The clinical presentation of multiple system atrophy (MSA) is characterized by progressive autonomic failure, parkinsonism, cerebellar dysfunction, and pyramidal features in various combinations. However, most patients with MSA have sleep problems as well. Studies have shown that Rapid Eye Movement (REM) sleep behavior disorder (RBD) is very common in MSA regardless of presenting motor symptoms (i.e. MSA-P or MSA-C), and is probably more common than in Lewy body disorders including Parkinson’s disease and dementia with Lewy bodies. Furthermore, in advanced stages of MSA, many patients suffer from sleep-disordered breathing, which includes snoring, sleep apnea, and stridor. In this blog, we asked two experts in this field, Drs. Tetsutaro Ozawa and Pietro Cortelli to discuss the clinical implication and management of sleep problems in MSA.
1. What do we know about RBD as a risk factor for MSA? Is it different from RBD in PD and DLB?
RBD is a parasomnia characterized by the loss of the normal muscle atonia during REM sleep, allowing dream enactment behaviors, potentially leading to self or co-sleeper injuries.1 Although RBD can be idiopathic, many studies have showed that most patients tend to develop a synucleinopathy. The estimated rate of phenoconversion from idiopathic RBD is 6.3% at 1 year, 31.5% at 5 years, 73.5% at 12 years.2 The prevalence of clinically suspected RBD is around 70% in MSA patients, whereas it was found to be as high as 90% when these patients were studied with polysomnograms (PSGs).3 This is much higher than the prevalence reported in PD (50%) and in DLB (76%) patients.4
In contrast to PD, where RBD prevalence seems to increase during the course of the disease and usually predates motor manifestations, RBD symptoms in MSA appear shortly before the onset of the other neurological symptoms and then disappear in a few years.5 However, a video-polysomnographic study on 2 MSA patients described a reduced frequency of RBD episodes associated with the appearance of a disrupted sleep pattern, nearly continuous motor and verbal abnormal behaviors and ambiguous and rapid oscillation of state, determining polysomnographic variables consistent with status dissociatus. Thus, it could be speculated that in MSA patients, RBD manifestations do not simply disappear, but progress to status dissociatus due to rapid neurodegeneration in the brainstem.6 Also, in MSA patients, during VPSG recording tonic sleep REM without atonia of the submental muscle is a more frequent electrophysiological finding compared to PD patients with RBD.4
As in PD patients, parkinsonian signs during RBD disappear,7 likely due to a transient bypass of the basal ganglia as confirmed also by an ictal SPECT study.8
RBD frequently occurs in patients with alpha-synucleinopathy, including PD, DLB, and MSA as a sign of the prodromal stage.9 However, previous studies of idiopathic RBD have shown that cases of phenoconversion to MSA are relatively rare compared to those to PD or DLB.2,10 To what extent RBD increases the risk of developing MSA remains to be elucidated. RBD symptoms in MSA patients were reported to occur prior to or at the onset of the motor symptoms and then disappear within a short period.5 Further video-polysomnography studies are needed to determine the characteristic features of RBD in patients with MSA.
2. How common is sleep-disordered breathing among patients with MSA and what is its clinical implication?
Sleep-disordered breathing of various types can occur in MSA. Although obstructive sleep apnea (OSA) and central apneas can occur in MSA patients, these are not as worrisome as laryngeal stridor, which is almost a pathognomonic feature of the disease and can potentially cause sudden death during sleep.11 Stridor is a harsh, high-pitched, inspiratory sound caused by a laryngeal narrowing, first occurring during sleep, attributed to denervation of laryngeal muscles or to adduction dystonia of vocal cords.12 The reported prevalence of stridor in MSA varies from 15 to 40% of patients depending on the methods of assessment.13 Stridor per se has not been associated with increased mortality, although early stridor onset (within 3 years since disease onset) has been found to be an independent risk factor for mortality. In addition, stridor treatment was associated with reduced mortality.14 The negative prognosis of stridor may be explained by two separate factors: (i) sudden death can occur directly due to stridor during sleep, or (ii), more likely, stridor may be associated with severe early changes in autonomic centers controlling respiration and other vital functions. Indeed, early autonomic failure onset in MSA patients is a known negative predictor of survival.14
Sleep-disordered breathing characterized by sleep apnea and laryngeal stridor is frequent in patients with MSA. The symptoms may occur in around 30-40% of patients with MSA,15 but the frequency may vary depending on the stage of the disease. Sleep-disordered breathing is considered to be a predisposing factor for nocturnal sudden death in patients with MSA.
