La maladie de Parkinson en France (serveur d'exploration)

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Ventilatory Dysfunction in Parkinson’s Disease

Identifieur interne : 000978 ( Pmc/Corpus ); précédent : 000977; suivant : 000979

Ventilatory Dysfunction in Parkinson’s Disease

Auteurs : Guillaume Baille ; Anna Maria De Jesus ; Thierry Perez ; David Devos ; Kathy Dujardin ; Christelle Monaca Charley ; Luc Defebvre ; Caroline Moreau

Source :

RBID : PMC:5008229

Abstract

In contrast to some other neurodegenerative diseases, little is known about ventilatory dysfunction in Parkinson’s disease (PD). To assess the spectrum of ventilation disorders in PD, we searched for and reviewed studies of dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders and the response to hypoxemia in PD. Among the studies, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under “off-drug” conditions. Although there are many reports of abnormal spirometry data in PD (mainly related to impairment of the inspiratory muscles), little is known about hypoventilation in PD. We conclude that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance. Hence, there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value.


Url:
DOI: 10.3233/JPD-160804
PubMed: 27314755
PubMed Central: 5008229

Links to Exploration step

PMC:5008229

Le document en format XML

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<p>In contrast to some other neurodegenerative diseases, little is known about ventilatory dysfunction in Parkinson’s disease (PD). To assess the spectrum of ventilation disorders in PD, we searched for and reviewed studies of dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders and the response to hypoxemia in PD. Among the studies, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under “off-drug” conditions. Although there are many reports of abnormal spirometry data in PD (mainly related to impairment of the inspiratory muscles), little is known about hypoventilation in PD. We conclude that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance. Hence, there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value.</p>
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<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">J Parkinsons Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">J Parkinsons Dis</journal-id>
<journal-id journal-id-type="publisher-id">JPD</journal-id>
<journal-title-group>
<journal-title>Journal of Parkinson's Disease</journal-title>
</journal-title-group>
<issn pub-type="ppub">1877-7171</issn>
<issn pub-type="epub">1877-718X</issn>
<issn-l>1877-7171</issn-l>
<publisher>
<publisher-name>IOS Press</publisher-name>
<publisher-loc>Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">27314755</article-id>
<article-id pub-id-type="pmc">5008229</article-id>
<article-id pub-id-type="publisher-id">JPD160804</article-id>
<article-id pub-id-type="doi">10.3233/JPD-160804</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Review</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Ventilatory Dysfunction in Parkinson’s Disease</article-title>
<alt-title alt-title-type="left-running-head">G. Baille et al.</alt-title>
<alt-title alt-title-type="right-running-head">Ventilatory Dysfunction in Parkinson’s Disease</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Baille</surname>
<given-names>Guillaume</given-names>
</name>
<xref ref-type="aff" rid="aff1">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>De Jesus</surname>
<given-names>Anna Maria</given-names>
</name>
<xref ref-type="aff" rid="aff2">b</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Perez</surname>
<given-names>Thierry</given-names>
</name>
<xref ref-type="aff" rid="aff2">b</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Devos</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff3">c</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dujardin</surname>
<given-names>Kathy</given-names>
</name>
<xref ref-type="aff" rid="aff1">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Charley</surname>
<given-names>Christelle Monaca</given-names>
</name>
<xref ref-type="aff" rid="aff4">d</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Defebvre</surname>
<given-names>Luc</given-names>
</name>
<xref ref-type="aff" rid="aff1">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Moreau</surname>
<given-names>Caroline</given-names>
</name>
<xref ref-type="aff" rid="aff1">a</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<aff id="aff1">
<label>a</label>
Service de Neurologie et Pathologie du Mouvement, Pôle de neurosciences et appareil locomoteur, CHRU de Lille, Lille, France / INSERM UMR 1171, LILLE France, Troubles cognitifs dégénératifs et vasculaires, Lille,
<country>France</country>
</aff>
<aff id="aff2">
<label>b</label>
Service d’Explorations Fonctionnelles Respiratoires, Hôpital Albert Calmette, CHRU de Lille, Lille,
<country>France</country>
</aff>
<aff id="aff3">
<label>c</label>
Service de Pharmacologie Médicale, Université de Lille, CHRU de Lille, France / INSERM UMR 1171, Lille,
<country>France</country>
</aff>
<aff id="aff4">
<label>d</label>
