Advertisement

Impact of tracheostomy invasive ventilation on survival in Japanese patients with multiple system atrophy

Open AccessPublished:January 13, 2022DOI:https://doi.org/10.1016/j.parkreldis.2022.01.008

      Highlights

      • Tracheostomy and TIV can prolong survival time in multiple system atrophy.
      • Unlike tracheostomy, TIV may reduce the risk of sudden death.
      • However, TIV cannot prevent all sudden deaths due to many contributing factors.
      • TIV should therefore be carefully chosen considering patients' quality of life.

      Abstract

      Introduction

      Tracheostomy invasive ventilation (TIV) is therapeutic intervention to prolong survival. However, few reports have addressed TIV in multiple system atrophy (MSA). This study sought to evaluate the impact of TIV on survival in MSA patients.

      Methods

      This retrospective cohort study examined medical records of probable or definite MSA for patients in Hyogo-Chuo National Hospital from January 2000 to September 2021 to investigate overall survival and cause of death in those with tracheostomy and TIV.

      Results

      The study enrolled 12 definite and 127 probable MSA patients. Mean age at onset was 61.3 ± 9.8 years, and median survival time was 9.0 years. Tracheostomy was performed in 53 patients, 21 of whom were ventilated. Mean time from onset to tracheostomy and TIV was 7.0 ± 3.0 and 8.4 ± 4.4 years, respectively. After propensity score matching, tracheostomy showed a significant prolongation of median survival compared with no tracheostomy (10.1 vs. 7.5 years, p = 0.001) and TIV significantly prolonged survival compared with tracheostomy alone (17.8 vs. 9.2 years, p = 0.023). On Cox regression analysis, the hazard ratio for tracheostomy was 0.35 (95% confidence interval [CI] 0.17–0.68, p = 0.002) and TIV was 0.22 (95% CI 0.07–0.89, p = 0.032). In MSA with TIV, sudden death was significantly lower compared with tracheostomy alone, and infection was the most common cause of death.

      Conclusion

      Results showed that TIV prolonged survival and reduced sudden death compared with tracheostomy alone in MSA, although sudden death can never be completely prevented.

      Keywords

      1. Introduction

      Multiple system atrophy (MSA) is a rare, adult-onset, neurodegenerative disorder characterized by various neurologic symptoms, including dysautonomia, parkinsonism, and cerebellar ataxia [
      • Fanciulli A.
      • Wenning G.K.
      Multiple-system atrophy.
      ]. Its two clinical phenotypes are MSA with predominant parkinsonism (MSA-P) and MSA with predominant cerebellar features (MSA-C). In advanced-stage MSA, therapeutic interventions including bladder catheterization, enteral nutrition, tracheostomy, and tracheostomy invasive ventilation (TIV) may be necessary. Several reports have documented the impact of these interventions on survival [
      • Coon E.A.
      • Sletten D.M.
      • Suarez M.D.
      • Mandrekar J.N.
      • Ahlskog J.E.
      • Bower J.H.
      • Matsumoto J.Y.
      • Silber M.H.
      • Benarroch E.E.
      • Fealey R.D.
      • Sandroni P.
      • Low P.A.
      • Singer W.
      Clinical features and autonomic testing predict survival in multiple system atrophy.
      ,
      • Shimohata T.
      • Aizawa N.
      • Nakayama H.
      • Taniguchi H.
      • Ohshima Y.
      • Okumura H.
      • Takahashi T.
      • Yokoseki A.
      • Inoue M.
      • Nishizawa M.
      Mechanisms and prevention of sudden death in multiple system atrophy.
      ,
      • Cortelli P.
      • Calandra-Buonaura G.
      • Benarroch E.E.
      • Giannini G.
      • Iranzo A.
      • Low P.A.
      • Martinelli P.
      • Provini F.
      • Quinn N.
      • Tolosa E.
      • Wenning G.K.
      • Abbruzzese G.
      • Bower P.
      • Alfonsi E.
      • Ghorayeb I.
      • Ozawa T.
      • Pacchetti C.
      • Pozzi N.G.
      • Vicini C.
      • Antonini A.
      • Bhatia K.P.
      • Bonavita J.
      • Kaufmann H.
      • Pellecchia M.T.
      • Pizzorni N.
      • Schindler A.
      • Tison F.
      • Vignatelli L.
      • Meissner W.G.
      Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment.
      ,
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • Righini M.
      • Bacchi-Reggiani M.L.
      • Cecere A.
      • Barletta G.
      • Guaraldi P.
      • Provini F.
      • Cortelli P.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      ,
      • Tada M.
      • Onodera O.
      • Tada M.
      • Ozawa T.
      • Piao Y.S.
      • Kakita A.
      • Takahashi H.
      • Nishizawa M.
      Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.
      ]. According to a previous retrospective study, early bladder catheterization within 3 years reportedly led to poor prognosis [
      • Coon E.A.
      • Sletten D.M.
      • Suarez M.D.
      • Mandrekar J.N.
      • Ahlskog J.E.
      • Bower J.H.
      • Matsumoto J.Y.
      • Silber M.H.
      • Benarroch E.E.
      • Fealey R.D.
      • Sandroni P.
      • Low P.A.
      • Singer W.
      Clinical features and autonomic testing predict survival in multiple system atrophy.
      ]. Sleep-related breathing disorders, such as stridor and sleep apnea, can cause sudden death [
      • Shimohata T.
      • Aizawa N.
      • Nakayama H.
      • Taniguchi H.
      • Ohshima Y.
      • Okumura H.
      • Takahashi T.
      • Yokoseki A.
      • Inoue M.
      • Nishizawa M.
      Mechanisms and prevention of sudden death in multiple system atrophy.
      ], and continuous positive airway pressure (CPAP) is a noninvasive therapy performed for mild and moderate stridor. However, the effect of CPAP on survival is uncertain, and tracheostomy is required for severe stridor [
      • Cortelli P.
      • Calandra-Buonaura G.
      • Benarroch E.E.
      • Giannini G.
      • Iranzo A.
      • Low P.A.
      • Martinelli P.
      • Provini F.
      • Quinn N.
      • Tolosa E.
      • Wenning G.K.
      • Abbruzzese G.
      • Bower P.
      • Alfonsi E.
      • Ghorayeb I.
      • Ozawa T.
      • Pacchetti C.
      • Pozzi N.G.
      • Vicini C.
      • Antonini A.
      • Bhatia K.P.
      • Bonavita J.
      • Kaufmann H.
      • Pellecchia M.T.
      • Pizzorni N.
      • Schindler A.
      • Tison F.
      • Vignatelli L.
      • Meissner W.G.
      Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment.
      ]. Retrospective studies have shown that tracheostomy prolongs survival [
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • Righini M.
      • Bacchi-Reggiani M.L.
      • Cecere A.
      • Barletta G.
      • Guaraldi P.
      • Provini F.
      • Cortelli P.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      ] and may reduce sudden death compared with CPAP [
      • Tada M.
      • Onodera O.
      • Tada M.
      • Ozawa T.
      • Piao Y.S.
      • Kakita A.
      • Takahashi H.
      • Nishizawa M.
      Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.
      ]. It is difficult to minimize the risk of sudden death by tracheostomy alone because the cause of sudden death is not limited to stridor. Multiple factors, including central respiratory disturbance, suffocation of sputum, and cardiac autonomic disturbance, are involved in sudden death [
      • Tada M.
      • Onodera O.
      • Tada M.
      • Ozawa T.
      • Piao Y.S.
      • Kakita A.
      • Takahashi H.
      • Nishizawa M.
      Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.
      ]; TIV is needed to prevent sudden death and prolong survival. To date, no reports have documented survival of MSA patients with TIV. Even if TIV can be proposed as a treatment option, clinicians are currently unable to provide sufficient information because no evidence is available regarding the clinical course and prognosis of MSA patients with TIV. Therefore, this study investigated the long-term prognosis and cause of death to determine whether TIV prolongs survival more effectively than tracheostomy alone.

