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An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis
Journal of the Neurological Sciences 376 (2017) 202–205
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis Kazuaki Nagashima, Natsumi Furuta, Kouki Makioka, Yukio Fujita, Masaki Ikeda, Yoshio Ikeda ⁎ Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
a r t i c l e
i n f o
Article history: Received 9 November 2016 Received in revised form 20 February 2017 Accepted 20 March 2017 Available online 21 March 2017 Keywords: Amyotrophic lateral sclerosis Percutaneous endoscopic gastrostomy Aphagia before PEG placement PaCO2 Prognostic factors
a b s t r a c t A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30 days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO2) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement. © 2017 Elsevier B.V. All rights reserved.
1. Introduction
2. Patients and methods
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes death within a few years without artificial respiratory support [1,2]. The major symptoms of ALS include generalized muscle weakness and atrophy due to the degeneration of upper and lower motor neurons. The facial, oropharyngeal, and respiratory muscles are also involved, causing dysarthria, dysphagia, and respiratory failure. ALS patients with severe dysphagia have difficulty maintaining adequate oral nutrition, and may require an alternate means of intake. Percutaneous endoscopic gastrostomy (PEG) is a major alternative procedure for nutritional support of ALS patients with dysphagia, and can help maintain body weight [3]. PEG placement is recommended when the forced vital capacity (FVC) is over 50% of predicted value according to the guidelines of the American Academy of Neurology (AAN), the European Federation of Neurological Societies (EFNS), and the Japanese Society of Neurology (JSN) [4–6]. However, the relevant risk factors at the time of PEG placement in ALS patients are unclear. Poor prognostic factors associated with early death or shorter survival after PEG placement were analyzed in 102 ALS patients in this study.
A total of 102 patients diagnosed with definite, probable, or possible ALS according to the revised El Escorial criteria in whom PEG therapy was instituted between April 1999 and June 2016 in the Department of Neurology, Gunma University Hospital, were enrolled in this study [7]. The subjects were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30 days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics including gender, age at onset, site of onset, disease duration from onset to PEG placement, age at PEG placement, riluzole use, respiratory and nutritional conditions before PEG placement, and survival time from PEG placement to death or permanent mechanical ventilation, were retrospectively analyzed from medical records. These parameters were compared for the poor prognosis and good prognosis groups, and the poor prognostic factors associated with early death or permanent mechanical ventilation were statistically analyzed. This study was approved by the Ethical Committee of Gunma University Graduate School of Medicine. Written informed consent for PEG placement was obtained from all ALS patients. Quantitative clinical parameters analyzed in this study were as follows. Respiratory function was evaluated with FVC (% of predicted
⁎ Corresponding author. E-mail address: [email protected] (Y. Ikeda).
http://dx.doi.org/10.1016/j.jns.2017.03.029 0022-510X/© 2017 Elsevier B.V. All rights reserved.
K. Nagashima et al. / Journal of the Neurological Sciences 376 (2017) 202–205
value) and PaCO2. The severity of ALS status was evaluated with the revised ALS functional rating scale (ALSFRS-R) [8]. Nutritional status was evaluated with according to body weight loss (N 10% of premorbid weight), body mass index (BMI), serum total protein, albumin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels, and aphagia before PEG placement. Aphagia represents the patients who were unable to ingest any food or drink before PEG placement. 2.1. Statistical analysis Statistical analysis was conducted using SPSS®22 software (IBM Japan, Tokyo, Japan). Quantitative data were expressed as means ± standard deviations. Parameters in the poor prognosis and good prognosis groups were compared using an unpaired Student's t-test, and categorical variables were compared using the χ2-test. Multivariate analysis was performed between two groups using a logistic regression model. Survival analyses from PEG placement to death or permanent mechanical ventilation were demonstrated using the Kaplan-Meier survival analysis, and compared by log-rank test. Kaplan-Meier survival analysis and log-rank test were performed on each parameter for all patients whose medical information was available for analysis. The prognostic factors for PEG placement were evaluated with a Cox proportional hazards regression model. The level of statistical significance was set at p b 0.05. 3. Results The participants in this study included 56 males and 46 females. The site of onset was bulbar in 46 patients and spinal in 56 patients. Five patients died within 30 days after PEG placement, and two needed permanent mechanical ventilation within 30 days after PEG placement. Seven patients (6.9%) met the criteria of the poor prognosis group. 3.1. Poor prognostic factors within 30 days after PEG placement Clinical and laboratory characteristics of the two groups are shown in Table 1. Lower ALSFRS-R scores and aphagia before PEG placement were significantly associated with poor prognosis (ALSFRS-R: p b 0.05, aphagia before PEG placement: p b 0.05). Higher PaCO2, lower serum