Unité des Troubles du Sommeil et de la Vigilance, CHRU de Lille/INSERM UMR 1171, Lille,
<country>France</country>
</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">
<label>*</label>
Correspondence to: Caroline Moreau, MD, PhD, Service de Neurologie et Pathologie du Mouvement, Pôle de neurosciences et appareil locomoteur, CHRU de Lille/INSERM UMR 1171,F-59037 Lille, France. Tel.: +003320446752; Fax: +003320446680; E-mail:
<email>caroline.moreau@chru-lille.fr</email>
. </corresp>
</author-notes>
<pub-date date-type="preprint" publication-format="electronic">
<day>16</day>
<month>6</month>
<year>2016</year>
</pub-date>
<pub-date date-type="pub" publication-format="electronic">
<day>20</day>
<month>8</month>
<year>2016</year>
</pub-date>
<pub-date date-type="collection" publication-format="electronic">
<year>2016</year>
</pub-date>
<volume>6</volume>
<issue>3</issue>
<fpage>463</fpage>
<lpage>471</lpage>
<history>
<date date-type="accepted">
<day>16</day>
<month>5</month>
<year>2016</year>
</date>
</history>
<permissions>
<copyright-statement>IOS Press and the authors. All rights reserved</copyright-statement>
<copyright-year>2016</copyright-year>
<license xlink:href="https://creativecommons.org/licenses/by-nc/4.0/" license-type="open-access">
<license-p>This is an open access article distributed under the terms of the
<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/">Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License</ext-link>
, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract>
<p>In contrast to some other neurodegenerative diseases, little is known about ventilatory dysfunction in Parkinson’s disease (PD). To assess the spectrum of ventilation disorders in PD, we searched for and reviewed studies of dyspnea, lung volumes, respiratory muscle function, sleep breathing disorders and the response to hypoxemia in PD. Among the studies, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under “off-drug” conditions. Although there are many reports of abnormal spirometry data in PD (mainly related to impairment of the inspiratory muscles), little is known about hypoventilation in PD. We conclude that ventilatory dysfunction in PD has been poorly studied and little is known about its frequency and clinical relevance. Hence, there is a need to characterize the different phenotypes of ventilation disorders in PD, study their relationships with disease progression and assess their prognostic value.</p>
</abstract>
<kwd-group>
<label>Keywords</label>
<kwd>Parkinson’s disease</kwd>
<kwd>pathophysiology</kwd>
<kwd>ventilatory function</kwd>
<kwd>review</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="sec0005">
<title>INTRODUCTION</title>
<p>Ventilatory dysfunction is known to have a role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis [
<xref rid="ref001" ref-type="bibr">1–4</xref>
]. However, little is known about the association between Parkinson’s disease (PD) and ventilatory dysfunction –despite the fact that James Parkinson noted the presence of respiratory abnormalities in his initial description of the disease (“He fetched his breath rather hard ... ”, [
<xref rid="ref005" ref-type="bibr">5</xref>
]). Furthermore, it is well known that aspiration pneumonia and pulmonary embolism are among the main causes of death in PD patients [
<xref rid="ref006" ref-type="bibr">6, 7</xref>
]. Ventilatory changes in PD might affect the patient’s quality of life by reducing levels of physical activity. However, ventilatory dysfunction in PD patients has not been well characterized even if, in 2010, a general review about respiratory problems in neurologic disorders was published [
<xref rid="ref008" ref-type="bibr">8</xref>
]. Nowadays, there are a number of outstanding questions. What are the frequency and the severity of ventilatory dysfunction in PD? When does it start? How might ventilatory dysfunction influence the course of the disease in terms of the phenotype and prognosis? Is it responsive to dopaminergic treatments? Here, we performed a review of the spectrum of ventilatory disorders in PD. Identified publications were classified into five groups, depending on the topic: (i) dyspnea, (ii) lung volumes, (iii) respiratory muscle function and (iv) sleep breathing disorders, (v) response to hypoxemia. Lastly, we discuss these impairments’ putative involvement in the neurodegenerative process.</p>
</sec>
<sec id="sec0010">
<title>LITERATURE SEARCH STRATEGY</title>
<p>We performed a systematic review of available literature in Pubmed with the appropriate search terms. Relevant publications in any language were identified by searching the PubMed bibliographic database (
<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/pubmed/">http://www.ncbi.nlm.nih.gov/pubmed/</ext-link>
) up 1950 until January 2015 with combinations of the keywords “pulmonary function AND Parkinson”, “lung AND Parkinson”, “breathing disorders AND Parkinson” (excluding nocturnal disorders), “ventilation AND Parkinson” and “hypoxemia AND Parkinson”. When relevant, additional references found in the identified publications were included in the review. Thus, we also considered reports of “breathing sleep disorders” in PD focusing on the articles about the impact of antiparkinsonian drugs.</p>
