Sleep-Related Symptoms in Multiple System Atrophy: Determinants and Impact on Disease Severity
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic dysfunction combined with parkinsonism and/or cerebellar ataxia. It is pathologically confirmed as an alpha-synucleinopathy due to the presence of alpha-synuclein in glial cytoplasmic inclusions (GCI). Once misfolded alpha-synuclein is released by oligodendrocytes, it may be taken up by neighboring neurons to form neuronal cytoplasmic inclusions, leading to neuronal death and subsequent reactive astrogliosis. The spread of toxic alpha-synuclein results in multisystem neuronal involvement, typical of MSA. MSA is categorized into two subtypes based on the predominant motor symptom: the parkinsonism subtype (MSA-P) and the cerebellar subtype (MSA-C).
MSA is not only characterized by motor symptoms but also by nonmotor symptoms such as urinary disorders, orthostatic hypotension, erectile dysfunction in men, sleep disorders, and constipation. Among these nonmotor symptoms, sleep disorders are common and can even arise before any overt motor symptoms develop. Sleep disorders in MSA patients include rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and nocturnal sleep disturbances. Previous studies have shown that 69% to 100% of MSA patients experience RBD, while EDS has been reported in 28% of Caucasian patients and 24% of Japanese patients with MSA. Additionally, the European Multiple System Atrophy registry reported that 19% of MSA patients suffer from insomnia. Sleep disorders have been linked to poor quality of life in MSA patients, yet they remain under-researched.
This cross-sectional study aimed to investigate the frequency and factors associated with sleep-related symptoms in MSA patients and to assess the impact of these sleep disturbances on disease severity. The study involved 165 patients with probable MSA, evaluated using the PD Sleep Scale-2 (PDSS-2) for Parkinson’s disease-related sleep problems (PD-SP), the Epworth Sleepiness Scale (ESS) for EDS, and the RBD Screening Questionnaire (RBDSQ) for RBD. Disease severity was assessed using the Unified MSA Rating Scale (UMSARS).
The study found that the frequency of PD-SP (PDSS-2 score ≥18), EDS (ESS score ≥10), and RBD (RBDSQ score ≥5) in MSA patients was 18.8%, 27.3%, and 49.7%, respectively. The coexistence of all three sleep-related symptoms was observed in 7.3% of patients. Compared to the MSA-C subtype, the MSA-P subtype was associated with a higher frequency of PD-SP and EDS but not RBD. Binary logistic regression revealed that the MSA-P subtype, higher total UMSARS score, and anxiety were associated with PD-SP. Male sex, higher total UMSARS score, the MSA-P subtype, and fatigue were associated with EDS. Male sex, higher total UMSARS score, and autonomic onset were associated with RBD. Stepwise linear regression showed that the number of sleep-related symptoms, disease duration, depression, fatigue, and total Montreal Cognitive Assessment (MoCA) score were predictors of disease severity in MSA patients.
The findings suggest that sleep-related disorders are associated with both MSA subtypes and the severity of the disease, indicating that sleep disorders may reflect the distribution and degree of dopaminergic/non-dopaminergic neuron degeneration in MSA. The study highlights the importance of assessing and managing sleep-related symptoms in MSA patients, as they significantly impact disease severity and quality of life.
The study included 165 patients with probable MSA, with a mean disease duration of 2.56 ± 1.34 years. Of these, 82 patients (49.7%) had MSA-P, and 83 patients (50.3%) had MSA-C. The frequency of PD-SP, EDS, and RBD was 18.8%, 27.3%, and 49.7%, respectively. The frequency of coexistence of all three sleep-related symptoms was 7.3%. After adjusting for age, disease duration, and levodopa equivalent daily dose (LEDD), the frequencies of PD-SP and EDS were significantly higher in MSA-P patients than in MSA-C patients. The frequency of RBD was not significantly different between the two subtypes.
The study also compared demographic and clinical characteristics between patients with and without PD-SP, EDS, and RBD. Patients with PD-SP had a higher frequency of the MSA-P subtype and higher UMSARS, Fatigue Severity Scale (FSS), Hamilton Depression Rating Scale-24 (HDRS-24), and Hamilton Anxiety Rating Scale (HARS) scores compared to those without PD-SP. Patients with EDS had a higher frequency of the MSA-P subtype and male sex, older age, older age at onset, higher UMSARS, FSS, HDRS-24, and HARS scores, and a higher proportion of dopamine agonist use compared to those without EDS. Patients with RBD had a higher frequency of male sex, overweight, and autonomic onset and higher UMSARS and FSS scores compared to those without RBD.