3. What are the neuropathologic features associated with sleep problems in MSA?
Neuronal cell loss associated with gliosis occurs widely in MSA. Pontomedullary structures including the magnocellular reticular formation and sublaterodorsal, pedunclopontine, and laterodorsal tegmental nuclei may contribute to the atonia during REM sleep. Depletion of cholinergic neurons in the pedunclopontine and laterodorsal tegmental nuclei was reported to occur in patients with MSA, but it is not likely the primary mechanism of RBD in MSA since the severity of neuronal loss did not relate to the presence or absence of RBD.16 Lesions in respiratory centers of the brainstem are responsible for sleep-disordered breathing in patients with MSA. For laryngeal stridor, the pathophysiology is still controversial.12 The dystonia hypothesis states that hyperactivity of the laryngeal adductor muscles leads to stridor in MSA patients. Another hypothesis is that neuronal cell loss in the raphe nucleus and nucleus ambiguus causes weakness or hypoactivity of the laryngeal abductor muscle that results in stridor.
Post-mortem studies of MSA patients with stridor have found a selective atrophy of the posterior cricoarytenoid muscle that correlated with the presence of glottic stenosis. The CNS involvement in stridor is less clear, and the role of neuronal loss in the nucleus ambiguous is under debate.17,18 A recent neuroimaging study found higher grey matter density in the cerebellum and lower density in the striatum in MSA patients with stridor compared to MSA patients without it.19 This finding is in line with striatal lesions triggering dystonia and the hypothesis that stridor has a dystonic nature.
Neuropathological features associated with RBD symptoms have been described not only in brainstem structures including the locus coeruleus and raphe nuclei but also in other regions including paramammillary nuclei, amygdala, thalamus and entorhinal cortex.
4. How can sleep-disordered breathing be diagnosed and what are the treatment options?
Polysomnography is needed to make a precise and comprehensive diagnosis of sleep problems, including sleep-disordered breathing. However, physicians can suspect the presence of laryngeal stridor when caregivers report a high-pitched breathing sound that was emitted by the patient during sleep or while awake. In such cases, physicians may encourage the patient and caregiver to record sounds when an episode of suspected stridor occurs. The imitation of stridor by the physician is very useful for the patient and caregiver to recognize the presence of stridor. Laryngoscopy can exclude vocal cord abnormalities related to different conditions.
Regarding the treatment options, continuous positive airway pressure (CPAP) can be useful in the symptomatic control of sleep-disordered breathing.20 However, whether CPAP improves survival in MSA patients is uncertain. Tracheostomy should be considered in cases of persistent and severe stridor because it might improve survival in MSA patients.21
Although patients with MSA commonly have stridor, not all of them complain about it to their physician. Thus, it is always important to ask the co-sleeper about patient strange noises during sleep or a change in the habitual snoring. In order to confirm stridor, an audio recording of an inspiratory crowing high-pitched sound on a videopolysomnography (VPSG) is necessary. A laryngoscopic exam may show the reduction of the glottis aperture, paradoxical cord movements and floppy glottis and it can also help in determining the severity of stridor and influence the treatment strategy.22
Stridor is a life-threatening condition and needs to be treated. Although there are no established guidelines, two main treatment options are available: CPAP and tracheostomy. Both treatments are effective, however CPAP, which is far less invasive, is usually considered first. If CPAP is not tolerated or stridor is particularly severe (present both during day and night, or immobile cords are seen on laryngoscopy), tracheostomy should be the preferred approach,11 although no longitudinal comparative study between these two treatments exists so far. Treating RBD symptoms is also very important in patients with CPAP or tracheostomy for stridor in order to ensure treatment efficacy.
Other experimental therapies have been proposed in stridor such as botulinum toxin, unilateral cordectomy, and laser arytenoidectomy,23 but there is not significant evidence of efficacy.
Central breathing disorders in MSA result from neurodegeneration of respiratory centers in the brainstem and consist in Cheyne-Stokes respiration during sleep, central apnea, and dysrhythmic breathing patterns.24 In these conditions, CPAP therapy may be ineffective or even harmful, and the use of adaptive servo-ventilation should be recommended.25
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