</sec>
<sec id="sec0015">
<title>DYSPNEA</title>
<p>Dyspnea corresponds to the subjective experience of respiratory discomfort, and consists of distinct sensations that vary in intensity [
<xref rid="ref009" ref-type="bibr">9</xref>
]. The phenomenon appears to result from the erroneous integration of sensory afferents but also has a marked emotional component [
<xref rid="ref010" ref-type="bibr">10</xref>
]. Dyspnea is a marker for poor quality of life and is associated with a loss of autonomy in ambulatory elderly patients [
<xref rid="ref011" ref-type="bibr">11</xref>
]. Very few studies assessed dyspnea in PD (
<xref ref-type="table" rid="jpd-6-jpd160804-t001">Table 1</xref>
).</p>
<sec id="sec0020">
<title>Dyspnea and fluctuations</title>
<p>In an observational study including all patients attended in a Movement Disorders department, most of the dyspnea was due to cardio-pulmonary diseases [
<xref rid="ref012" ref-type="bibr">12</xref>
]. Using the classification of non-motor fluctuations in PD [
<xref rid="ref013" ref-type="bibr">13</xref>
], dyspnea can be considered as an “autonomic disorder” (with cough and stridor) or as a “sensory disturbance”. Among non-motor fluctuations, in a cohort composed of advanced-PD patients, 40% reported dyspnea [
<xref rid="ref014" ref-type="bibr">14</xref>
]. Several studies have shown that the perception of dyspnea is impaired in PD patients [
<xref rid="ref015" ref-type="bibr">15, 16</xref>
]. This misperception was associated with symptoms of anxiety and non-motor fluctuations [
<xref rid="ref017" ref-type="bibr">17, 18</xref>
]. Indeed, PD patients report that they feel dyspnea more frequently in the “off-drug” condition [
<xref rid="ref014" ref-type="bibr">14, 19</xref>
].</p>
</sec>
<sec id="sec0025">
<title>Impact of treatments on dyspnea</title>
<p>However, dopamine does not seem to be the only neurotransmitter involved in dyspnea. Although there is still a doubt about the role of serotonin [
<xref rid="ref020" ref-type="bibr">20</xref>
], anti-inflammatory drugs like steroids may interfere in dyspnea sensation [
<xref rid="ref021" ref-type="bibr">21</xref>
]. After the administration of L-DOPA, improvements in lung function were not correlated with the reduction in the symptoms reported by the patients [
<xref rid="ref015" ref-type="bibr">15</xref>
]. Paradoxically, antiparkinsonian medications can trigger dyspnea. Thus, L-DOPA-induced dyskinesia has been reported as a possible cause of dysregulated breathing [
<xref rid="ref022" ref-type="bibr">22</xref>
], perhaps as a result of the loss of muscle control. Likewise, a longitudinal study has shown that dyspnea can be a side effect of subthalamic nucleus deep brain stimulation [
<xref rid="ref023" ref-type="bibr">23</xref>
]. The authors mentioned the following mechanisms underlying this phenomenon: An alteration of dyspnea perception, a bronchoconstriction, a disturbance in upper airway control or a disturbed respiratory muscle control. Surprisingly, a fixed epiglottis has been observed in subthalamic nucleus deep brain stimulation patients [
<xref rid="ref024" ref-type="bibr">24</xref>
].</p>
<p>Therefore, the precise mechanisms of dyspnea and the effect of treatments remain unknown.</p>
</sec>
</sec>
<sec id="sec0030">
<title>LUNG VOLUMES</title>
<sec id="sec0035">
<title>Restrictive patterns</title>
<p>Since the 1960 s, many studies have used spirometry to assess lung capacity in PD patients (
<xref ref-type="table" rid="jpd-6-jpd160804-t002">Table 2</xref>
). Even though the pulmonary fibrosis caused by ergotamine derivatives has become very rare, restrictive pulmonary syndrome has been reported in patients with severe PD (i.e. Hoehn & Yahr scores between III and V [
<xref rid="ref025" ref-type="bibr">25</xref>
]). Nevertheless, in this paper, the severity of the restrictive patterns is unknown as their definition was based on a qualitative analyze of the low-flow volume loop. The precise prevalence of these patterns in PD remains unclear but a recent study found 56.7% of restrictive pulmonary dysfunction in a 30 patients cohort with a mean disease duration of 4.9 years ± 3.1 [
<xref rid="ref026" ref-type="bibr">26</xref>
]. The loss of chest wall compliance and the camptocormia have been suggested as a mechanism [
<xref rid="ref027" ref-type="bibr">27, 28</xref>
]. Actually, chest expansion was much lower in PD than in control group (1.8 cm ± 0.8 vs. 4.3 cm ± 1.0). A gender effect has been suggested: Women may present a more severe restrictive syndrome, even after adjustment for the severity of PD [
<xref rid="ref029" ref-type="bibr">29, 30</xref>
]. Beyond the severity, restrictive patterns affected more women (more than 50%) than men (about 10% - [
<xref rid="ref029" ref-type="bibr">29</xref>
]). On the contrary, in a kinematic and spirometric analysis of PD subjects suffering from a speech deficit, no lung volumes abnormalities was observed [
<xref rid="ref031" ref-type="bibr">31</xref>