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triglyceride, and older age at onset were associated with poor prognosis; however, these were not statistically significant. Multivariate analysis was performed for age at onset, PaCO2, aphagia before PEG placement, site of onset, and riluzole use using a logistic regression model. PaCO2 and aphagia before PEG placement were significantly associated with poor prognosis group (Table 2). 3.2. Prognostic risk factors for survival after PEG placement Kaplan-Meier survival analysis and log-rank test revealed that %FVC (≥ 50 vs. b50%), age at onset (≥ 60 vs. b60 years), and duration from onset to PEG placement (≥20 vs. b20 months) were significantly associated with survival (Table 3). On the other hand, gender, site of onset, PaCO2, aphagia before PEG placement, riluzole use, body weight loss (N10% of premorbid weight) and BMI were not significantly associated with survival after PEG placement (Table 3). Lower ALSFRS-R (b20) and lower serum albumin (b 4.0 g/dl) showed a tendency of having shorter survival after PEG placement, but these were not statistically significant. (Table 3). PaCO2 did not show a statistically significant association with survival from PEG placement to death with the log-rank test, but the Kaplan-Meier survival analysis for PaCO2 (cut-off levels ranged from 35% to 55%) showed a tendency for shorter median survival in patients with higher PaCO2 (Table 3). Finally, multivariate analysis of the prognostic factors after PEG placement was performed using a Cox proportional hazards regression model. This analysis demonstrated that PaCO2 and duration from onset to PEG placement were significantly associated with shorter survival (Table 4). 4. Discussion PEG placement is a standard alternative method used for feeding of ALS patients with severe dysphagia. In ALS patients, malnutrition is an independent prognostic factor, and nutritional support through a PEG tube helps maintain body weight and enables longer survival [3,9–12]. On the other hand, a subset of ALS patients have early death or respiratory failure immediately after PEG placement. However, poor prognostic factors or favorable timing for PEG placement have not been identified. This study included a large number of Japanese ALS patients in an investigation of prognostic factors after PEG placement. Poor prognosis group corresponds to 6.9% of all ALS patients in this study. This
Table 1 Comparisons of clinical and laboratory items between good and poor prognosis groups. Variables
Good prognosis (n = 95)
Poor prognosis (n = 7)
p value
Total (n = 102)
Gender (Male/Female) Site of onset (bulbar/spinal) Age at onset (years) Age at PEG placement (years) Duration from onset to PEG placement (months) %FVC (n = 73) PaCO2 (mmHg) (n = 95) ALSFRS-R (n = 56) Serum total protein (g/dl) (n = 102) Serum albumin (g/dl) (n = 98) Total cholesterol (mg/dl) (n = 89) HDL cholesterol (mg/dl) (n = 72) LDL cholesterol (mg/dl) (n = 82) Triglyceride (mg/dl) (n = 85) Riluzole use (Yes/No) (n = 102) Aphagia before PEG placement (Yes/No) (n = 85) BW loss (N10% of premorbid weight) (Yes/No) (n = 34) BMI (kg/m2) (n = 83)
52/43 44/51 61.2 ± 11.8 63.1 ± 11.5 25.2 ± 23.3 62.8 ± 23.4 (n = 67) 42.5 ± 5.8 (n = 88) 30.3 ± 8.5 (n = 53) 6.9 ± 0.6 (n = 95) 4.0 ± 0.5 (n = 91) 194.5 ± 39.9 (n = 83) 51.9 ± 13.8 (n = 68) 118.3 ± 31.2 (n = 77) 120.8 ± 60.8 (n = 80) 69/26 7/71 25/6 20.0 ± 3.4 (n = 78)
4/3 2/5 68.6 ± 11.6 70.1 ± 11.2 17.4 ± 12.5 56.2 ± 21.9 (n = 6) 46.7 ± 6.2 (n = 7) 15.0 ± 5.6 (n = 3) 6.7 ± 0.5 (n = 7) 3.9 ± 0.3 (n = 7) 216.7 ± 48.2 (n = 6) 61.7 ± 18.5 (n = 4) 119.4 ± 33.0 (n = 5) 72.0 ± 22.8 (n = 5) 3/4 3/4 3/0 19.2 ± 5.1 (n = 5)
0.90 (χ2) 0.66 (χ2) 0.11 0.12 0.39 0.51 0.07 p b 0.05⁎ 0.45 0.82 0.20 0.18 0.94 0.08 0.10 (χ2) p b 0.05 (χ2)⁎ 0.36 (χ2) 0.62
56/46 46/56 61.7 ± 11.8 63.6 ± 11.5 24.6 ± 22.7 62.2 ± 23.3 42.8 ± 5.9 29.5 ± 9.0 6.9 ± 0.6 4.0 ± 0.5 196.0 ± 40.5 52.4 ± 14.1 118.3 ± 31.1 117.9 ± 60.3 72/30 10/75 28/6 19.9 ± 3.5
Data are expressed by means ± standard deviations. PEG: percutaneous endoscopic gastrostomy, FVC: forced vital capacity, PaCO2: arterial carbon dioxide pressure, ALSFRS-R: revised amyotrophic lateral sclerosis functional rating scale, BW: body weight, BMI: body mass index, n = number, χ2: χ2 test. Poor prognosis: the patients who died or needed permanent mechanical ventilation within 30 days after PEG placement. Good prognosis: the patients who did not meet the criteria of the poor group. Qualitative data were expressed as number, and quantitative data were expressed as means ± standard deviations. ⁎ Indicates statistically significant (p b 0.05).
