Multiple system atrophy (MSA) is a rare neurodegenerative disease whose symptoms include parkinsonism, autonomic failure and cerebellar and pyramidal impairment in different combinations, leading to a sub-classification in type C or type P depending on prevailing symptoms.
Sleep disorders in MSA include insomnia, nocturnal motor agitation linked to REM sleep behavior disorder in up to 90% of patients, and a 28% prevalence of restless legs syndrome. Sleep-disordered breathing (SDB) is also one of the most reported nocturnal disorders and includes obstructive sleep apnea (OSA) in 15% to 37% of cases,1 central sleep apnea (CSA), sleep hypoventilation and, most typically, stridor, a life-threatening condition that may lead to acute respiratory failure and sudden death.2 Comparing MSA to Parkinson disease and progressive supranuclear palsy, Gama et al.3 found that MSA is at an increased risk for both OSA and diurnal respiratory complaints, mainly linked to two different mechanisms: the upper airway (UA) obstruction at the glottis level, and brainstem neurodegeneration.
Some, if not all of these disorders may severely impact quality of life by inducing daytime sleepiness and fatigue,4 ultimately impairing life expectancy in patients with MSA. Therefore, timely adequate diagnosis of SDB is mandatory in order to implement the best tailored treatment.
Continuous positive airway pressure (CPAP) is the gold standard for treatment of OSA, by achieving both UA patency and stabilization, and has recently also proven to be an effective treatment option for stridor, alone or in combination with OSA,5 where it might be preferable to invasive tracheostomy. Instead, adaptive servoventilation is indicated for CSA or complex OSA with CSA emerging during CPAP titration.6
CPAP low fixed pressures (4–8 cmH2O) are generally effective and well tolerated to eliminate stridor.7 Life expectancy in treated patients with MSA with stridor has increased, becoming similar to that of those without stridor.5 Sudden death in MSA, however, may not only result from suffocation due to vocal cord abductor paralysis, but might also be the result of disordered central respiration or a iatrogenic consequence of CPAP acting on a floppy epiglottis with worsening UA obstruction.8,9 The high prevalence (71%) of floppy epiglottis in patients with MSA may be typical of the disease and depend on an abnormal laryngeal tone.10
As far as OSA is concerned, a recent meta-analysis exploring the association between the presence of OSA and mortality showed that the former is not an independent factor associated with mortality in MSA.11 Surprisingly, exploring the natural course of OSA in MSA, some authors12 reported that despite a general trend to an increased severity of OSA with time, 29% of patients, half of which had decreased their body mass index, showed spontaneous improvement over time. The outcome was instead worse for early onset OSA in the course of MSA.
The worst prognosis is associated with sleep-related breathing disorders other than OSA, usually observed in the later stages of MSA. These disorders include CSA, Cheyne-Stokes breathing both during sleep and wakefulness, and dysrhythmic breathing patterns.2 An underlying neurodegeneration of the brainstem with its pontomedullary centers of breathing regulation may explain the latter disorder.13
In this issue, Nakayama et al. explore the contribution of “breathing instability” to the development of OSA in a cohort of patients with MSA compared to healthy controls by a novel method assessing approximate entropy of polygraphically recorded chest respiratory movements during wakefulness prior to sleep onset.14 Their positive results may indeed elucidate another important factor (ie, breathing instability) besides anatomical collapsibility of UA that might substantially contribute to OSA in MSA.15 This mechanism could potentially play a major role in patients with MSA with low body mass index and with mixed apnea-dominant OSA. Breathing instability may be present from the early stages of MSA and be improved not only by CPAP, but also by lower loop gain with supplemental oxygen or acetazolamide administration.16 Breathing irregularities along with typical hypokinesia, rigidity, dystonia, and paralysis of the UA muscles might consistently impact breathing dynamics in MSA during both sleep and wakefulness, as seen in other severe SDB-related conditions such as heart failure, cerebral infarction and opioid chronic treatment.