]. Nevertheless, most of the studies used the forced vital capacity (FVC) to define the restrictive pattern although the guidelines recommend using the total lung capacity (TLC).</p>
</sec>
<sec id="sec0040">
<title>Obstructive patterns</title>
<p>An analysis of the flow-volume curve highlighted a severe obstructive pulmonary syndrome in patients with advanced-PD [
<xref rid="ref032" ref-type="bibr">32</xref>
], and some researchers have reported abnormalities in the upper airways [
<xref rid="ref033" ref-type="bibr">33, 34</xref>
]. Some of the participants in these studies were patients with active tobacco intoxication [
<xref rid="ref035" ref-type="bibr">35, 36</xref>
], and so the results may also have depended on the patients’ willingness to perform the test. Furthermore, once more, upper airway obstruction was set from the flow-volume loop tracing with difficulty to assess quantitatively. Therefore, the frequency of upper airway obstruction remains unknown even if some researchers estimated an occurrence between one fifth and two-third of the patients [
<xref rid="ref030" ref-type="bibr">30, 35, 36</xref>
]. After testing 58 PD patients, Sabaté et al. suggested that the obstructive pulmonary syndrome was associated with bradykinesia, hypertonia and radiologic signs of cervical and dorsal arthrosis [
<xref rid="ref030" ref-type="bibr">30</xref>
]. In contrast, no obstructive pulmonary syndrome was found in a cohort of 12 patients with advanced-PD (even in the “off-drug” condition) [
<xref rid="ref025" ref-type="bibr">25</xref>
]. In 1989, a respiratory flutter phenomenon (flow-volume loop oscillation of 4–8 Hz) was observed (see
<xref ref-type="fig" rid="jpd-6-jpd160804-g001">Fig. 1</xref>
; [
<xref rid="ref032" ref-type="bibr">32</xref>
]) and found to be correlated with dyskinesia and tremor. It should be due to a vibration of the vocal cords and the supraglottic structures. However, this feature does not seem to be specific for PD since it was described in other extrapyramidal disorders [
<xref rid="ref033" ref-type="bibr">33</xref>
]. At last, two studies have highlighted the occurrence of mixed pulmonary dysfunction (association of obstructive and obstructive ventilatory syndromes) in PD patients [
<xref rid="ref028" ref-type="bibr">28, 30</xref>
].</p>
</sec>
<sec id="sec0045">
<title>Effect of antiparkinsonian drugs on lungs volumes</title>
<p>Regarding the dopasensitivity, some researchers consider that the effect of L-DOPA in the restrictive syndrome is only partial [
<xref rid="ref029" ref-type="bibr">29</xref>
] although others did not highlight any signification variation due to treatment [
<xref rid="ref025" ref-type="bibr">25</xref>
].Yet, even on “on drug condition”, FVC remained below the norm [
<xref rid="ref029" ref-type="bibr">29</xref>
]. Some researchers suggest that acute and chronic administrationL-DOPA can improve the flow-volume curve [
<xref rid="ref035" ref-type="bibr">35, 36</xref>
]. These results must be interpreted with caution, since some of the studies included patients with asthma or obstructive bronchopulmonary disease [
<xref rid="ref035" ref-type="bibr">35, 36</xref>
]. Furthermore, it has been suggested that obstructive pulmonary syndrome is due to bronchoconstriction caused by sympathetic hyperactivation [
<xref rid="ref037" ref-type="bibr">37</xref>
].</p>
</sec>
</sec>
<sec id="sec0050">
<title>RESPIRATORY MUSCLES</title>
<sec id="sec0055">
<title>Inspiratory and expiratory muscles weakness</title>
<p>Several studies have evidenced weakness of both inspiratory and expiratory muscles in PD (
<xref ref-type="table" rid="jpd-6-jpd160804-t003">Table 3</xref>
; [
<xref rid="ref026" ref-type="bibr">26, 38–41</xref>
]). The maximal inspiratory mouth pressures (MIP) seems to be more affected than the maximal expiratory mouth pressure (MEP) according to several researchers [
<xref rid="ref026" ref-type="bibr">26, 42</xref>
]. Besides, in this latter paper, inspiratory muscles weakness is very severe [
<xref rid="ref042" ref-type="bibr">42</xref>
]. The correlation with respiratory symptoms remains unclear, since some of the studies included patients with severe PD and limitations in their activities of daily living. There are few studies of the pathophysiology of this respiratory muscle weakness. Tremor (mainly action tremor) may be involved [
<xref rid="ref043" ref-type="bibr">43</xref>
] or jerky movements of the diaphragm [
<xref rid="ref044" ref-type="bibr">44</xref>
]. Accessory muscles seem to be affected in PD, although data on diaphragm function in PD are scarce. Vercueil et al. observed a differential impact of the disease on inspiratory muscles (preservation of diaphragmatic activity and impaired accessory inspiratory muscles, mainly intercostal muscles) [
<xref rid="ref045" ref-type="bibr">45</xref>
]. A link between respiratory muscles disturbance and impaired lung volumes has been suggested [
<xref rid="ref046" ref-type="bibr">46</xref>
]. Spirometry results would be the consequence of a reduced efficiencyduring repetitive motor tasks. Furthermore, respiratory muscles strength seems to decrease with the course of the disease since a negative correlation was highlighted between MIP, MEP and the motor section of UPDRS [