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K. Nagashima et al. / Journal of the Neurological Sciences 376 (2017) 202–205
Table 2 Multivariate analysis of the poor prognostic factors between good and poor prognosis groups. Variables
Odds ratio
95% CI
p value
Age at onset (years) PaCO2 (mmHg) Aphagia before PEG placement (Yes/No) Site of onset (spinal/bulbar) Riluzole use (No/Yes)
1.067 1.210 24.849 2.192 2.412
0.975–1.167 1.030–1.420 1.918–321.952 0.255–18.858 0.341–17.038
0.158 0.02⁎ 0.014⁎ 0.475 0.377
PaCO2: arterial carbon dioxide pressure, CI: confidence interval. ⁎ Indicates statistically significant (p b 0.05).
Table 4 Multivariate analysis of the poor prognostic factors for survival after PEG placement in all ALS patients.
Variables Duration from onset to PEG placement (months) PaCO2 (mmHg) Aphagia before PEG placement (Yes/No) Site of onset (bulbar/spinal) Riluzole use (No/Yes)
Hazard ratio
95% CI
p value
0.963
0.939–0.988 0.003⁎
1.102 1.892 1.484 1.119
1.043–1.165 0.807–4.434 0.849–2.591 0.629–1.991
0.001⁎ 0.142 0.166 0.701
PaCO2: arterial carbon dioxide pressure, CI: confidence interval. ⁎ Indicates statistically significant (p b 0.05).
result was comparable to the previous reports describing mortality within 30 days after PEG placement (2–25%) [11,13,14]. In our study, there were significant differences with PaCO2 and aphagia before PEG placement between good and poor prognosis groups on multivariate analysis (Table 2). Kasarskis et al. and Pena et al. previously reported that %FVC was the risk factor within 30 days mortality after PEG placement [14,15]. However, they did not evaluate PaCO2 and aphagia before PEG placement unlike our study. Shimizu et al. reported a significant association between death or permanent mechanical ventilation within 6 months after PEG placement and higher PaCO2 in their ALS patients [16]. Bokuta et al. also reported that the association between higher PaCO2 and shorter survival period was more significant than the association between lower %FVC and shorter survival period [17]. This report also showed that ALS patients with PaCO2 40 mmHg or lower showed longer survival after PEG placement than those with PaCO2 40 mmHg or higher. In the present study, the cut-off level of PaCO2 for PEG placement in ALS patients was not determined (Table 3), but the PaCO2 level was found to be a significant prognostic factor by multivariate analysis (Table 4). Lower BMI, body weight loss (N 10% of premorbid weight), and serum levels of total protein, total cholesterol, HDL cholesterol, and LDL cholesterol showed no correlation with poor prognosis within 30 days and survival after PEG placement (Tables 1 and 3). Dorst et al. reported that mild weight loss (b 5 kg) and higher serum cholesterol at the time of PEG placement were associated with better survival [18)]. Several reports also revealed that hypercaloric enteral nutrition prolonged post-PEG survival [18,19]. Then aphagia before PEG placement is potentially a poor prognostic factor. ALS patients with age at onset older than 60 years showed a significantly shorter survival after PEG placement with the log-rank test (Table 3). Similar to our results, Chio et al. and Pena et al. reported that age at onset older than 60 or
55 years were a poor prognostic factor after PEG placement, respectively [11,15]. Duration from onset to PEG placement had no statistical impact for poor prognosis after PEG placement by Student's t-test (Table 1), but shorter duration from onset to PEG placement was significantly associated with shorter survival after PEG placement by multivariate analyses between two groups and survival after PEG placement (Tables 3 and 4). The average duration from onset to PEG placement of all ALS patients was 24.6 ± 22.7 months in this study. This result was almost the same as the duration in the previous reports [11,15,17]. Present study first revealed an association between duration from onset to PEG placement and survival after PEG placement (Tables 3 and 4), and this association had not been reported so far. It is speculated that the ALS patients who were required earlier PEG placement would show rapid disease progression. In addition, riluzole use was evaluated with regard to poor prognosis within 30 days (Tables 1 and 2) and survival after PEG placement (Tables 3 and 4). There was no significant difference between two groups by χ2-test (Table 1) and a multivariate analysis (Table 2). Kaplan-Meier survival analysis and a multivariate analysis for survival also showed no significant association between riluzole use and survival after PEG placement (Tables 3 and 4). These results might be influenced by a limited number of participants in this study. Present study has the technical limitation of being retrospective and observational, and data for parametric items were incomplete. However, this is the first report to identify the poor prognostic factors associated with early death and shorter survival after PEG placement in ALS patients. In conclusion, preoperative evaluation of indication for PEG placement in ALS patients should include both %FVC and PaCO2, as well as nutritional parameters, especially the existence of aphagia before PEG placement.