      2. Methods

      2.1 Study design and participants

      This study retrospectively examined the medical records of 204 probable or definite MSA patients in Hyogo-Chuo National Hospital from January 1, 2000 to September 1, 2021. In the authors’ institution, patients with advanced-stage neurodegenerative diseases continue to be hospitalized until death and can be closely observed for a long time. MSA was diagnosed using the second consensus criteria [
      • Gilman S.
      • Wenning G.K.
      • Low P.A.
      • Brooks D.J.
      • Mathias C.J.
      • Trojanowski J.Q.
      • Wood N.W.
      • Colosimo C.
      • Dürr A.
      • Fowler C.J.
      • Kaufmann H.
      • Klockgether T.
      • Lees A.
      • Poewe W.
      • Quinn N.
      • Revesz T.
      • Robertson D.
      • Sandroni P.
      • Seppi K.
      • Vidailhet M.
      Second consensus statement on the diagnosis of multiple system atrophy.
      ]. To ensure diagnostic accuracy, only probable and definite MSA patients were selected (204 patients). Exclusion criteria were as follows: medical information insufficient for analysis (15 patients); transfer to another hospital in observation period (50 patients). This study enrolled 139 probable or definite MSA patients for whom the final outcome (survival or death) could be confirmed. Informed consent for therapeutic interventions was obtained at hospitalization and before treatments. Neurologists at our institution determined the indications for tracheostomy and TIV to be medically necessary after consent of the patient and their family. Tracheostomy was performed when the stridor was severe and CPAP provided insufficient efficacy. Stridor was clinically assessed at the bedside, and severity was determined based on the degree of respiratory impairment using pulse oximetry. Furthermore, vocal fold mobility was assessed by otolaryngologists using a laryngeal fiberscope. If the vocal cords were bilaterally located in the median or paramedian position, a tracheostomy was indicated owing to the risk of airway obstruction. TIV was performed when hypoxemia (SpO2 < 90% or PaO2 60 mmHg) or hypercarbonemia (PaCO2 > 60 mmHg) was confirmed through saturation monitoring or blood gas analysis. Intervention-free survival time was assessed based on the time that the patient required continuous therapeutic intervention. We excluded situations where ventilators were temporarily needed for pneumonia or other conditions. If the patient did not prefer invasive treatment, supportive care was continued. Information regarding cause of death was obtained from medical records and death certificates. If an autopsy was performed, pathological findings were also assessed. When performing TIV, UMSARS part IV (Global Disability Scale) was used to assess activities of daily living and quality of life (QOL). Informed consent was obtained from all the 139 enrolled patients through the institution website using opt-out method. Local ethics committee of Hyogo-Chuo National Hospital approved this study on November 9, 2020 (approval number: 20-05).

      2.2 Statistical analysis

      Summary statistics were presented as mean (standard deviation) or frequency (percent). Baseline evaluation measures were compared using the t-test. The frequencies between subgroups were analyzed using Fisher exact test. Survival curves were calculated using Kaplan–Meier analysis. Hazard ratio was calculated with the Cox hazard model, and the survival curves were compared using log-rank test. Propensity score matching (PSM) was used to adjust baseline differences among groups. Propensity scores were estimated using a multivariable logistic regression model accounting for the following patient parameters: age at onset, sex, clinical phenotype (MSA-P or MSA-C), and therapeutic intervention-free survival times, for the interventions of bladder catheterization, enteral nutrition, tracheostomy, and TIV. In each group, patients were matched at a 1:1 ratio using a caliper width of 0.2 standard deviation of the logit of the propensity score. The covariate balance was assessed using standardized mean difference, for which a value of <0.1 was considered to be well balanced. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using EZR, version 1.52 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R version 4.1.0 (The R Foundation for Statistical Computing, Vienna, Austria) [
      • Kanda Y.
      Investigation of the freely available easy-to-use software 'EZR' for medical statistics.
      ].