<xref rid="ref026" ref-type="bibr">26</xref>
].</p>
</sec>
<sec id="sec0060">
<title>Effect of antiparkinsonian drugs on respiratory muscles</title>
<p>Continuous subcutaneous infusion of Apomorphine has a positive effect on upper airways and chest wall muscle coordination [
<xref rid="ref042" ref-type="bibr">42</xref>
]. But the MIP was not normalized. Other researchers did not find any significant effect of L-DOPA on mouth pressure values [
<xref rid="ref041" ref-type="bibr">41</xref>
]. Likewise, two other studies did not evidence any respiratory muscle weakness in PD patients [
<xref rid="ref023" ref-type="bibr">23, 33</xref>
]. Lastly, it is still not clear whether the onset of muscleweakness occurs early in PD, although Guedes et al. has suggested that this is indeed the case. Yet, the mean disease duration in their cohort was 9.1 ± 0.3 years [
<xref rid="ref041" ref-type="bibr">41</xref>
].</p>
</sec>
</sec>
<sec id="sec0065">
<title>SLEEP BREATHING DISORDERS</title>
<sec id="sec0070">
<title>Occurrence of sleep apnea syndrome in PD</title>
<p>It has been known for decades that PD is associated with sleep disorders such as insomnia, excessive daytime sleepness, REM (rapid-eye movement) and sleep behavioral disorders. However, there is still debate as to the prevalence of sleep apnea syndrome (SAS) in PD patients [
<xref rid="ref047" ref-type="bibr">47</xref>
]. According to Shill et al. [
<xref rid="ref048" ref-type="bibr">48</xref>
], the presence of restrictive or obstructive patterns in PD could be a predisposition to SAS. Some researchers have reported an abnormally high prevalence of SAS in PD (relative to healthy, age-matched controls), whereas others have reported normal or below-normal values [
<xref rid="ref047" ref-type="bibr">47, 49–51</xref>
]. The body mass index was a major source of bias in these studies, and most of the patients included were suffering from late-stage PD. Moreover, no predictive clinical features of SAS have been identified [
<xref rid="ref051" ref-type="bibr">51</xref>
]. Some researchers have mentioned peripheral SAS caused by upper airway obstruction [
<xref rid="ref048" ref-type="bibr">48</xref>
]. However, an occurrence of 48% of sleep breathing disorders with a predominance of central SAS has been observed [
<xref rid="ref052" ref-type="bibr">52</xref>
].</p>
<p>Interestingly, a recent study found that 43.3% of
<italic>de novo</italic>
PD patients (with a mean ± SD duration of disease of 9.7 ± 9.5 months) had an apnea-hypopnea index higher than 5 per hour [
<xref rid="ref053" ref-type="bibr">53</xref>
]. The researchers observed an average of 15.9 ± 20.9 desaturation episodes per hour. Nevertheless, the study lacked an age-matched control group. Furthermore, no other studies (except those with obese patients) have evidenced significant oxyhemoglobindesaturation [
<xref rid="ref047" ref-type="bibr">47</xref>
]. In conclusion, there is some evidence of mild nocturnal desaturation in early-stage PD but the underlying mechanisms have not been characterized. The functional consequences of these sleep breathing disorders are unclear, although vigilance does not seem to be affected [
<xref rid="ref054" ref-type="bibr">54</xref>
].</p>
</sec>
<sec id="sec0075">
<title>Impact of antiparkinsonian drugs on sleep breath disorders</title>
<p>No effect of antiparkinsonian drugs was reported in a review about treatment of sleep disorders in PD [
<xref rid="ref055" ref-type="bibr">55</xref>
]. In a study, dopamine agonist enhanced the risk of central SAS (mainly during REM-sleep) without any difference in terms of Epworth Sleepiness Scale [
<xref rid="ref053" ref-type="bibr">53</xref>
].</p>
</sec>
</sec>
<sec id="sec0080">
<title>THE RESPONSE TO HYPOXIA</title>
<p>In 1998, Serebrovskaya et al. showed that PD patients had abnormally low alveolar ventilation during severe hypoxia [
<xref rid="ref056" ref-type="bibr">56</xref>
]. This result could not be attributed to a mechanical restriction of lung function. It is suggested that the altered response to minor and major hypoxia resulted from a PD-associated impairment of chemoreception [
<xref rid="ref056" ref-type="bibr">56</xref>
]. Other researchers confirmed these results in patients with advanceddisease [
<xref rid="ref016" ref-type="bibr">16</xref>
] and patient with early-stage disease [
<xref rid="ref057" ref-type="bibr">57</xref>
]. Other studies found a reduced ventilatory response to hypercapnia [
<xref rid="ref058" ref-type="bibr">58</xref>
]. The putative mechanism is related to low ventilatory chemosensitivity and autonomic dysfunction.</p>
</sec>
<sec id="sec0085">
<title>INVOLVEMENT IN THE NEURODEGENERATIVE PROCESS</title>
<p>Neurodegeneration of the substantia nigra pars compacta (the hallmark of PD) is accompanied by extensive loss of neurons in extranigral sites, including the brainstem nuclei involved in sleep physiology and respiratory control [
<xref rid="ref059" ref-type="bibr">59, 60</xref>
]. This localized neurodegeneration in some parts of the brainstem may account for the occurrence of ventilatory disorders in PD. However, a number of questions have yet to be resolved.