Table 3 Survival analysis after PEG placement by Kaplan-Meier method. Variables
# of cases
Median survival ± SD (months)
Log-rank (p value)
Gender (Male vs. Female) Site of onset (bulbar vs. spinal) Age at onset (≥60 vs. b60 years) Duration from onset to PEG placement (≥20 vs. b20 months) %FVC (≥50 vs. b50%) PaCO2 (≥35 vs. b35 mmHg) PaCO2 (≥40 vs. b40 mmHg) PaCO2 (≥55 vs. b55 mmHg) ALSFRS-R (≥20 vs. b20) Serum total protein (≥6.9 vs. b6.9 g/dl) Serum albumin (≥4.0 vs. b4.0 g/dl) Total cholesterol (≥205 vs. b205 mg/dl) HDL cholesterol (≥56 vs. b56 mg/dl) LDL cholesterol (≥119 vs. b119 mg/dl) Triglyceride (≥95 vs. b95 mg/dl) Riluzole use (Yes vs. No) Aphagia before PEG placement (Yes vs. No) BW loss (N10% of premorbid weight) (Yes vs. No) BMI (≥18.5 vs. b18.5 kg/m2)
73 73 73 73 51 68 68 68 35 102 98 89 54 82 59 60 63 25 53
9.0 ± 2.7 vs. 8.0 ± 2.1 8.0 ± 2.3 vs. 13.0 ± 3.7 4.0 ± 1.5 vs. 15.0 ± 0.9 15.0 ± 1.4 vs. 6.0 ± 1.6 11.0 ± 4.5 vs. 3.0 ± 1.3 8.0 ± 1.2 vs. 21.0 ± 15.5 8.0 ± 3.4 vs. 9.0 ± 2.4 1.0 ± 0.0 vs. 9.0 ± 2.4 9.0 ± 4.1 vs. 2.0 ± 1.1 8.0 ± 1.6 vs. 9.0 ± 7.3 13.0 ± 3.9 vs. 7.0 ± 2.1 9.0 ± 5.1 vs. 9.0 ± 2.5 13.0 ± 5.5 vs. 9.0 ± 1.9 6.0 ± 4.4 vs. 9.0 ± 2.8 9.0 ± 2.4 vs. 9.0 ± 6.1 11.0 ± 2.0 vs. 4.0 ± 2.6 2.0 ± 2.1 vs. 8.0 ± 1.1 9.0 ± 2.8 vs. 3.0 ± 5.5 8.0 ± 1.7 vs. 15.0 ± 3.0
0.681 0.118 0.008⁎ 0.007⁎ 0.005⁎ 0.803 0.879 0.068 0.081 0.074 0.077 0.356 0.799 0.892 0.467 0.488 0.188 0.925 0.200
PEG: percutaneous endoscopic gastrostomy, SD: standard deviations, FVC: forced vital capacity, PaCO2: arterial carbon dioxide pressure, ALSFRS-R: revised amyotrophic lateral sclerosis functional rating scale, BW: body weight, BMI: body mass index. ⁎ Indicates statistically significant (p b 0.05).
K. Nagashima et al. / Journal of the Neurological Sciences 376 (2017) 202–205
Declaration of interest The authors report that they have no conflicts of interest. Acknowledgements The authors thank the ALS patients for their participation in this study, and Dr. H. Fujita for suggestions about the statistical approach. This study was supported in part by Grants-in-Aid for Scientific Research (C) 16K09665 (to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan as well as Grant-in-Aid for Scientific Research (C) 26461264 (to M.I.) and (to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. References [1] H. Watanabe, N. Atsuta, R. Nakamura, A. Hirakawa, H. Watanabe, M. Ito, J. Senda, Y. Izumi, M. Morita, H. Tomiyama, A. Taniguchi, I. Aiba, K. Abe, K. Mizoguchi, M. Oda, O. Kano, K. Okamoto, S. Kuwabara, K. Hasegawa, T. Imai, M. Aoki, S. Tsuji, I. Nakano, R. Kaji, G. Sobue, Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients, Amyotroph. Lateral Scler. Frontotemporal Degener 16 (2015) 230–236. [2] M.C. Kiernan, S. Vucic, B.C. Cheah, M.R. Turner, A. Eisen, O. Hardiman, J.R. Burrell, M.C. Zoing, Amyotrophic lateral sclerosis, Lancet 377 (2011) 942–955. [3] H. Mitsumoto, M. Davidson, D. Moore, N. Gad, M. Brandis, S. Ringel, J. Rosenfeld, J.M. Shefner, R. Sufit, F.A. Anderson, ALS CARE Study Group, Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction, Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4 (2003) 177–185. [4] R.G. Miller, C.E. Jackson, E.J. Kasarskis, J.D. England, R.N. Forshew, W. Johnson, S. Kalra, J.S. Katz, H. Mitsumoto, J. Rosenfeld, C. Shoesmith, M.J. Strong, S.C. Woolley, Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the quality standards Subcommittee of the American Academy of Neurology, Neurology 73 (2009) 1218–1226. [5] P.M. Anderson, S. Abrahams, G.D. Borasio, M. de Carvalho, A. Chio, P. Van Damme, O. Hardiman, K. Kollewe, K.E. Morrison, S. Petri, P.F. Pradat, V. Silani, B. Tomik, M. Wasner, M. Weber, EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) – revised report of an EFNS task force, Eur. J. Neurol. 19 (2012) 360–375. [6] I. Nakano, et al., (Eds.), Practical Guideline for Amyotrophic Lateral Sclerosis (ALS), 2013, Societas Neurologica Japonica, Nankodo, Japan 2013, pp. 112–113. [7] B.R. Brooks, R.G. Miller, M. Swash, T.L. Munsat, World Federation of Neurology Research Group on Motor Neuron D, El Escorial revisited: revised criteria for the
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Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis Kazuaki Nagashima, Natsumi Furuta, Kouki Makioka, Yukio Fujita, Masaki Ikeda, Yoshio Ikeda ⁎ Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
a r t i c l e
i n f o
Article history: Received 9 November 2016 Received in revised form 20 February 2017 Accepted 20 March 2017 Available online 21 March 2017 Keywords: Amyotrophic lateral sclerosis Percutaneous endoscopic gastrostomy Aphagia before PEG placement PaCO2 Prognostic factors
a b s t r a c t A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30 days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO2) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement. © 2017 Elsevier B.V. All rights reserved.
