Longitudinal study of a cohort of MSA-C patients in South Italy: survival and clinical features.

Sixty-six patients with possible or probable MSA (multiple system atrophy) cerebellar type, personally observed between 2006 and 2018 were retrospectively reviewed. The time point of data collection was January 1, 2019. Forty-nine patients lost independent walking after a median time of 5 years (95% C. I. 4-6). Thirty-two patients were confined to wheelchair after a median time of 7 years (95% C. I. 7-8). Twenty-seven patients were deceased after a median time of 9 years (95% C. I. 8-10). A later onset predicted an earlier loss of independent walking (HR 1.07; 95% C.I. 1.03-1.11; p = 0.001). Higher UMSARS score predicted shorter time to loss of independent walking (HR 1.04; 95% C.I. 1.02-1.06; p = 0.001) and to wheelchair (HR 1.03; 95% C.I. 1.01-1.06; p = 0.021). No predictor of time to death was found.

[Prognostic factors for inability to walk independently in patients with multiple system atrophy].

Objective: To explore the prognostic factors for inability to walk independently in patients with multiple system atrophy (MSA). Methods: A total of 123 patients with clinically confirmed MSA admitted to Navy General Hospital and Dongfang Hospital affiliated to the Second Clinical Medical College of Beijing University of Chinese Medicine, from February 2013 to February 2016, were retrospectively reviewed. Clinical data and all records were collected and all subjects were followed up by a telephone call in February 2016. The second milestone of activities of daily living scale (ADL), defined as inability to walk independently, was taken as the primary outcome. Eight possible prognostic factors were investigated and the survival analysis was performed with Cox proportional hazards model regression. Results: Of all the MSA patients, 74 subjects were men and 49 were women with a sex radio of 1.51∶1(M∶F). Seventy cases were diagnosed with MSA-cerebellar type (MSA-C) and 53 with MSA-Parkinson type (MSA-P) (C∶P=1.32∶1). Mean age at the onset of first symptom was (53±8) years old. All patients had severe autonomic nervous dysfunction. At the last follow-up, 56 cases (45.5%) were unable to walk independently. The median survival time from the onset of MSA to inability to walk independently was 73 months. The age of onset ≥ 55 years (HR=1.969, 95%CI 1.095-3.542, P=0.024) and the interval time from disease onset to combined motor and autonomic involvement≤3 years (HR=2.308, 95%CI 1.158-4.600, P=0.017) were independent prognostic factors for inability to walk independently, while gender, MSA clinical subtypes, initial symptoms, alcohol intake, smoking and toxic exposure were not indicators for independent walking (P>0.05). Conclusions: The prognostic factors for inability to walk independently in patients with MSA are the age of onset ≥55 years and the interval time from disease onset to combined motor and autonomic involvement≤3 years. Although factors including gender, MSA clinical subtypes, initial symptoms, alcohol intake, smoking and toxic exposure are not the predictive factors for inability to walk independently in our MSA patients, their roles in the prognosis of MSA still need further investigation.

Clinical features and autonomic testing predict survival in multiple system atrophy.

Multiple system atrophy is characterized by autonomic failure along with motor symptoms of parkinsonism and/or cerebellar ataxia. There are differing reports on the influence of certain clinical features, including motor subtype (multiple system atrophy-parkinsonism versus multiple system atrophy-cerebellar ataxia), age of onset, gender, and early autonomic symptoms, on the survival in patients with multiple system atrophy. We sought to evaluate overall survival and predictors of survival in a large cohort of patients with multiple system atrophy seen at a single referral centre where objective autonomic testing is routinely performed for this indication. All cases of multiple system atrophy evaluated at Mayo Clinic, Rochester and assessed with an autonomic reflex screen between January 1998 and December 2012 were retrospectively reviewed. A total of 685 patients were identified; 594 met criteria for probable multiple system atrophy, and 91 for possible multiple system atrophy. Multiple system atrophy-parkinsonism was the predominant subtype in 430 patients (63%). Average age of onset was earlier in multiple system atrophy-cerebellar ataxia (58.4 years) compared to multiple system atrophy-parkinsonism (62.3 years; P < 0.001). Median disease duration from symptom onset to death was 7.51 years (95% confidence interval 7.18-7.78) while time from diagnosis to death was 3.33 years (95% confidence interval 2.92-3.59). There was no difference in survival between motor subtypes of multiple system atrophy (P = 0.232). An initial motor symptom was most common (61%) followed by autonomic onset (28%) and combined motor and autonomic symptoms (11%). The initial onset of either motor or autonomic symptoms did not influence length of survival. However, a number of clinical and autonomic laboratory features predicted unfavourable survival in a univariate analysis. A multivariate model retained the following unfavourable predictors of survival: (i) falls within 3 years of onset (hazard ratio 2.31, P < 0.0001); (ii) bladder symptoms (hazard ratio 1.96, P < 0.0001); (iii) urinary catheterization within 3 years of symptom onset (hazard ratio 1.67, P < 0.003); (iv) orthostatic intolerance within 1 year of symptom onset (hazard ratio 1.28, P < 0.014); (v) older age of onset (hazard ratio 1.02, P = 0.001); and (vi) degree of autonomic failure as measured by a validated composite autonomic severity score (hazard ratio 1.07, P < 0.0023). We conclude that carefully selected clinical features can be used to predict survival in patients with multiple system atrophy. Autonomic testing adds an additional, independent predictor of survival, demonstrating its value not only in the diagnosis of multiple system atrophy but also as prognostic marker.