<list list-type="simple" id="list0005">
<list-item id="listitem0005">
<p>(i) Since hypoxemia has already been described as one of the mechanisms of cell death in PD [
<xref rid="ref061" ref-type="bibr">61</xref>
], does the alteration in pulmonary function accelerate the disease progression? Do cerebral or brainstem structures morphometric alterations impact on the occurrence of ventilator disorders? In a cerebral MRI study, Gama et al. found an association between excessive daytime sleepiness and middle cerebellar peduncle atrophy in PD [
<xref rid="ref062" ref-type="bibr">62</xref>
]. It would be interesting to perform a polysomnography and MRI study in this type of patient population.</p>
</list-item>
<list-item id="listitem0010">
<p>(ii) When does hypoxemia occur? Asymptomatic hypoxemic episodes seem to occur even in
<italic>de novo</italic>
untreated patients [
<xref rid="ref049" ref-type="bibr">49</xref>
], although larger patient vs. control cohort studies are required.</p>
</list-item>
<list-item id="listitem0015">
<p>(iii) If hypoxemia does occur, can it influence the disease phenotype? As already observed in non-parkinsonian elderly patients [
<xref rid="ref063" ref-type="bibr">63</xref>
], Neikrug et al. also highlighted obstructive SAS as a predictor of cognitive impairment in PD [
<xref rid="ref064" ref-type="bibr">64</xref>
]. However, in a cohort of 740 early-stage PD patients, pulmonary dysfunction was not found to be a risk factor for cognitive impairment [
<xref rid="ref065" ref-type="bibr">65</xref>
]. The main limit of this study is the absence of precise evaluation of the ventilatory function. Furthermore, motor status before and after the treatment of sleep apnea in PD patients has never assessed. However, some researchers found evidence of an abnormally low sympathetic response to hypoxia in patients with PD [
<xref rid="ref057" ref-type="bibr">57</xref>
]. Here again, only a large, prospective cohort follow-up will be able to address this point.</p>
</list-item>
</list>
</p>
</sec>
<sec id="sec0090">
<title>CONCLUSION</title>
<p>Ventilatory dysfunction is an underestimated feature of PD. The heterogeneity of the papers hinders the assessment of the frequency and the severity of lung volumes alterations (restrictive and obstructive patterns), the respiratory muscles weakness and the dyspnea, even in advanced PD. The effect of antiparkinsonian drugs is still controversial. Among the studies included in this paper, we identified some limitations: (i) small study populations (mainly composed of patients with advanced PD), (ii) the absence of long-term follow-up and (iii) the absence of functional evaluations under “off-drug” conditions.</p>
<p>Recent data suggested that ventilator dysfunction could affect even early-stage. However, there are too few literature data to adequately confirm thishypothesis.</p>
<p>In conclusion, future research will have to investigate (i) the prevalence of respiratory dysfunction in early-stage patients, (ii) the pathophysiological mechanisms underlying this dysfunction and (iii) any long-term correlations between respiratory muscle weakness, altered lung volumes, breathing sleep disorders and the onset of motor and non-motor signs of PD.</p>
<p>Our manuscript was copy-edited by David Fraser (Biotech Communication SARL).</p>
</sec>
</body>
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<fig id="jpd-6-jpd160804-g001" orientation="portrait" position="float">
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<caption>
<p>A flow-volume loop in a PD patient (personal observation). Ordinate: Flow (L/s), Abscissa: Volume (L). Ventilatory flutter is predominant during inspiration (black arrow).</p>
</caption>
<graphic xlink:href="jpd-6-jpd160804-g001"></graphic>
</fig>
<table-wrap id="jpd-6-jpd160804-t001" orientation="portrait" position="float">
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<caption>
<p>Summary of the literature data on dyspnea in PD. HY: Hoehn and Yahr, DBS: Deep brain stimulation. VIM: Ventrale intermediate nucleus of the thalamus, NA: Not available</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="justify" span="1"></col>
</colgroup>
<thead valign="top">
<tr>
<td rowspan="1" colspan="1">Study</td>
<td rowspan="1" colspan="1">Number of patients</td>
<td rowspan="1" colspan="1">Disease duration (year)</td>
<td rowspan="1" colspan="1">Clinical scores</td>
<td rowspan="1" colspan="1">Control group</td>
<td rowspan="1" colspan="1">Misperception of dyspnea</td>
<td rowspan="1" colspan="1">Main results</td>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref016" ref-type="bibr">16</xref>
]</td>
<td align="center" rowspan="1" colspan="1">25</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">HY 2–3</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">Impaired perception of dyspnea</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref016" ref-type="bibr">14</xref>
]</td>
<td align="center" rowspan="1" colspan="1">50</td>
<td rowspan="1" colspan="1">12.7 ± 5.4</td>
<td rowspan="1" colspan="1">UPDRS III 44.4 ± 13.4“on drug”</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">90% of patients with dyspnea on “off drug” condition</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref015" ref-type="bibr">15</xref>
]</td>
<td align="center" rowspan="1" colspan="1">20</td>
<td rowspan="1" colspan="1">7.5 ± 1.1</td>
<td rowspan="1" colspan="1">HY 2–3</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">No link between reduction in dyspnea and increase in lung volumes</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref023" ref-type="bibr">23</xref>
]</td>
<td align="center" rowspan="1" colspan="1">13</td>
<td rowspan="1" colspan="1">Patients withDBS</td>