1. Introduction
2. Patients and methods
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes death within a few years without artificial respiratory support [1,2]. The major symptoms of ALS include generalized muscle weakness and atrophy due to the degeneration of upper and lower motor neurons. The facial, oropharyngeal, and respiratory muscles are also involved, causing dysarthria, dysphagia, and respiratory failure. ALS patients with severe dysphagia have difficulty maintaining adequate oral nutrition, and may require an alternate means of intake. Percutaneous endoscopic gastrostomy (PEG) is a major alternative procedure for nutritional support of ALS patients with dysphagia, and can help maintain body weight [3]. PEG placement is recommended when the forced vital capacity (FVC) is over 50% of predicted value according to the guidelines of the American Academy of Neurology (AAN), the European Federation of Neurological Societies (EFNS), and the Japanese Society of Neurology (JSN) [4–6]. However, the relevant risk factors at the time of PEG placement in ALS patients are unclear. Poor prognostic factors associated with early death or shorter survival after PEG placement were analyzed in 102 ALS patients in this study.
A total of 102 patients diagnosed with definite, probable, or possible ALS according to the revised El Escorial criteria in whom PEG therapy was instituted between April 1999 and June 2016 in the Department of Neurology, Gunma University Hospital, were enrolled in this study [7]. The subjects were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30 days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics including gender, age at onset, site of onset, disease duration from onset to PEG placement, age at PEG placement, riluzole use, respiratory and nutritional conditions before PEG placement, and survival time from PEG placement to death or permanent mechanical ventilation, were retrospectively analyzed from medical records. These parameters were compared for the poor prognosis and good prognosis groups, and the poor prognostic factors associated with early death or permanent mechanical ventilation were statistically analyzed. This study was approved by the Ethical Committee of Gunma University Graduate School of Medicine. Written informed consent for PEG placement was obtained from all ALS patients. Quantitative clinical parameters analyzed in this study were as follows. Respiratory function was evaluated with FVC (% of predicted
⁎ Corresponding author. E-mail address: [email protected] (Y. Ikeda).
http://dx.doi.org/10.1016/j.jns.2017.03.029 0022-510X/© 2017 Elsevier B.V. All rights reserved.
K. Nagashima et al. / Journal of the Neurological Sciences 376 (2017) 202–205
value) and PaCO2. The severity of ALS status was evaluated with the revised ALS functional rating scale (ALSFRS-R) [8]. Nutritional status was evaluated with according to body weight loss (N 10% of premorbid weight), body mass index (BMI), serum total protein, albumin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels, and aphagia before PEG placement. Aphagia represents the patients who were unable to ingest any food or drink before PEG placement. 2.1. Statistical analysis Statistical analysis was conducted using SPSS®22 software (IBM Japan, Tokyo, Japan). Quantitative data were expressed as means ± standard deviations. Parameters in the poor prognosis and good prognosis groups were compared using an unpaired Student's t-test, and categorical variables were compared using the χ2-test. Multivariate analysis was performed between two groups using a logistic regression model. Survival analyses from PEG placement to death or permanent mechanical ventilation were demonstrated using the Kaplan-Meier survival analysis, and compared by log-rank test. Kaplan-Meier survival analysis and log-rank test were performed on each parameter for all patients whose medical information was available for analysis. The prognostic factors for PEG placement were evaluated with a Cox proportional hazards regression model. The level of statistical significance was set at p b 0.05. 3. Results The participants in this study included 56 males and 46 females. The site of onset was bulbar in 46 patients and spinal in 56 patients. Five patients died within 30 days after PEG placement, and two needed permanent mechanical ventilation within 30 days after PEG placement. Seven patients (6.9%) met the criteria of the poor prognosis group. 3.1. Poor prognostic factors within 30 days after PEG placement Clinical and laboratory characteristics of the two groups are shown in Table 1. Lower ALSFRS-R scores and aphagia before PEG placement were significantly associated with poor prognosis (ALSFRS-R: p b 0.05, aphagia before PEG placement: p b 0.05). Higher PaCO2, lower serum