      3. Results

      3.1 Baseline characteristics

      Of the 139 patients with MSA, 95 patients died, 12 of who underwent autopsy (Table 1). All autopsy cases were pathologically confirmed by neuropathologists; some of these cases were reported in a previous study [
      • Sekiya H.
      • Kowa H.
      • Koga H.
      • Takata M.
      • Satake W.
      • Futamura N.
      • Funakawa I.
      • Jinnai K.
      • Takahashi M.
      • Kondo T.
      • Ueno Y.
      • Kanagawa M.
      • Kobayashi K.
      • Toda T.
      Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation.
      ]. We diagnosed 12 (8.6%) patients with definite MSA and 127 (91.4%) with probable MSA. We diagnosed 94 (67.6%) patients with MSA-C and 45 (32.4%) with MSA-P. Mean age at onset was 61.3 ± 9.8 years in all patients with MSA, 60.0 ± 8.8 years in those with MSA-C, and 64.0 ± 11.2 years in those with MSA-P. On univariate Cox proportional hazard analysis of patients’ baseline characteristics, only age at onset had a significant effect on survival (hazard ratio 1.06, 95% confidence interval [CI] 1.04–1.09, p < 0.001). Patients with older-onset MSA had a poorer prognosis. Mean hospitalization period was 2.9 years, with the longest being 19.7 years. Tracheostomy was performed for 53 (38.1%) patients, 21 (15.1%) of whom were ventilated. Some patients with TIV were able to communicate simply using eye contact, but verbal communication using speech-assistive devices was difficult for all patients. UMSARS part IV scores of all MSA patients were 5 points during TIV therapy (i.e., totally dependent, helpless, and bedridden). Mean time from onset to tracheostomy was 7.0 ± 3.0 years and from onset to TIV was 8.4 ± 4.4 years. Median survival time (MST) for all 139 patients with MSA was 9.0 (95% CI 8.1–11.0) years, and MST for the MSA patients without therapeutic interventions (natural course) was 7.4 (95% CI 5.7–8.0) years. On univariate Cox proportional hazard analysis, the hazard ratios of the time to need therapeutic interventions were as follows: bladder catheterization, 0.82 (95% CI 0.76–0.88, p < 0.001); enteral nutrition, 0.71 (95% CI 0.64–0.78, p < 0.001); tracheostomy, 0.80 (95% CI 0.74–0.86, p < 0.001); and TIV 0.71 (0.65–0.77, p < 0.001). The prognosis may be worse if treatment is required earlier and the time to need therapeutic interventions has a significant impact on survival.
      Table 1Characteristics of the study population.
      OverallMSA-CMSA-Pp value
      Number of patients, n (%)139 (100)94 (67.6)45 (32.4)
      Age at onset, years (SD)61.3 (9.8)60.0 (8.8)64.0 (11.2)0.023
      Sex, n (%)Female70 (50.4)43 (45.7)27 (60.0)0.147
      Male69 (49.6)51 (54.3)18 (40.0)
      Diagnostic certainty, n (%)Probable127(91.4)86 (91.5)41 (91.1)1.000
      Definite12 (8.6)8 (8.5)4 (9.9)
      Death, n (%)95 (68.3)66 (70.2)29 (64.4)0.560
      Hospitalization period, years (SD)2.9 (3.8)3.1 (3.9)2.6 (3.6)0.494
      Therapeutic intervention, n (%)Bladder Catheterization97 (69.8)64 (68.1)33 (73.3)0.561
      Enteral Nutrition76 (54.7)46 (48.9)30 (66.7)0.068
      Tracheostomy53 (38.1)37 (39.4)16 (35.6)0.712
      TIV21 (15.1)16 (17.0)5 (11.1)0.453
      Intervention-free survival, years (SD)Bladder Catheterization6.3 (3.7)6.4 (3.5)6.2 (4.0)0.776
      Enteral Nutrition6.6 (2.6)6.9 (2.7)6.0 (2.3)0.045
      Tracheostomy7.0 (3.0)7.2 (3.0)6.5 (3.0)0.215
      TIV8.4 (4.4)8.5 (4.2)8.2 (4.8)0.776
      MSA, multiple system atrophy; TIV, tracheostomy invasive ventilation.

      3.2 Survival and tracheostomy

      Eighty-six patients did not undergo tracheostomy and 32 patients underwent tracheostomy without ventilation. The age at onset was significantly younger for the tracheostomy group versus no tracheostomy group (58.7 vs. 64.1 years, p = 0.005). Time to bladder catheterization was significantly longer for the tracheostomy group versus no tracheostomy group (6.9 vs. 5.5 years, p = 0.034) (Table 2). After adjusting for background factors, MST was significantly prolonged in the tracheostomy group versus no tracheostomy group (10.1 vs. 7.5 years, p = 0.001) (Fig. 1). On Cox regression analysis, hazard ratio of tracheostomy was 0.35 (95% CI 0.17–0.68, p = 0.002). Tracheostomy was shown to significantly extend survival time by approximately 4 years.
      Table 2Clinical characteristics of MSA patients with tracheostomy and TIV before and after propensity score matching.
      Propensity score matchingTracheostomy (T)Tracheostomy Invasive ventilation (TIV)
      BeforeAfterBeforeAfter
      non TTp valueSMDnon TTp valueSMDT onlyTIVp valueSMDT onlyTIVp valueSMD
      Number of patients, n8632282832211010
      Age at onset years (SD)64.1 (9.4)58.7 (8.6)0.0050.60060.3 (9.6)59.5 (7.6)0.7410.08958.7 (8.6)53.6 (7.9)0.0340.61853.8 (6.9)53.8 (9.6)0.9960.002
      Sex, n female/male45/4115/170.6800.10915/1312/160.5930.21615/1710/111.0000.0154/63/71.0000.211
      Clinical phenotype, n