SDB reflects indeed a complex and composite central nervous system and neuromuscular dysfunction in patients with MSA requiring sophisticated diagnostics and tailored therapeutic management.
The author has seen and approved this manuscript. Work for this study was performed at the Sleep Medicine Center, Neurophysiopathology and Movement Disorders Unit, Department of Clinical and Experimental Medicine, AOU Policlinic G. Martino, Messina. The author reports no conflicts of interest.
Silvestri R. Sleep-disordered breathing in multiple system atrophy: pathophysiology and new insights for diagnosis and treatment. J Clin Sleep Med. 2018;14(10):1641–1642.
Ferini-Strambi L, Marelli S. Sleep dysfunction in multiple system atrophy. Curr Treat Options Neurol. 2012;14(5):464–473. [PubMed]
Iranzo A. Sleep and breathing in multiple system atrophy. Curr Treat Options Neurol. 2007;9(5):347–353. [PubMed]
Gama RL, Távora DG, Bomfim RC, Silva CE, Bruin VMD, Bruin PFD. Sleep disturbances and brain MRI morphometry in Parkinsons disease, multiple system atrophy and progressive supranuclear palsy - a comparative study. Parkinsonism Relat Disord. 2010;16(4):275–279. [PubMed]
Moreno-López C, Santamaría J, Salamero M, et al. Excessive daytime sleepiness in multiple system atrophy (SLEEMSA Study). Arch Neurol. 2011;68(2)
Rekik S, Martin F, Dodet P, et al. Stridor combined with other sleep breathing disorders in multiple system atrophy: a tailored treatment? Sleep Med. 2018;42:53–60. [PubMed]
Suzuki M, Saigusa H, Shibasaki K, Kodera K. Multiple system atrophy manifesting as complex sleep-disordered breathing. Auris Nasus Larynx. 2010;37(1):110–113. [PubMed]
Ghorayeb I, Yekhlef F, Bioulac B, Tison F. Continuous positive airway pressure for sleep-related breathing disorders in multiple system atrophy: long-term acceptance. Sleep Med. 2005;6(4):359–362. [PubMed]
Shimohata T, Nakayama H, Aizawa N, Nishizawa M. Discontinuation of continuous positive airway pressure treatment in multiple system atrophy. Sleep Med. 2014;15(9):1147–1149. [PubMed]
Shimohata T, Aizawa N, Nakayama H, et al. Mechanisms and prevention of sudden death in multiple system atrophy. Parkinsonism Relat Disord. 2016;30:1–6. [PubMed]
Gaig C, Iranzo A. Sleep-disordered breathing in neurodegenerative diseases. Curr Neurol Neurosci Rep. 2012;12(2):205–217. [PubMed]
Flabeau O, Ghorayeb I, Perez P, et al. Impact of sleep apnea syndrome on survival in patients with multiple system atrophy. Parkinsonism Relat Disord. 2017;35:92–95. [PubMed]
Ohshima Y, Nakayama H, Matsuyama N, et al. Natural course and potential prognostic factors for sleep-disordered breathing in multiple system atrophy. Sleep Med. 2017;34:13–17. [PubMed]
Benarroch EE. Brainstem respiratory control: substrates of respiratory failure of multiple system atrophy. Mov Disord. 2007;22(2):155–161. [PubMed]
Nakayama H, Hokari S, Ohshima Y, Matsuto T, Shimohata T. Breathing irregularity is independently associated with the severity of obstructive sleep apnea in patients with multiple system atrophy. J Clin Sleep Med. 2018;14(10):1661–1667
Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013;188(8):996–1004. [PubMed Central][PubMed]
Orr JE, Edwards BA, Malhotra A. CrossTalk opposing view: loop gain is not a consequence of obstructive sleep apnoea. J Physiol. 2014;592(14):2903–2905. [PubMed]