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triglyceride, and older age at onset were associated with poor prognosis; however, these were not statistically significant. Multivariate analysis was performed for age at onset, PaCO2, aphagia before PEG placement, site of onset, and riluzole use using a logistic regression model. PaCO2 and aphagia before PEG placement were significantly associated with poor prognosis group (Table 2). 3.2. Prognostic risk factors for survival after PEG placement Kaplan-Meier survival analysis and log-rank test revealed that %FVC (≥ 50 vs. b50%), age at onset (≥ 60 vs. b60 years), and duration from onset to PEG placement (≥20 vs. b20 months) were significantly associated with survival (Table 3). On the other hand, gender, site of onset, PaCO2, aphagia before PEG placement, riluzole use, body weight loss (N10% of premorbid weight) and BMI were not significantly associated with survival after PEG placement (Table 3). Lower ALSFRS-R (b20) and lower serum albumin (b 4.0 g/dl) showed a tendency of having shorter survival after PEG placement, but these were not statistically significant. (Table 3). PaCO2 did not show a statistically significant association with survival from PEG placement to death with the log-rank test, but the Kaplan-Meier survival analysis for PaCO2 (cut-off levels ranged from 35% to 55%) showed a tendency for shorter median survival in patients with higher PaCO2 (Table 3). Finally, multivariate analysis of the prognostic factors after PEG placement was performed using a Cox proportional hazards regression model. This analysis demonstrated that PaCO2 and duration from onset to PEG placement were significantly associated with shorter survival (Table 4). 4. Discussion PEG placement is a standard alternative method used for feeding of ALS patients with severe dysphagia. In ALS patients, malnutrition is an independent prognostic factor, and nutritional support through a PEG tube helps maintain body weight and enables longer survival [3,9–12]. On the other hand, a subset of ALS patients have early death or respiratory failure immediately after PEG placement. However, poor prognostic factors or favorable timing for PEG placement have not been identified. This study included a large number of Japanese ALS patients in an investigation of prognostic factors after PEG placement. Poor prognosis group corresponds to 6.9% of all ALS patients in this study. This
Table 1 Comparisons of clinical and laboratory items between good and poor prognosis groups. Variables
Good prognosis (n = 95)
Poor prognosis (n = 7)
p value
Total (n = 102)
Gender (Male/Female) Site of onset (bulbar/spinal) Age at onset (years) Age at PEG placement (years) Duration from onset to PEG placement (months) %FVC (n = 73) PaCO2 (mmHg) (n = 95) ALSFRS-R (n = 56) Serum total protein (g/dl) (n = 102) Serum albumin (g/dl) (n = 98) Total cholesterol (mg/dl) (n = 89) HDL cholesterol (mg/dl) (n = 72) LDL cholesterol (mg/dl) (n = 82) Triglyceride (mg/dl) (n = 85) Riluzole use (Yes/No) (n = 102) Aphagia before PEG placement (Yes/No) (n = 85) BW loss (N10% of premorbid weight) (Yes/No) (n = 34) BMI (kg/m2) (n = 83)
52/43 44/51 61.2 ± 11.8 63.1 ± 11.5 25.2 ± 23.3 62.8 ± 23.4 (n = 67) 42.5 ± 5.8 (n = 88) 30.3 ± 8.5 (n = 53) 6.9 ± 0.6 (n = 95) 4.0 ± 0.5 (n = 91) 194.5 ± 39.9 (n = 83) 51.9 ± 13.8 (n = 68) 118.3 ± 31.2 (n = 77) 120.8 ± 60.8 (n = 80) 69/26 7/71 25/6 20.0 ± 3.4 (n = 78)
4/3 2/5 68.6 ± 11.6 70.1 ± 11.2 17.4 ± 12.5 56.2 ± 21.9 (n = 6) 46.7 ± 6.2 (n = 7) 15.0 ± 5.6 (n = 3) 6.7 ± 0.5 (n = 7) 3.9 ± 0.3 (n = 7) 216.7 ± 48.2 (n = 6) 61.7 ± 18.5 (n = 4) 119.4 ± 33.0 (n = 5) 72.0 ± 22.8 (n = 5) 3/4 3/4 3/0 19.2 ± 5.1 (n = 5)
0.90 (χ2) 0.66 (χ2) 0.11 0.12 0.39 0.51 0.07 p b 0.05⁎ 0.45 0.82 0.20 0.18 0.94 0.08 0.10 (χ2) p b 0.05 (χ2)⁎ 0.36 (χ2) 0.62
56/46 46/56 61.7 ± 11.8 63.6 ± 11.5 24.6 ± 22.7 62.2 ± 23.3 42.8 ± 5.9 29.5 ± 9.0 6.9 ± 0.6 4.0 ± 0.5 196.0 ± 40.5 52.4 ± 14.1 118.3 ± 31.1 117.9 ± 60.3 72/30 10/75 28/6 19.9 ± 3.5
Data are expressed by means ± standard deviations. PEG: percutaneous endoscopic gastrostomy, FVC: forced vital capacity, PaCO2: arterial carbon dioxide pressure, ALSFRS-R: revised amyotrophic lateral sclerosis functional rating scale, BW: body weight, BMI: body mass index, n = number, χ2: χ2 test. Poor prognosis: the patients who died or needed permanent mechanical ventilation within 30 days after PEG placement. Good prognosis: the patients who did not meet the criteria of the poor group. Qualitative data were expressed as number, and quantitative data were expressed as means ± standard deviations. ⁎ Indicates statistically significant (p b 0.05).