      MSA-C/MSA-P
      57/2921/121.0000.01419/919/91.0000.00121/1116/50.5440.2347/37/31.0000.001
      Bladder Catheterization free survivalyears (SD)5.5 (2.6)6.9 (4.4)0.0340.3916.3 (2.3)6.0 (3.7)07210.0966.9 (4.4)8.6 (4.9)0.2090.3536.5 (4.3)7.2 (2.5)0.7190.163
      Enteral Nutrition free survivalyears (SD)6.2 (2.4)7.0 (3.1)0.1160.3076.6 (2.4)6.4 (2.5)0.8590.0487.0 (3.1)7.6 (2.3)0.4310.2307.2 (3.6)7.1 (1.7)0.9600.023
      Tracheostomy free survivalyears (SD)6.6 (2.7)7.2 (3.6)0.3630.1766.8 (2.4)6.8 (3.5)0.9460.0187.2 (3.6)8.0 (3.0)0.3950.2487.1 (3.9)6.7 (2.6)0.7910.120
      TIV free survivalyears (SD)12.0 (5.3)10.2 (3.7)0.1980.38110.2 (4.2)10.4 (4.5)0.9330.038
      MSA, multiple system atrophy; MSA-C, MSA with predominant cerebellar features; MSA-P, MSA with predominant parkinsonism; TIV, tracheostomy invasive ventilation; T, tracheostomy; SD, standard deviation; SMD, standardized mean difference.
      Fig. 1
      Fig. 1Kaplan–Meier curves of survival probability for MSA patients with T (A) and TIV (B) adjusted using propensity score matching.
      T, Tracheostomy; TIV, tracheostomy invasive ventilation.

      3.3 Survival and TIV

      Among the 53 patients with tracheostomy, 21 underwent TIV, whose average age at onset was significantly lower than that of the patients with tracheostomy alone (53.6 vs. 58.7 years, p = 0.034) (Table 2). After adjusting for background factors, TIV significantly prolonged survival compared with tracheostomy alone (17.8 vs. 9.2 years, p = 0.023). On Cox regression analysis, hazard ratio of TIV was 0.25 (95% CI 0.07–0.89, p = 0.032). There was no significant difference in survival in the clinical phenotypes (MSA-C/MSA-P). TIV was shown to significantly extend survival time by approximately 8 years.

      3.4 Cause of death in MSA

      Deaths of 95 patients were classified as follows: 31 (32.6%) sudden deaths, 20 (21.1%) natural course, 10 (10.5%) tracheostomy alone, and 1 (1.1%) TIV (Table 3). Sudden death was significantly lower in the TIV group versus the non-TIV group (7.1% vs. 37.0%, p = 0.03); sudden death could not be prevented by TIV. Among the 31 sudden deaths, 22 (71.0%) occurred during sleep. In the MSA patients with tracheostomy alone, the common causes of death other than sudden death were central respiratory failure (22.7%) and infection (18.2%). In the MSA with TIV, infection (42.9%) and malignancy (14.3%) were common causes of death. Of the six patients who died of infections, there was only one case of ventilator-associated pneumonia (VAP), indicating that ventilator complications were an unexpectedly rare cause of death, possibly because of the advances in ventilator performance, adequate infection education, and appropriate antimicrobial therapy. There were no significant ventilator-associated complications that were deemed to be clinically life threatening.
      Table 3Cause of death in MSA patients.
      Cause of death, n (%)Overall (n = 95)Natural Course (n = 59)Tracheostomy (n = 22)TIV (n = 14)
      Sudden death31 (32.6)20 (33.9)10 (45.5)1 (7.1)
      Respiratory failure24 (25.3)19 (32.2)5 (22.7)0 (0.0)
      Heart failure3 (3.2)1 (1.7)1 (4.5)1 (7.1)
      Renal failure2 (2.1)0 (0.0)1 (4.5)1 (7.1)
      Infection17 (17.9)7 (11.9)4 (18.2)6 (42.9)
      Malignancy4 (4.2)1 (1.7)1 (4.5)2 (14.3)
      Wasting syndrome6 (6.3)5 (8.5)0 (0.0)1 (7.1)
      Suffocation1 (1.1)1 (1.7)0 (0.0)0 (0.0)
      Others7 (7.8)5 (8.5)0 (0.0)2 (14.3)
      MSA, multiple system atrophy; TIV, tracheostomy invasive ventilation.