Multiple system atrophy: prognostic indicators of survival.

Neurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10-point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7-10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9-9.8] vs. 9.8 [4.6-13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1-10.2] vs. 13.7 [8.5-14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01-1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88-38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01-9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid-requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA.

Severity of sleep apnea as a prognostic factor for mortality in patients with multiple system atrophy.

BACKGROUND: We determined whether the severity of sleep apnea increases the risk of mortality in patients with multiple system atrophy (MSA) with and without stridor. MethodsThis retrospective study included patients who underwent polysomnography within one year after diagnosis of probable MSA. Stridor, sleep apnea, and arousal from sleep were determined using full-night polysomnography. Disease severity was measured using the Unified MSA Rating Scale (UMSARS). Survival data were collected and analyzed using Cox regression analysis. RESULTS: Sixty-four patients with MSA were included. During a median follow-up of 34.5 months, 49 (76.6 %) patients died. Stridor was present in 56.3 % of patients. Patients with stridor had more severe sleep apnea and shorter sleep time than those without, but the hazard ratio (HR) for death did not differ between patients with and without stridor. Among patients without stridor, apnea-hypopnea index ≥30/h (HR, 6.850; 95 % confidence interval [CI], 1.983-23.664; p = 0.002) and a score of UMSARS I + II (HR, 1.080; 95 % CI, 1.040-1.121; p < 0.001) were independently associated with death. In contrast, among patients with stridor, frequent arousals from sleep (HR, 0.254; 95 % CI, 0.089-0.729; p = 0.011) were a significant factor associated with longer survival, while MSA-cerebellar type tended to be associated with poor survival (HR, 2.195; 95 % CI, 0.941-5.120; p = 0.069). CONCLUSION: The severity of sleep apnea might be a significant predictor of shorter survival in MSA patients without stridor, whereas frequent arousals from sleep might be a significant predictor for longer survival in MSA patients with stridor.

Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by autonomic dysfunction with parkinsonism (MSAp) or cerebellar (MSAc) symptoms. At autopsy, α-synuclein inclusions in glial cells of the brain are needed to confirm a definite diagnosis. We determined the 10 year incidence of MSA, point prevalence and survival in a well defined population with a high number of neurologists. METHODS: Cases were identified from the only neurology department and all practising neurologists in Iceland, over a 10 year period. The diagnosis of MSA was in accordance with the Second Consensus Criteria of MSA. FINDINGS: 19 incidence cases were diagnosed with MSA (11 women, eight men) during the study period, giving an average annual incidence of 0.7:100 000 (95% CI 0.4 to 1.1). Ten cases were alive on the prevalence day, giving a point prevalence of 3.4:100 000 (95% CI 1.6 to 6.3). 16 of the cases had probable and three possible MSA; 16 had MSAp and three had MSAc. Mean age at symptom onset was 65 years and mean age at diagnosis was 68 years. Patients were followed for an average of 31 months, and 15 died during the follow-up period. Survival from symptom onset was mean 5.7 years. The 1 and 5 year survival rates from diagnosis were 74% and 28%, respectively. INTERPRETATION: We reported on the incidence of MSA (both MSAp and MSAc) in a nationwide study where a definite diagnosis of MSA was confirmed in four out of five patients autopsied. We found survival to be shorter than reported in other studies.

Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue?

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 ± 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype.

Mortality and prognosis in patients with neurogenic orthostatic hypotension.

The prognosis of neurogenic orthostatic hypotension (NOH) has been poorly studied. The aim of this study was to evaluate retrospectively comorbidities and causes of death in patients with NOH. Clinical information and causes of death were obtained for 104 patients (45 with multiple system atrophy, 9 with pure autonomic failure, 43 with Parkinson's disease, and 7 with other types of autonomic neuropathy) referred to the Autonomic Unit from 1996 to 2009. Cardiovascular diseases (hypertension, cardiac comorbidities, atrial fibrillation and heart failure) were present in 53 (51%) NOH patients. At the end of follow-up, 44 patients were deceased. Type of NOH was the main factor associated with mortality. The main causes of death were infectious/respiratory (54%) and cardiac (16%). In NOH patients, cardiovascular diseases are frequent, although mortality is mainly due to infectious and respiratory causes. Detection of cardiovascular diseases may be useful in the choice of anti-hypotensive treatments.

Survival of Korean patients with multiple system atrophy.

METHODS: We conducted a retrospective medical record review to determine the survival of 455 Korean multiple system atrophy (MSA) patients and examined the effect of clinical factors that could possibly influence survival. The patients comprised 222 men and 233 women. RESULTS: Age at onset was 60.1 ± 8.8 years (mean ± SD) and did not differ between the sexes. Parkinsonism was the most prevalent initial symptom, followed by cerebellar dysfunction and dysautonomia. Age at onset was significantly older in patients with predominant parkinsonism at the last visit (MSA-P) than in the other patients. At the time of data collection, 107 patients had died. Median survival time was 10 years. The survival rate of women was slightly better than that of men, especially in MSA-P patients. CONCLUSIONS: Survival was not affected by age at onset, initial symptom, or predominant symptom at the last visit or by the presence of autonomic symptoms or multiple symptoms at disease onset.

Inflammatory cytokine levels in multiple system atrophy: A protocol for systematic review and meta-analysis.

BACKGROUND: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that progresses very rapidly and has a poor prognosis. Some studies indicate that the level of inflammatory cytokines may be related to MSA. However, no consistent conclusion has been drawn yet. The purpose of our research is to perform a meta-analysis to investigate whether the level of inflammatory cytokines is altered in MSA. METHODS: Case-control studies on inflammatory cytokine levels in MSA will be searched in the following 3 databases: PubMed, Embase, and Web of Science from the database start time to March 17, 2020. Two independent authors will conduct research selection, data extraction, and quality evaluation. Data synthesis, subgroup analysis, sensitivity analysis, and the meta-analysis will be performed using Stata15.0 software. RESULTS: This study will provide a comprehensive review of all studies on inflammatory cytokine levels in MSA. CONCLUSION: To the best of our knowledge, this study will be the first meta-analysis that provides the quantitative evidence of inflammatory cytokine levels in MSA. REGISTRATION NUMBER: INPLASY202060034.

Sex and gender influence symptom manifestation and survival in multiple system atrophy.

To evaluate the influence of sex and gender on clinical characteristics and survival in multiple system atrophy (MSA), we reviewed MSA patients with autonomic testing 1998-2012. Of 685 patients, 52% were male. Median survival overall was 7.3 years for males, 7.6 years for females. Survival from diagnosis was 2.9 years in males, 3.8 years in females. Females were more likely to initially manifest motor symptoms. Males were more likely to have orthostatic intolerance and early catheterization. In conclusion, our data show longer survival from diagnosis in females and slight overall survival benefit which may be related to initial motor manifestations.

Earlier age of onset in multiple system atrophy with smoking and heavy alcohol use.

OBJECTIVE: To determine whether smoking or alcohol use impacts the age of onset and disease duration in multiple system atrophy (MSA). METHODS: All patients diagnosed with MSA at Mayo Clinic, Rochester between 1998 and 2012 completed standardized questionnaires surveying smoking and alcohol use at the time of presentation. RESULTS: Of 551 patients with smoking and alcohol use data, 281 were past or present smokers with age of onset of 60.76 years compared to 62.97 years in controls (p = 0.0144). Age of onset in the 87 heavy alcohol users was 56.87 years compared to 62.97 years in controls (p = 0.0133). There was no difference in disease duration for smokers (p = 0.2758) or heavy alcohol users (p = 0.4820) compared to controls. CONCLUSION: Our findings show that smoking history and/or heavy alcohol use is associated with younger age of onset in MSA but do not influence survival.