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Table 2 Multivariate analysis of the poor prognostic factors between good and poor prognosis groups. Variables
Odds ratio
95% CI
p value
Age at onset (years) PaCO2 (mmHg) Aphagia before PEG placement (Yes/No) Site of onset (spinal/bulbar) Riluzole use (No/Yes)
1.067 1.210 24.849 2.192 2.412
0.975–1.167 1.030–1.420 1.918–321.952 0.255–18.858 0.341–17.038
0.158 0.02⁎ 0.014⁎ 0.475 0.377
PaCO2: arterial carbon dioxide pressure, CI: confidence interval. ⁎ Indicates statistically significant (p b 0.05).
Table 4 Multivariate analysis of the poor prognostic factors for survival after PEG placement in all ALS patients.
Variables Duration from onset to PEG placement (months) PaCO2 (mmHg) Aphagia before PEG placement (Yes/No) Site of onset (bulbar/spinal) Riluzole use (No/Yes)
Hazard ratio
95% CI
p value
0.963
0.939–0.988 0.003⁎
1.102 1.892 1.484 1.119
1.043–1.165 0.807–4.434 0.849–2.591 0.629–1.991
0.001⁎ 0.142 0.166 0.701
PaCO2: arterial carbon dioxide pressure, CI: confidence interval. ⁎ Indicates statistically significant (p b 0.05).
result was comparable to the previous reports describing mortality within 30 days after PEG placement (2–25%) [11,13,14]. In our study, there were significant differences with PaCO2 and aphagia before PEG placement between good and poor prognosis groups on multivariate analysis (Table 2). Kasarskis et al. and Pena et al. previously reported that %FVC was the risk factor within 30 days mortality after PEG placement [14,15]. However, they did not evaluate PaCO2 and aphagia before PEG placement unlike our study. Shimizu et al. reported a significant association between death or permanent mechanical ventilation within 6 months after PEG placement and higher PaCO2 in their ALS patients [16]. Bokuta et al. also reported that the association between higher PaCO2 and shorter survival period was more significant than the association between lower %FVC and shorter survival period [17]. This report also showed that ALS patients with PaCO2 40 mmHg or lower showed longer survival after PEG placement than those with PaCO2 40 mmHg or higher. In the present study, the cut-off level of PaCO2 for PEG placement in ALS patients was not determined (Table 3), but the PaCO2 level was found to be a significant prognostic factor by multivariate analysis (Table 4). Lower BMI, body weight loss (N 10% of premorbid weight), and serum levels of total protein, total cholesterol, HDL cholesterol, and LDL cholesterol showed no correlation with poor prognosis within 30 days and survival after PEG placement (Tables 1 and 3). Dorst et al. reported that mild weight loss (b 5 kg) and higher serum cholesterol at the time of PEG placement were associated with better survival [18)]. Several reports also revealed that hypercaloric enteral nutrition prolonged post-PEG survival [18,19]. Then aphagia before PEG placement is potentially a poor prognostic factor. ALS patients with age at onset older than 60 years showed a significantly shorter survival after PEG placement with the log-rank test (Table 3). Similar to our results, Chio et al. and Pena et al. reported that age at onset older than 60 or
55 years were a poor prognostic factor after PEG placement, respectively [11,15]. Duration from onset to PEG placement had no statistical impact for poor prognosis after PEG placement by Student's t-test (Table 1), but shorter duration from onset to PEG placement was significantly associated with shorter survival after PEG placement by multivariate analyses between two groups and survival after PEG placement (Tables 3 and 4). The average duration from onset to PEG placement of all ALS patients was 24.6 ± 22.7 months in this study. This result was almost the same as the duration in the previous reports [11,15,17]. Present study first revealed an association between duration from onset to PEG placement and survival after PEG placement (Tables 3 and 4), and this association had not been reported so far. It is speculated that the ALS patients who were required earlier PEG placement would show rapid disease progression. In addition, riluzole use was evaluated with regard to poor prognosis within 30 days (Tables 1 and 2) and survival after PEG placement (Tables 3 and 4). There was no significant difference between two groups by χ2-test (Table 1) and a multivariate analysis (Table 2). Kaplan-Meier survival analysis and a multivariate analysis for survival also showed no significant association between riluzole use and survival after PEG placement (Tables 3 and 4). These results might be influenced by a limited number of participants in this study. Present study has the technical limitation of being retrospective and observational, and data for parametric items were incomplete. However, this is the first report to identify the poor prognostic factors associated with early death and shorter survival after PEG placement in ALS patients. In conclusion, preoperative evaluation of indication for PEG placement in ALS patients should include both %FVC and PaCO2, as well as nutritional parameters, especially the existence of aphagia before PEG placement.