<td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">Yes (VIM)</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">link between DBS and dyspnea</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="jpd-6-jpd160804-t002" orientation="portrait" position="float">
<label>Table 2</label>
<caption>
<p>Summary of the literature data on pulmonary function and PD. HY: Hoehn and Yahr, NS: Not significant, UPDRS: Unified Parkinson’s Disease Rating Scale, MSA: Multiple system atrophy</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="justify" span="1"></col>
</colgroup>
<thead valign="top">
<tr>
<td rowspan="1" colspan="1">Study</td>
<td rowspan="1" colspan="1">Number of patients</td>
<td rowspan="1" colspan="1">Disease duration (year)</td>
<td rowspan="1" colspan="1">Clinical scores</td>
<td rowspan="1" colspan="1">Control group</td>
<td rowspan="1" colspan="1">Spirometry</td>
<td rowspan="1" colspan="1">Dopasensitivity</td>
<td rowspan="1" colspan="1">Main results</td>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref037" ref-type="bibr">37</xref>
]</td>
<td align="center" rowspan="1" colspan="1">31</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">obstruction</td>
<td rowspan="1" colspan="1">No</td>
<td rowspan="1" colspan="1">bronchoconstriction due to hyperactivity of the sympathetic system</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref034" ref-type="bibr">34</xref>
]</td>
<td align="center" rowspan="1" colspan="1">23</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">proximal obstruction</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref036" ref-type="bibr">36</xref>
]</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">obstruction</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">partial</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref033" ref-type="bibr">33</xref>
]</td>
<td align="center" rowspan="1" colspan="1">27</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">proximal obstruction</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref032" ref-type="bibr">32</xref>
]</td>
<td align="center" rowspan="1" colspan="1">31</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">12 HY3, 11 HY4, 8 HY5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">obstruction</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">link with PD progression</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref032" ref-type="bibr">32</xref>
]</td>
<td align="center" rowspan="1" colspan="1">31</td>
<td rowspan="1" colspan="1">8</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">mixed</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">description of ventilatory flutter</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref031" ref-type="bibr">31</xref>
]</td>
<td align="center" rowspan="1" colspan="1">19</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">no impact of lung volumes on dysarthria</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref028" ref-type="bibr">28</xref>
]</td>
<td align="center" rowspan="1" colspan="1">63</td>
<td rowspan="1" colspan="1">5 ± 0.68</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">mixed</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">link with UPDRS III score</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref030" ref-type="bibr">30</xref>
]</td>
<td align="center" rowspan="1" colspan="1">58</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">mixed</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">link with clinical aspects of PD (bradykinesia, hypertonia, dorsal and cervical arthrosis)</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref048" ref-type="bibr">48</xref>
]</td>
<td align="center" rowspan="1" colspan="1">review</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">review</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">restriction associated with hypertonia, obstruction pulmonary syndrome associated with upper airway obstruction</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref035" ref-type="bibr">35</xref>
]</td>
<td align="center" rowspan="1" colspan="1">21</td>
<td rowspan="1" colspan="1">5 (mean)</td>
<td rowspan="1" colspan="1">HY 2–4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">obstruction</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">lung volumes improved by L-DOPA</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref027" ref-type="bibr">27</xref>
]</td>
<td align="center" rowspan="1" colspan="1">40</td>
<td rowspan="1" colspan="1">     /</td>
<td rowspan="1" colspan="1">HY 1–3</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">restriction</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref046" ref-type="bibr">46</xref>
]</td>
<td align="center" rowspan="1" colspan="1">21</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">obstruction</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">abnormal agonist-antagonist muscle activity impacts on lungs volumes</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref025" ref-type="bibr">25</xref>
]</td>
<td align="center" rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">HY 3–5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">restriction</td>
<td rowspan="1" colspan="1">NS</td>
<td rowspan="1" colspan="1">no obstructive syndrome, even in the “off-drug” condition</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref029" ref-type="bibr">29</xref>
]</td>
<td align="center" rowspan="1" colspan="1">53</td>
<td rowspan="1" colspan="1">2.8 in women, 3.2 in men</td>
<td rowspan="1" colspan="1">UPDRS 45 off, 14.6 on</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">restriction</td>
<td rowspan="1" colspan="1">partial</td>
<td rowspan="1" colspan="1">female patients had worse pulmonary function</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref026" ref-type="bibr">26</xref>