Survival in multiple system atrophy.

We here report survival in patients with multiple system atrophy (MSA) in a large, prospectively studied group of patients with MSA. Eighty-five of 100 patients were known to have died. Three patients were rediagnosed as having PD. Twenty-four patients came to autopsy, which showed MSA in 22 and idiopathic Parkinson's disease in 2. The median survival time was 8.6 and 7.3 years for men and women, respectively (hazard ratio for women was 1.49, 95% CI 0.97-2.31, P = 0.07). Except for rediagnosis as PD, no predictive factors for better survival could be identified. These data confirm the relatively poor prognosis of MSA of less than 9 years on average.

Frequency of nocturnal sudden death in patients with multiple system atrophy.

Sudden death has been reported in patients with multiple system atrophy (MSA), although the frequency of this event has not been well delineated. We investigated the frequency and potential causes of sudden death in patients with MSA. During the 5-year observation period, 10 of 45 patients with probable MSA died. The causes of death included sudden death of unknown etiology (seven patients), aspiration pneumonia (one patient), asphyxia after vomiting (one patient), and lung cancer (one patient). The mean survival time of patients with sudden death was 63.0 +/- 24.7 months (range, 39-116 months). Among seven patients who experienced sudden death, six were found to have died during sleep. Among these patients, two had been treated with tracheostomy and three with continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) during sleep, suggesting that these treatments do not always prevent sudden death in patients with MSA. Nocturnal sudden death should be recognized as the most common mechanism of death in patients with MSA.

Survival analysis and prognostic nomogram model for multiple system atrophy.

OBJECTIVE: The purpose of our study was to explore the factors associated with the survival of multiple system atrophy (MSA) patients and to produce a prognostic nomogram to predict survival in an individual MSA patient. METHODS: 220 probable MSA patients were included from 2009 to 2013. Disease severity was measured by the Unified Multiple System Atrophy Rating Scale (UMSARS). The univariate and multivariable Cox regression analyses were used to identify factors associated with survival in MSA patients. A nomogram model predicting the probability of survival was formulated based on the results of the multivariate Cox analysis. The results were validated using bootstrap resampling and a prospective study on 80 patients included from January 2014 to August 2015 at the same institution. RESULTS: Median survival from symptom onset to death was 6.4 years (95%CI = 6.1-6.7). The multivariate Cox survival model suggested that autonomic onset, higher UMSARS score, frequent falls, orthostatic hypotension(OH) and shorter diagnostic delay were associated with poor survival. The nomogram model for the multivariate Cox survival model had a concordance index of 0.677 in primary cohort, which showed a concordance index of 0.721 in validation cohort. CONCLUSION: Autonomic onset, higher UMSARS score, frequent falls, OH and shorter diagnostic delay at baseline were independent markers for poor survival in MSA. The prognostic nomogram model created by the significant independent factors for longer survival provided an effective way to predict the probability of longer survival in an individual MSA patient.

Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy?

INTRODUCTION: Loss of brainstem serotonergic neurons in MSA patients is implicated in respiratory dysfunction including stridor and may increase the risk of sudden death. Augmenting serotonergic transmission through selective serotonergic reuptake inhibitors (SSRIs) has been proposed to improve stridor and prolong survival in multiple system atrophy (MSA). We sought to determine whether MSA patients on an SSRI during their disease course have improved survival compared to those not on an SSRI. METHODS: Review of all MSA patients from 1998 to 2012 at Mayo Clinic, Rochester who completed autonomic function testing. Use of SSRI medications was obtained from patient-provided medication lists in the electronic medical record. Clinical symptoms were collected from patient histories; the presence of stridor was obtained from clinical histories and polysomnogram. Surviving patients were called to assess for stridor and SSRI use. RESULTS: Of 685 MSA patients, 132 (19%) were on an SSRI. Median time from symptom onset to death was 7.5 years with no difference based on SSRI use (p = .957). Rates of stridor were similar in SSRI users and non-users based on patient report and polysomnography (p = .494 and p = .181, respectively). SSRI use was associated with parkinsonism (p = .027) and falls (p = .002). Stridor was similar in SSRI users and those not on an SSRI. CONCLUSIONS: There was no difference in survival in MSA patients on an SSRI. However, SSRI use was associated with higher rates of parkinsonism and falls.

Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.

BACKGROUND: Multiple system atrophy (MSA) is diverse in clinical phenotype, disease progression, and prognosis. Sudden death is a leading cause of death in patients with MSA. OBJECTIVE: To determine what clinical factors affect the progression and survival prognosis of those with MSA. DESIGN: A retrospective review of the medical records of 49 consecutive Japanese patients with pathologically confirmed MSA (29 men and 20 women; mean +/- SD age at onset, 59.8 +/- 6.5 years). Cox proportional hazards models were used to compare the risks of being in a wheelchair-bound state, being in a bedridden state, and having a shorter survival. RESULTS: Thirty-one patients were diagnosed as having cerebellar type MSA, and 18 were diagnosed as having parkinsonian type MSA. Twenty-nine patients with cerebellar type MSA and 17 patients with parkinsonian type MSA had autonomic dysfunction. The median times from disease onset to being in a wheelchair-bound state, being in a bedridden state, death, and the development of autonomic dysfunction were 3.5, 5.0, 7.0, and 2.5 years, respectively. Patients with an early development of autonomic dysfunction (within 2.5 years from the onset of MSA) had significantly higher risks of being in a wheelchair-bound state (multivariate-adjusted hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.04-9.15), being in a bedridden state (HR, 3.87; 95% CI, 1.77-8.48), having a shorter survival (HR, 3.40; 95% CI, 1.61-7.15), and sudden death (HR, 7.22; 95% CI, 1.49-35.07). CONCLUSION: The early development of autonomic dysfunction is an independent predictive factor for rapid disease progression and shorter survival in patients with MSA.

[Multiple system atrophy: prognostic factors in the "MSA-Aquitaine" cohort]. / Atrophie multisystématisée: survie et facteurs pronostiques dans la cohorte "MSA-Aquitaine".

INTRODUCTION: Multiple system atrophy (MSA) is a common cause of atypical parkinsonism, of poor prognosis. MSA is associated with short survival but data stemming from clinical or pathological studies are sparse and contrasted. Factors predicting survival in MSA are not fully established. We investigated the survival and prognostic factors of MSA in the cohort "MSA-Aquitaine". METHODS: This was a retrospective study of an unselected cohort of patients included throughout Aquitaine based on the Consensus Conference statement concerning MSA diagnostic criteria, with prospective follow-up on mortality. All patients received a standard clinical examination and disease history was collected through medical records and interviews of patients. Survival was ascertained by telephonic calls. RESULTS: From 1 November 1998 to 1 April 2002, we diagnosed 86 patients (43 men and 43 women) with "probable" or "possible" MSA. Median survival from study inclusion was 2.4 years and was 10.2 years from clinical onset, very similar to the other series. Low age at study, diabetes, dysphagia, Hoehn and Yahr stage 5 can predict shorter survival in patients with MSA. CONCLUSION: We confirm that the prognosis for MSA patients is poor and that some factors may predict shorter survival.

Impact of sleep apnea syndrome on survival in patients with multiple system atrophy.

INTRODUCTION: Sleep apnea is very frequent in multiple system atrophy (MSA) and may contribute to the poor prognosis. The aim of the present study was to prospectively assess the relation between sleep apnea and survival in 30 consecutive MSA patients recruited at the French Reference Center for MSA. METHODS: Patients with "probable" MSA according to current consensus diagnosis criteria were enrolled in this prospective cohort study. All patients received full polysomnography at baseline and were then followed for up to 4.5 years. The prognostic role of sleep apnea was assessed by a Cox model in an univariate analysis and then adjusted on other potential factors. RESULTS: Analyzable polysomnographic recordings were available for 28 patients. Sleep apnea was found in 11 patients. During follow-up, 15 patients died, including 9 with baseline sleep apnea. In an univariate analysis, sleep apnea, Unified MSA Rating Scale I + II score at baseline and at year one, and disease duration were associated with mortality. However, when adjusting for disease duration and baseline Unified MSA Rating Scale score, the association between sleep apnea and mortality was no longer significant. CONCLUSIONS: Sleep apnea was not an independent factor associated with mortality in this prospective cohort study.