      4. Discussion

      This study is the first to evaluate the impact of TIV on survival and cause of death in MSA patients. In our cohort, the number of MSA-C cases was higher than that of MSA-P cases. This result is similar to a previous Japanese study [
      • Yabe I.
      • Soma H.
      • Takei A.
      • Fujiki N.
      • Yanagihara T.
      • Sasaki H.
      MSA-C is the predominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA.
      ]. MST for all MSA patients and natural course patients was 9.0 years and 7.4 years, respectively. These results are similar to those of previous studies conducted in Europe, America, China, and Japan [
      • Wenning G.K.
      • Geser F.
      • Krismer F.
      • Seppi K.
      • Duerr S.
      • Boesch S.
      • Köllensperger M.
      • Goebel G.
      • Pfeiffer K.P.
      • Barone P.
      • Pellecchia M.T.
      • Quinn N.P.
      • Koukouni V.
      • Fowler C.J.
      • Schrag A.
      • Mathias C.J.
      • Giladi N.
      • Gurevich T.
      • Dupont E.
      • Ostergaard K.
      • Nilsson C.F.
      • Widner H.
      • Oertel W.
      • Eggert K.M.
      • Albanese A.
      • del Sorbo F.
      • Tolosa E.
      • Cardozo A.
      • Deuschl G.
      • Hellriegel H.
      • Klockgether T.
      • Dodel R.
      • Sampaio C.
      • Coelho M.
      • Djaldetti R.
      • Melamed E.
      • Gasser T.
      • Kamm C.
      • Meco G.
      • Colosimo C.
      • Rascol O.
      • Meissner W.G.
      • Tison F.
      • Poewe W.
      The natural history of multiple system atrophy: a prospective European cohort study.
      ,
      • Foubert-Samier A.
      • Pavy-Le Traon A.
      • Guillet F.
      • Le-Goff M.
      • Helmer C.
      • Tison F.
      • Rascol O.
      • Proust-Lima C.
      • Meissner W.G.
      Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study.
      ,
      • Low P.P.A.
      • Reich S.G.
      • Jankovic J.
      • Shults C.W.
      • Stern M.B.
      • Novak P.
      • Tanner C.M.
      • Gilman S.
      • Marshall F.J.
      • Wooten F.
      • Racette B.
      • Chelimsky T.
      • Singer W.
      • Sletten D.M.
      • Sandroni P.
      • Mandrekar J.
      Natural history of multiple system atrophy in the USA: a prospective cohort study.
      ,
      • Zhang L.
      • Cao B.
      • Zou Y.
      • Wei Q.Q.
      • Ou R.
      • Liu W.
      • Zhao B.
      • Yang J.
      • Wu Y.
      • Shang H.
      Causes of death in Chinese patients with multiple system atrophy.
      ,
      • Watanabe H.
      • Saito Y.
      • Terao S.
      • Ando T.
      • Kachi T.
      • Mukai E.
      • Aiba I.
      • Abe Y.
      • Tamakoshi A.
      • Doyu M.
      • Hirayama M.
      • Sobue G.
      Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.
      ].
      Few studies of MSA have assessed the effects of tracheostomy on survival [
      • Cortelli P.
      • Calandra-Buonaura G.
      • Benarroch E.E.
      • Giannini G.
      • Iranzo A.
      • Low P.A.
      • Martinelli P.
      • Provini F.
      • Quinn N.
      • Tolosa E.
      • Wenning G.K.
      • Abbruzzese G.
      • Bower P.
      • Alfonsi E.
      • Ghorayeb I.
      • Ozawa T.
      • Pacchetti C.
      • Pozzi N.G.
      • Vicini C.
      • Antonini A.
      • Bhatia K.P.
      • Bonavita J.
      • Kaufmann H.
      • Pellecchia M.T.
      • Pizzorni N.
      • Schindler A.
      • Tison F.
      • Vignatelli L.
      • Meissner W.G.
      Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment.
      ]; however, none have reported assessing TIV and cause of death in ventilated MSA patients. Several studies have shown that various factors affect survival, including age at onset, sex, and clinical phenotype, autonomic dysfunction, and clinical symptoms, as assessed by UMSARS [
      • Wenning G.K.
      • Geser F.
      • Krismer F.
      • Seppi K.
      • Duerr S.
      • Boesch S.
      • Köllensperger M.
      • Goebel G.
      • Pfeiffer K.P.
      • Barone P.
      • Pellecchia M.T.
      • Quinn N.P.
      • Koukouni V.
      • Fowler C.J.
      • Schrag A.
      • Mathias C.J.
      • Giladi N.
      • Gurevich T.
      • Dupont E.
      • Ostergaard K.
      • Nilsson C.F.
      • Widner H.
      • Oertel W.
      • Eggert K.M.
      • Albanese A.
      • del Sorbo F.
      • Tolosa E.
      • Cardozo A.
      • Deuschl G.
      • Hellriegel H.
      • Klockgether T.
      • Dodel R.
      • Sampaio C.
      • Coelho M.
      • Djaldetti R.
      • Melamed E.
      • Gasser T.
      • Kamm C.
      • Meco G.
      • Colosimo C.
      • Rascol O.
      • Meissner W.G.
      • Tison F.
      • Poewe W.
      The natural history of multiple system atrophy: a prospective European cohort study.
      ,
      • Foubert-Samier A.
      • Pavy-Le Traon A.
      • Guillet F.
      • Le-Goff M.
      • Helmer C.
      • Tison F.
      • Rascol O.
      • Proust-Lima C.
      • Meissner W.G.
      Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study.
      ,
      • Low P.P.A.
      • Reich S.G.
      • Jankovic J.
      • Shults C.W.
      • Stern M.B.
      • Novak P.
      • Tanner C.M.
      • Gilman S.
      • Marshall F.J.
      • Wooten F.
      • Racette B.
      • Chelimsky T.
      • Singer W.
      • Sletten D.M.
      • Sandroni P.
      • Mandrekar J.
      Natural history of multiple system atrophy in the USA: a prospective cohort study.
      ,
      • Zhang L.
      • Cao B.
      • Zou Y.
      • Wei Q.Q.
      • Ou R.
      • Liu W.
      • Zhao B.
      • Yang J.
      • Wu Y.
      • Shang H.
      Causes of death in Chinese patients with multiple system atrophy.
      ,
      • Watanabe H.
      • Saito Y.
      • Terao S.
      • Ando T.
      • Kachi T.
      • Mukai E.
      • Aiba I.
      • Abe Y.
      • Tamakoshi A.
      • Doyu M.
      • Hirayama M.
      • Sobue G.
      Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.
      ]. The present study showed that the age at onset and time to need therapeutic interventions had a significant impact on survival.
