderate Parkinson's disease. ► This occurs before there is functionally important muscle weakness. ► Non-motor brainstem involvement is an early abnormality in Parkinson's disease.

Introduction

Parkinson's disease (PD) has always been thought to involve a disturbance of respiration. James Parkinson observed in 1817 that his patients “fetched their breath rather hard” in his monograph, “An Essay on the Shaking Palsy” (Parkinson, 1817). Despite this early recognition of involvement of the respiratory system, the exact abnormalities and their causation remain unclear.

The pathology of PD typically consists of degeneration of the neuronal cytoskeleton and the accumulation of proteinaceous inclusions called Lewy bodies. Although previously thought to occur principally in dopaminergic neurons in the mid-brain (sustantia nigra), the Braak staging hypothesis based on pathological studies (Braack and Braak, 2000) suggests that the earliest evidence of disease is in the medulla, enteric nervous system and olfactory bulb. It is proposed that the disease then slowly spreads trans-neuronally to the mid-brain, causing the classical motor features, and finally to the cortex with progressive cognitive and limbic symptoms. The hypothesis implies that there may be early pre-motor, autonomic and olfactory dysfunctions and there is now accumulating evidence supporting this, particularly relating to postural hypotension, cardiac denervation, bowel motility and hyposmia (Goldstein et al., 2010, Cheshire, 2010). These findings raise the possibility that brain-stem (medullary) ventilatory control mechanisms may be affected in PD, and should be evident in those who have progressed to mild-moderate disease.

Respiratory involvement with PD could occur through both peripheral and central mechanisms. Motor manifestations such as rigidity, tremor and weakness affect the upper airway and the respiratory pump muscles. Non-motor brain stem involvement has effect at the level of respiratory control. Literature since the 1950s has yielded disparate findings. Peripheral involvement studies have demonstrated normal (Onodera et al., 2000) and restrictive (Nakano et al., 1972, De Pandis et al., 2002, Izquierdo-Alonso et al., 1994) flow volume characteristics, upper airway dysfunction (Izquierdo-Alonso et al., 1994) and reduced peak expiratory flow (Nakano et al., 1972, Izquierdo-Alonso et al., 1994, Polatli et al., 2001). Observations of reduced respiratory flow and volume have shown improvement while “on” levodopa therapy as compared to “off” (Nakano et al., 1972, De Pandis et al., 2002). Investigations into brainstem mediated function have been limited. Respiratory control studies have demonstrated a reduced sensitivity to progressive hypoxia (Onodera et al., 2000, Serebrovskaya et al., 1998) with no effect on progressive hypercapnia (Onodera et al., 2000). As respiratory drive under normal circumstances is more influenced by CO2 than O2 concentration, we sought to clarify whether ventilatory response to hypercapnia was altered in PD. The aim of this study was to comprehensively describe the effects of idiopathic PD both on non motor respiratory control, using ventilation, occlusion pressures, and peripheral respiratory function.

Section snippets

Subjects

Patients with a diagnosis of idiopathic PD were recruited from a hospital-based PD clinic. Exclusion criteria included any clinically significant respiratory or cardiovascular disease, neurological disease other than PD, a significant smoking history (>10 pack years), structural abnormalities of the chest wall or recent upper respiratory tract infection. All testing was performed with the patient taking their usual medications; the timing of medication use in relation to the tests was not

Demographics and group description

19 subjects (17 male) with a diagnosis of idiopathic PD were recruited. Demographics and disease history and severity are shown in Table 1.

By UPDRS motor examination, average scores reflect mild-moderate impairment (Fahn and Elton, 1987). H&Y staging (1967) classified subjects as having unilateral disease (Stage 1: n = 2), unilateral disease plus axial involvement (Stage 1.5: n = 1), bilateral disease, without impairment of balance (Stage 2: n = 4), mild bilateral disease (Stage 2.5: n = 4) or

Main findings

This patient group with mild-moderate PD on optimal treatment has normal respiratory flow and volumes. Respiratory muscle weakness is common, but insufficient to cause restriction. Respiratory control is however abnormal. There is a marked impairment of the response to hypercapnia but not to mild hypoxia. This abnormality of respiratory drive is consistent with the Braak (Braack and Braak, 2000) hypothesis suggesting early brainstem involvement in PD.

Subject selection as compared to previous studies

Our finding of normal respiratory flow and

Conclusion

In summary, an abnormal ventilatory response to CO2 is a feature of mild-moderate PD independent of mechanical factors, which were mostly preserved. Respiratory function and ventilatory response may worsen as the disorder progresses, but at later stages measurement becomes more difficult. Idiopathic PD and other Parkinsonian syndromes are associated with excess morbidity and mortality from respiratory causes (Brown, 1994), with pneumonia continuing to be the leading cause of death in end-stage

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