Table 3 Survival analysis after PEG placement by Kaplan-Meier method. Variables
# of cases
Median survival ± SD (months)
Log-rank (p value)
Gender (Male vs. Female) Site of onset (bulbar vs. spinal) Age at onset (≥60 vs. b60 years) Duration from onset to PEG placement (≥20 vs. b20 months) %FVC (≥50 vs. b50%) PaCO2 (≥35 vs. b35 mmHg) PaCO2 (≥40 vs. b40 mmHg) PaCO2 (≥55 vs. b55 mmHg) ALSFRS-R (≥20 vs. b20) Serum total protein (≥6.9 vs. b6.9 g/dl) Serum albumin (≥4.0 vs. b4.0 g/dl) Total cholesterol (≥205 vs. b205 mg/dl) HDL cholesterol (≥56 vs. b56 mg/dl) LDL cholesterol (≥119 vs. b119 mg/dl) Triglyceride (≥95 vs. b95 mg/dl) Riluzole use (Yes vs. No) Aphagia before PEG placement (Yes vs. No) BW loss (N10% of premorbid weight) (Yes vs. No) BMI (≥18.5 vs. b18.5 kg/m2)
73 73 73 73 51 68 68 68 35 102 98 89 54 82 59 60 63 25 53
9.0 ± 2.7 vs. 8.0 ± 2.1 8.0 ± 2.3 vs. 13.0 ± 3.7 4.0 ± 1.5 vs. 15.0 ± 0.9 15.0 ± 1.4 vs. 6.0 ± 1.6 11.0 ± 4.5 vs. 3.0 ± 1.3 8.0 ± 1.2 vs. 21.0 ± 15.5 8.0 ± 3.4 vs. 9.0 ± 2.4 1.0 ± 0.0 vs. 9.0 ± 2.4 9.0 ± 4.1 vs. 2.0 ± 1.1 8.0 ± 1.6 vs. 9.0 ± 7.3 13.0 ± 3.9 vs. 7.0 ± 2.1 9.0 ± 5.1 vs. 9.0 ± 2.5 13.0 ± 5.5 vs. 9.0 ± 1.9 6.0 ± 4.4 vs. 9.0 ± 2.8 9.0 ± 2.4 vs. 9.0 ± 6.1 11.0 ± 2.0 vs. 4.0 ± 2.6 2.0 ± 2.1 vs. 8.0 ± 1.1 9.0 ± 2.8 vs. 3.0 ± 5.5 8.0 ± 1.7 vs. 15.0 ± 3.0
0.681 0.118 0.008⁎ 0.007⁎ 0.005⁎ 0.803 0.879 0.068 0.081 0.074 0.077 0.356 0.799 0.892 0.467 0.488 0.188 0.925 0.200
PEG: percutaneous endoscopic gastrostomy, SD: standard deviations, FVC: forced vital capacity, PaCO2: arterial carbon dioxide pressure, ALSFRS-R: revised amyotrophic lateral sclerosis functional rating scale, BW: body weight, BMI: body mass index. ⁎ Indicates statistically significant (p b 0.05).
K. Nagashima et al. / Journal of the Neurological Sciences 376 (2017) 202–205
Declaration of interest The authors report that they have no conflicts of interest. Acknowledgements The authors thank the ALS patients for their participation in this study, and Dr. H. Fujita for suggestions about the statistical approach. This study was supported in part by Grants-in-Aid for Scientific Research (C) 16K09665 (to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan as well as Grant-in-Aid for Scientific Research (C) 26461264 (to M.I.) and (to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. References [1] H. Watanabe, N. Atsuta, R. Nakamura, A. Hirakawa, H. Watanabe, M. Ito, J. Senda, Y. Izumi, M. Morita, H. Tomiyama, A. Taniguchi, I. Aiba, K. Abe, K. Mizoguchi, M. Oda, O. Kano, K. Okamoto, S. Kuwabara, K. Hasegawa, T. Imai, M. Aoki, S. Tsuji, I. Nakano, R. Kaji, G. Sobue, Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients, Amyotroph. Lateral Scler. Frontotemporal Degener 16 (2015) 230–236. [2] M.C. Kiernan, S. Vucic, B.C. Cheah, M.R. Turner, A. Eisen, O. Hardiman, J.R. Burrell, M.C. Zoing, Amyotrophic lateral sclerosis, Lancet 377 (2011) 942–955. [3] H. Mitsumoto, M. Davidson, D. Moore, N. Gad, M. Brandis, S. Ringel, J. Rosenfeld, J.M. Shefner, R. Sufit, F.A. Anderson, ALS CARE Study Group, Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction, Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4 (2003) 177–185. [4] R.G. Miller, C.E. Jackson, E.J. Kasarskis, J.D. England, R.N. Forshew, W. Johnson, S. Kalra, J.S. Katz, H. Mitsumoto, J. Rosenfeld, C. Shoesmith, M.J. Strong, S.C. Woolley, Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the quality standards Subcommittee of the American Academy of Neurology, Neurology 73 (2009) 1218–1226. [5] P.M. Anderson, S. Abrahams, G.D. Borasio, M. de Carvalho, A. Chio, P. Van Damme, O. Hardiman, K. Kollewe, K.E. Morrison, S. Petri, P.F. Pradat, V. Silani, B. Tomik, M. Wasner, M. Weber, EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) – revised report of an EFNS task force, Eur. J. Neurol. 19 (2012) 360–375. [6] I. Nakano, et al., (Eds.), Practical Guideline for Amyotrophic Lateral Sclerosis (ALS), 2013, Societas Neurologica Japonica, Nankodo, Japan 2013, pp. 112–113. [7] B.R. Brooks, R.G. Miller, M. Swash, T.L. Munsat, World Federation of Neurology Research Group on Motor Neuron D, El Escorial revisited: revised criteria for the
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