      In observational studies, background factors may be biased because they are not randomly assigned to treatment groups. Randomized controlled trials are considered the gold standard approach for estimating the effects of treatments. However, these trials are difficult to conduct because of many practical reasons, particularly for rare diseases. Therefore, the present study evaluated the effect of treatment on survival by statistically correcting the bias of background factors.
      The propensity score is the probability of treatment assignment conditional on measured baseline characteristics [
      • Rosenbaum P.R.
      • Rubin D.B.
      The central role of the propensity score in observational studies for causal effects.
      ]. Recently, PSM method is used to correct background factor bias in observational studies by estimating the effectiveness of treatment. This study investigated the effect of tracheostomy and TIV on survival in MSA patients using Cox hazards model with the PSM method.
      A tracheostomy, a surgical procedure that opens the airway by making a hole in front of the neck, avoids various respiratory disorders and sudden death in MSA [
      • Cortelli P.
      • Calandra-Buonaura G.
      • Benarroch E.E.
      • Giannini G.
      • Iranzo A.
      • Low P.A.
      • Martinelli P.
      • Provini F.
      • Quinn N.
      • Tolosa E.
      • Wenning G.K.
      • Abbruzzese G.
      • Bower P.
      • Alfonsi E.
      • Ghorayeb I.
      • Ozawa T.
      • Pacchetti C.
      • Pozzi N.G.
      • Vicini C.
      • Antonini A.
      • Bhatia K.P.
      • Bonavita J.
      • Kaufmann H.
      • Pellecchia M.T.
      • Pizzorni N.
      • Schindler A.
      • Tison F.
      • Vignatelli L.
      • Meissner W.G.
      Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment.
      ]. In this study, 53 patients underwent tracheostomy, 21 of whom received TIV. Tracheostomy and TIV tended to be selected for patients with significantly younger age at onset. The adjusted MST of the tracheostomy group was significantly longer than the no tracheostomy group. Similar to previous reports [
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • Righini M.
      • Bacchi-Reggiani M.L.
      • Cecere A.
      • Barletta G.
      • Guaraldi P.
      • Provini F.
      • Cortelli P.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      ], a significant prolongation of survival with tracheostomy was shown. It is speculated that tracheostomy prevents death by improving noncentral respiratory disorders. Furthermore, the adjusted MST of the TIV group was significantly longer than that for the tracheostomy alone group. To the best of our knowledge, this study is the first to assess the impact of TIV on survival in patients with MSA. The longer survival time for patients with TIV versus tracheostomy alone was attributed to the fact that TIV can treat central respiratory dysfunction which tracheostomy alone cannot address.
      Sudden death has a strong impact on the survival of MSA patients. A previous study on the cause of death in definite MSA patients showed a high rate of sudden death (38.1%), including one tracheostomy patient [
      • Papapetropoulos S.
      • Tuchman A.
      • Laufer D.
      • Papatsoris A.G.
      • Papapetropoulos N.
      • Mash D.C.
      Causes of death in multiple system atrophy.
      ]. In another Chinese prospective study, sudden death was noted in 19 (14.5%) of the 131 probable MSA patients [
      • Zhang L.
      • Cao B.
      • Zou Y.
      • Wei Q.Q.
      • Ou R.
      • Liu W.
      • Zhao B.
      • Yang J.
      • Wu Y.
      • Shang H.
      Causes of death in Chinese patients with multiple system atrophy.
      ]. In this study, 18 (32.7%) sudden deaths occurred among 55 patients without tracheostomy and 10 (45.5%) sudden deaths occurred among 22 patients with tracheostomy. Tracheostomy did not reduce sudden death; among sudden deaths, respiratory arrest was identified in two patients with tracheostomy and in four patients who had a natural course. This detection of respiratory arrest was possible because vital signs can be closely observed using biological monitors for inpatients. The respiratory arrest was thought to be related to central respiratory disturbance. The reason why tracheostomy did not reduce sudden death is thought to be that sudden deaths are mostly caused by central respiratory disorders in advanced-stage MSA. Tracheostomy prolongs survival by avoiding noncentral respiratory disturbance such as stridor and sleep apnea, and tracheostomy is thought to have limited effectiveness in preventing all sudden deaths.
      The frequency of sudden death was significantly lower in MSA patients with TIV than for without TIV, suggesting the preventive effect of ventilation on sudden death. In contrast, among the 14 deceased patients with TIV, 1 case was sudden death. In this case, cardiac autonomic disturbance was considered the cause of sudden death because the monitor observed sudden dysrhythmia. The existence of sudden deaths in ventilated MSA patients indicates that TIV cannot completely prevent sudden death. This limitation is thought to be because sudden death involves several other factors, such as the cardiac autonomic disturbance [
      • Tada M.
      • Onodera O.
      • Tada M.
      • Ozawa T.
      • Piao Y.S.
      • Kakita A.
      • Takahashi H.
      • Nishizawa M.
      Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.
      ]. Other than sudden death, infection was common cause of death in MSA with TIV, but VAP was unexpectedly low among the fatal infections in this study. Although various complications associated with long-term use of ventilators have been reported previously [
      • Sue R.D.
      • Susanto I.
      Long-term complications of artificial airways.
      ], there were no significant ventilator-associated complications that could be considered clinically life threatening.