The study further compared patients with and without sleep-related symptoms with respect to MSA subtypes. Among MSA-P patients, those with PD-SP had higher UMSARS, FSS, HDRS-24, and HARS scores and a lower score in the naming domain of the MoCA compared to those without PD-SP. Among MSA-P patients, those with EDS had higher UMSARS, FSS, HDRS-24, and HARS scores and a higher proportion of dopamine agonist use compared to those without EDS. Among MSA-P patients, those with RBD had higher UMSARS and FSS scores compared to those without RBD. Among MSA-C patients, those with PD-SP had higher HDRS-24 and HARS scores compared to those without PD-SP. Among MSA-C patients, those with EDS showed a higher frequency of male sex compared to those without EDS. Among MSA-C patients, those with RBD showed a higher frequency of male sex, overweight, and autonomic onset and higher UMSARS scores compared to those without RBD.
Binary logistic regression showed that the MSA-P subtype (OR = 3.861; P = 0.005), higher total UMSARS score (OR = 1.042; P = 0.022), and anxiety (OR = 4.755; P = 0.001) were associated with PD-SP. Male sex (OR = 3.309; P = 0.005), higher total UMSARS score (OR = 1.036; P = 0.032), the MSA-P subtype (OR = 2.733; P = 0.012), and fatigue (OR = 3.654; P = 0.005) were associated with EDS. Male sex (OR = 2.614; P = 0.005), higher total UMSARS score (OR = 1.052; P = 0.001), and autonomic onset (OR = 0.486; P = 0.044) were associated with RBD in MSA patients.
Stepwise linear regression analysis was performed to investigate the impact of sleep disturbances on disease severity. The total UMSARS score was used to represent disease severity and acted as the dependent variable, while the number of sleep-related symptoms (0–3; PD-SP, EDS, or RBD) acted as the independent variable. Other covariables included sex, age, subtype, disease duration, fatigue, depression, anxiety, and MoCA score. The final model showed that disease duration, depression, fatigue, total MoCA score, and the number of sleep-related symptoms (PD-SP, EDS, and RBD) were significant predictors of disease severity in MSA patients.
The study’s findings suggest that sleep-related symptoms are common in MSA patients and are associated with both MSA subtypes and disease severity. The MSA-P subtype, male sex, autonomic onset, anxiety, fatigue, and higher total UMSARS score were found to be associated with sleep-related symptoms. The study also indicated that there may be a link between MSA subtypes and specific sleep disorders, which may reflect the underlying differences in the neuropathologies of the two MSA subtypes. Additionally, a higher number of sleep-related symptoms was found to have a significant impact on disease severity, emphasizing the importance of clinical assessment and management of sleep-related symptoms in MSA patients.
The study’s strengths include its large sample size, comprehensive evaluation of demographic and clinical characteristics, and multiple study design. It is the first study to systematically investigate the factors associated with three common sleep problems (PD-SP, EDS, and RBD) in MSA patients and their impact on MSA subtypes and disease severity. The findings imply a potential association between sleep disorders and the distribution and degree of dopaminergic/non-dopaminergic neuron degeneration, which may provide inspiration for future etiology studies.
However, the study has several limitations. First, the patients’ diagnoses of MSA were not confirmed by autopsy, although all patients were diagnosed according to strict diagnostic criteria. Second, the study lacked polysomnography for objective assessment of RBD, sleep-disordered breathing (SDB) disorders, and periodic limb movements. As a result, SDB disorders such as nocturnal stridor and obstructive sleep apneas, as well as periodic limb movements, were not included in the analysis. Third, the study was cross-sectional, which can only offer correlations rather than causality. Further prospective studies are needed to confirm the impact of sleep-related disorders on disease severity or survival.
In conclusion, the study demonstrated that sleep-related symptoms are common in MSA patients and are associated with both MSA subtypes and disease severity. The findings highlight the importance of assessing and managing sleep-related symptoms in MSA patients, as they significantly impact disease severity and quality of life. The study provides valuable insights into the potential link between sleep disorders and the underlying neuropathology of MSA, which may inform future research and clinical practice.
doi.org/10.1097/CM9.0000000000001211
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