]</td>
<td align="center" rowspan="1" colspan="1">30</td>
<td rowspan="1" colspan="1">4.9 ± 3.1</td>
<td rowspan="1" colspan="1">UPDRS 32.4“on drug”</td>
<td rowspan="1" colspan="1">Yes (and MSA)</td>
<td rowspan="1" colspan="1">mixed</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">correlation with motor section of UPDRS</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="jpd-6-jpd160804-t003" orientation="portrait" position="float">
<label>Table 3</label>
<caption>
<p>Summary of the literature data on respiratory muscle weakness and PD. HY: Hoehn and Yahr, inspi: Inspiratory muscles, expi: Expiratory muscles, NS: Not significant. UPDRS: Unified Parkinson’s Disease rating Scale</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="justify" span="1"></col>
</colgroup>
<thead valign="top">
<tr>
<td rowspan="1" colspan="1">Study</td>
<td rowspan="1" colspan="1">Number of</td>
<td rowspan="1" colspan="1">Disease</td>
<td rowspan="1" colspan="1">Clinical</td>
<td rowspan="1" colspan="1">Control</td>
<td rowspan="1" colspan="1">Muscles</td>
<td rowspan="1" colspan="1">Dopasensitivity</td>
<td rowspan="1" colspan="1">main results</td>
</tr>
<tr>
<td rowspan="1" colspan="1">patients</td>
<td rowspan="1" colspan="1">duration (year)</td>
<td rowspan="1" colspan="1">scores</td>
<td rowspan="1" colspan="1">group</td>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref036" ref-type="bibr">36</xref>
]</td>
<td align="center" rowspan="1" colspan="1">6</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Inspi and expi</td>
<td rowspan="1" colspan="1">Yes</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref040" ref-type="bibr">40</xref>
]</td>
<td align="center" rowspan="1" colspan="1">9</td>
<td rowspan="1" colspan="1">2 to 14</td>
<td rowspan="1" colspan="1">HY 1–3</td>
<td rowspan="1" colspan="1">Yes</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref042" ref-type="bibr">42</xref>
]</td>
<td align="center" rowspan="1" colspan="1">10</td>
<td rowspan="1" colspan="1">6 to 20</td>
<td rowspan="1" colspan="1">HY 2–4</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">inspi</td>
<td rowspan="1" colspan="1">Yes(apomorphine)</td>
<td rowspan="1" colspan="1">due to lack of muscle coordination</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref027" ref-type="bibr">27</xref>
]</td>
<td align="center" rowspan="1" colspan="1">40</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">HY 1–3</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">normal</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref039" ref-type="bibr">39</xref>
]</td>
<td align="center" rowspan="1" colspan="1">66</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">HY 3–5</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">inspi and expi</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">abnormal response to mild hypoxia</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref029" ref-type="bibr">29</xref>
]</td>
<td align="center" rowspan="1" colspan="1">35</td>
<td rowspan="1" colspan="1">      3</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">inspi and expi</td>
<td rowspan="1" colspan="1">Yes</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref041" ref-type="bibr">41</xref>
]</td>
<td align="center" rowspan="1" colspan="1">26</td>
<td rowspan="1" colspan="1">9.1 ± 0,3</td>
<td rowspan="1" colspan="1">UPDRS 43 “on drug”</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">inspi and expi</td>
<td rowspan="1" colspan="1">NS</td>
<td rowspan="1" colspan="1">respiratory muscle weakness in early-stage PD</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref026" ref-type="bibr">26</xref>
]</td>
<td align="center" rowspan="1" colspan="1">30</td>
<td rowspan="1" colspan="1">4.9 ± 3.1</td>
<td rowspan="1" colspan="1">UPDRS 32.4 “on drug”</td>
<td rowspan="1" colspan="1">Yes (and MSA)</td>
<td rowspan="1" colspan="1">inspi and expi</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">correlation with motor section of UPDRS</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="jpd-6-jpd160804-t004" orientation="portrait" position="float">
<label>Table 4</label>
<caption>
<p>Summary of the literature data on dyspnea and PD. HY: Hoehn and Yahr</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="justify" span="1"></col>
</colgroup>
<thead valign="top">
<tr>
<td rowspan="1" colspan="1">Study</td>
<td rowspan="1" colspan="1">Number of</td>
<td rowspan="1" colspan="1">Disease</td>
<td rowspan="1" colspan="1">Clinical</td>
<td rowspan="1" colspan="1">Control</td>
<td rowspan="1" colspan="1">Main results</td>
</tr>
<tr>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">patients</td>
<td rowspan="1" colspan="1">duration (year)</td>
<td rowspan="1" colspan="1">scores</td>
<td rowspan="1" colspan="1">group</td>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref056" ref-type="bibr">56</xref>
] (article in Russian)</td>
<td rowspan="1" colspan="1">7</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">abnormal response to hypoxemia</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref057" ref-type="bibr">57</xref>
]</td>
<td rowspan="1" colspan="1">19</td>
<td rowspan="1" colspan="1">5.7 ± 0.3</td>
<td rowspan="1" colspan="1">HY 3–5</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1">reduced response to hypoxia</td>
</tr>
<tr>
<td rowspan="1" colspan="1">[
<xref rid="ref058" ref-type="bibr">58</xref>
]</td>
<td rowspan="1" colspan="1">12</td>
<td rowspan="1" colspan="1">9.3 ± 4.6</td>
<td rowspan="1" colspan="1">HY 1.5 ± 0.7</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">reduced response to hypoxia</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
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