      4.1 Limitations

      This study has several limitations. First, because not all cases underwent autopsy, comorbid disease could not be ruled out, and the cause of death may not necessarily be accurate. The advantage of this study is that it allows long-term follow-up and enrollment of probable and definite cases to make the diagnosis more reliable. Of the 95 deceased MSA patients, autopsy was performed in 12 (8.7%) cases, all of which were pathologically confirmed to be MSA. Second, this analysis was a single-center, retrospective cohort study with a relatively small sample size, and even with statistically adjusted background factors, selection bias cannot be completely ruled out for unknown factors. Therefore, it is necessary to prospectively study more MSA cases in a multicenter collaboration. Prospective studies such as randomized controlled trials are difficult for many practical reasons; for instance, it is ethically impossible to randomize the therapeutic intervention and technically difficult to conduct a blinded study. Therefore, even retrospective studies, such as the present study, can evaluate the survival impact of TIV on MSA to some extent. Third, our results were based on patients admitted to a hospital, which is not necessarily substitutable under non-hospital settings, such as a home or sophisticated nursing care facility. Fourth, the differences in ventilator usage among different countries also need to be considered. In Japan, TIV for neurodegenerative diseases tends to be selected more often than in other countries. In addition to medical resources and the medical insurance system, differences in the preferences of neurologists and patients have also been suggested to play a role [
      • Rabkin J.
      • Ogino M.
      • Goetz R.
      • McElhiney M.
      • Hupf J.
      • Heitzman D.
      • Heiman-Patterson T.
      • Miller R.
      • Katz J.
      • Lomen-Hoerth C.
      • Imai T.
      • Atsuta N.
      • Morita M.
      • Tateishi T.
      • Matsumura T.
      • Mitsumoto H.
      Japanese and American ALS patient preferences regarding TIV (tracheostomy with invasive ventilation): a cross-national survey.
      ]. Hence, differences in treatment decisions by country and region are also important. Although our study findings are difficult to generalize across all MSA patients, we believe the results demonstrate the impact of TIV on survival under certain medical resources. In order to clarify the impact of TIV on prolonging the survival of patients, further research is needed to consider the different situations in different cases. Finally, even if TIV improves the prognosis of patients with MSA, QOL is also important in invasive treatments. Patients with younger age at onset chose invasive treatments after completely understanding the disadvantages of such treatments. In contrast, the most common reason for not choosing tracheostomy or TIV was concern about the decline in ADL/QOL. In patients with advanced-stage MSA, it is impossible to assess QOL in detail because of the difficulty in communicating due to the progression of motor and cognitive dysfunction. We evaluated UMSARS part IV as a surrogate marker for QOL assessment. Higher scores may reflect lower QOL, which may be important for making treatment decisions. Further research, including the establishment of methods for communicating with advanced-stage patients, is warranted, and TIV should be selected with sufficient informed consent and under rigorous criteria.

      Funding

      This work was supported by Grants-in-Aid from the Research Committee of Ataxia , Health Labour Sciences Research Grant , the Ministry of Health, Labour and Welfare, Japan ( JPMH20FC1041 ).

      Authors’ contributions

      KN: conception, execution, statistical analysis, and writing the first draft. KS, HY, and NF: review and critical revision. All authors have read and approved the final manuscript.

      Declaration of competing interest

      None.

      Acknowledgement

      The authors would like to thank Enago (www.enago.jp) for the English language review.

      References

        • Fanciulli A.
        • Wenning G.K.
        Multiple-system atrophy.
        N. Engl. J. Med. 2015; 372: 1375-1376https://doi.org/10.1056/NEJMra1311488
        • Coon E.A.
        • Sletten D.M.
        • Suarez M.D.
        • Mandrekar J.N.
        • Ahlskog J.E.
        • Bower J.H.
        • Matsumoto J.Y.
        • Silber M.H.
        • Benarroch E.E.
        • Fealey R.D.
        • Sandroni P.
        • Low P.A.
        • Singer W.
        Clinical features and autonomic testing predict survival in multiple system atrophy.
        Brain. 2015; 138: 3623-3631https://doi.org/10.1093/brain/awv274
        • Shimohata T.
        • Aizawa N.
        • Nakayama H.
        • Taniguchi H.
        • Ohshima Y.
        • Okumura H.
        • Takahashi T.
        • Yokoseki A.
        • Inoue M.
        • Nishizawa M.
        Mechanisms and prevention of sudden death in multiple system atrophy.
        Park. Relat. Disord. 2016; 30: 1-6https://doi.org/10.1016/j.parkreldis.2016.04.011
        • Cortelli P.
        • Calandra-Buonaura G.
        • Benarroch E.E.
        • Giannini G.
        • Iranzo A.
        • Low P.A.
        • Martinelli P.
        • Provini F.
        • Quinn N.
        • Tolosa E.
        • Wenning G.K.
        • Abbruzzese G.
        • Bower P.
        • Alfonsi E.
        • Ghorayeb I.
        • Ozawa T.
        • Pacchetti C.
        • Pozzi N.G.
        • Vicini C.
        • Antonini A.
        • Bhatia K.P.
        • Bonavita J.
        • Kaufmann H.
        • Pellecchia M.T.
        • Pizzorni N.
        • Schindler A.
        • Tison F.
        • Vignatelli L.
        • Meissner W.G.
        Stridor in multiple system atrophy: consensus statement on diagnosis, prognosis, and treatment.
        Neurology. 2019; 93: 630-639https://doi.org/10.1212/WNL.0000000000008208
        • Giannini G.
        • Calandra-Buonaura G.
        • Mastrolilli F.
        • Righini M.
        • Bacchi-Reggiani M.L.
        • Cecere A.
        • Barletta G.
        • Guaraldi P.
        • Provini F.
        • Cortelli P.
        Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
        Neurology. 2016; 87: 1375-1383https://doi.org/10.1212/WNL.0000000000003156
        • Tada M.
        • Onodera O.
        • Tada M.
        • Ozawa T.
        • Piao Y.S.
        • Kakita A.
        • Takahashi H.
        • Nishizawa M.
        Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.
        Arch. Neurol. 2007; 64: 256-260https://doi.org/10.1001/archneur.64.2.256
        • Gilman S.
        • Wenning G.K.
        • Low P.A.
        • Brooks D.J.
        • Mathias C.J.
        • Trojanowski J.Q.
        • Wood N.W.
        • Colosimo C.
        • Dürr A.
        • Fowler C.J.
        • Kaufmann H.
        • Klockgether T.
        • Lees A.
        • Poewe W.
        • Quinn N.
        • Revesz T.
        • Robertson D.
        • Sandroni P.
        • Seppi K.
        • Vidailhet M.
        Second consensus statement on the diagnosis of multiple system atrophy.
        Neurology. 2008; 71: 670-676https://doi.org/10.1212/01.wnl.0000324625.00404.15
        • Kanda Y.
        Investigation of the freely available easy-to-use software 'EZR' for medical statistics.
        Bone Marrow Transplant. 2013; 48: 452-458https://doi.org/10.1038/bmt.2012.244
        • Sekiya H.
        • Kowa H.
        • Koga H.
        • Takata M.
        • Satake W.
        • Futamura N.
        • Funakawa I.
        • Jinnai K.
        • Takahashi M.
        • Kondo T.
        • Ueno Y.
        • Kanagawa M.
        • Kobayashi K.
        • Toda T.
        Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation.
        Acta Neuropathol. 2019; 137: 455-466https://doi.org/10.1007/s00401-019-01961-w
        • Yabe I.
        • Soma H.
        • Takei A.
        • Fujiki N.
        • Yanagihara T.
        • Sasaki H.
        MSA-C is the predominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA.
        J. Neurol. Sci. 2006; 249: 115-121https://doi.org/10.1016/j.jns.2006.05.064
        • Wenning G.K.
        • Geser F.
        • Krismer F.
        • Seppi K.
        • Duerr S.
        • Boesch S.
        • Köllensperger M.
        • Goebel G.
        • Pfeiffer K.P.
        • Barone P.
        • Pellecchia M.T.
        • Quinn N.P.
        • Koukouni V.
        • Fowler C.J.
        • Schrag A.
        • Mathias C.J.
        • Giladi N.
        • Gurevich T.
        • Dupont E.
        • Ostergaard K.
        • Nilsson C.F.
        • Widner H.
        • Oertel W.
        • Eggert K.M.
        • Albanese A.
        • del Sorbo F.
        • Tolosa E.
        • Cardozo A.
        • Deuschl G.
        • Hellriegel H.
        • Klockgether T.
        • Dodel R.
        • Sampaio C.
        • Coelho M.
        • Djaldetti R.
        • Melamed E.
        • Gasser T.
        • Kamm C.
        • Meco G.
        • Colosimo C.
        • Rascol O.
        • Meissner W.G.
        • Tison F.
        • Poewe W.
        The natural history of multiple system atrophy: a prospective European cohort study.
        Lancet Neurol. 2013; 12: 264-274https://doi.org/10.1016/S1474-4422(12)70327-7
        • Foubert-Samier A.
        • Pavy-Le Traon A.
        • Guillet F.
        • Le-Goff M.
        • Helmer C.
        • Tison F.
        • Rascol O.
        • Proust-Lima C.
        • Meissner W.G.
        Disease progression and prognostic factors in multiple system atrophy: a prospective cohort study.
        Neurobiol. Dis. 2020; 139: 104813https://doi.org/10.1016/j.nbd.2020.104813
        • Low P.P.A.
        • Reich S.G.
        • Jankovic J.
        • Shults C.W.
        • Stern M.B.
        • Novak P.
        • Tanner C.M.
        • Gilman S.
        • Marshall F.J.
        • Wooten F.
        • Racette B.
        • Chelimsky T.
        • Singer W.
        • Sletten D.M.
        • Sandroni P.
        • Mandrekar J.
        Natural history of multiple system atrophy in the USA: a prospective cohort study.
        Lancet Neurol. 2015; 14: 710-719https://doi.org/10.1016/S1474-4422(15)00058-7
        • Zhang L.
        • Cao B.
        • Zou Y.
        • Wei Q.Q.
        • Ou R.
        • Liu W.
        • Zhao B.
        • Yang J.
        • Wu Y.
        • Shang H.
        Causes of death in Chinese patients with multiple system atrophy.
        Aging Dis. 2018; 9: 102-108https://doi.org/10.14336/AD.2017.0711
        • Watanabe H.
        • Saito Y.
        • Terao S.
        • Ando T.
        • Kachi T.
        • Mukai E.
        • Aiba I.
        • Abe Y.
        • Tamakoshi A.
        • Doyu M.
        • Hirayama M.
        • Sobue G.
        Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.
        Brain. 2002; 125: 1070-1083https://doi.org/10.1093/brain/awf117
        • Rosenbaum P.R.
        • Rubin D.B.
        The central role of the propensity score in observational studies for causal effects.
        Biometrika. 1983; 70: 41-55https://doi.org/10.1093/biomet/70.1.41
        • Papapetropoulos S.
        • Tuchman A.
        • Laufer D.
        • Papatsoris A.G.
        • Papapetropoulos N.
        • Mash D.C.
        Causes of death in multiple system atrophy.
        J. Neurol. Neurosurg. Psychiatry. 2007; 78: 327-329https://doi.org/10.1136/jnnp.2006.103929
        • Sue R.D.
        • Susanto I.
        Long-term complications of artificial airways.
        Clin. Chest Med. 2003; 24: 457-471https://doi.org/10.1016/S0272-5231(03)00048-0
        • Rabkin J.
        • Ogino M.
        • Goetz R.
        • McElhiney M.
        • Hupf J.
        • Heitzman D.
        • Heiman-Patterson T.
        • Miller R.
        • Katz J.
        • Lomen-Hoerth C.
        • Imai T.
        • Atsuta N.
        • Morita M.
        • Tateishi T.
        • Matsumura T.
        • Mitsumoto H.
        Japanese and American ALS patient preferences regarding TIV (tracheostomy with invasive ventilation): a cross-national survey.
        Amyotroph. Lateral. Scler. Frontotemp. Degener. 2014; 15: 185-191https://doi.org/10.3109/21678421.2014.896928