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Malnutrition at the time of diagnosis is associated with a shorter disease duration in ALS
Journal of the Neurological Sciences 297 (2010) 36–39
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Malnutrition at the time of diagnosis is associated with a shorter disease duration in ALS Nadège Limousin a,⁎, Hélène Blasco b,c, Philippe Corcia a,b, Paul H. Gordon d, Bertrand De Toffol a, Christian Andres b,c, Julien Praline a,b a
Centre SLA, Service de Neurologie et de Neurophysiologie Clinique, CHRU, Tours, France INSERM UMR 930, Université François-Rabelais, Tours, France Laboratoire de Biochimie et Biologie Moléculaire, CHRU, Tours, France d Centre SLA, Fédération des Maladies du Système Nerveux, Hôpital de la Salpétrière, Paris, France b c
a r t i c l e
i n f o
Article history: Received 28 April 2010 Received in revised form 24 June 2010 Accepted 30 June 2010 Available online 31 July 2010 Keywords: Amyotrophic lateral sclerosis Malnutrition Gastrostomy Body mass index Body weight
a b s t r a c t Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. During the course of the illness, malnutrition can occur and may shorten survival. The aim of our study was to determine whether clinical nutritional parameters that are used in daily practice are associated with prognosis and whether they can help guide therapeutic decisions. Methods: We retrospectively reviewed a cohort of ALS patients in our institution between January 2002 and January 2006. Clinical and demographic outcomes were compiled. To evaluate predictors of survival, we analyzed several clinical nutritional parameters available in daily practice (body mass index, weight loss exceeding 10% of premorbid weight at the time of diagnosis and during the course of the disease and the use of technical supports such as percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation). Results: Sixty-three patients were retrospectively studied. Thirteen patients had weight loss exceeding 10% of premorbid weight at the time of diagnosis and thirty patients had weight loss meeting this criterion at final examination. Weight loss exceeding 10% at the time of diagnosis was associated with a shorter duration of disease (17 ± 6 months versus 35± 26 months; p = 0.002). A linear correlation was found between mean disease duration and time between onset and diagnosis (p b 0.0001). The subgroup of patients with a PEG had a longer survival time than the other subgroup of patients (p = 0.02). Conclusions: In ALS patients, early and marked weight loss significantly predicts a worse prognosis. The percentage of premorbid weight loss is a suitable and useful measure that can be used in daily practice to identify patients with a poor prognosis. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by progressive degeneration of upper and lower motor neurons that has a median survival of approximately 36 months [1]. During the course of ALS, malnutrition and loss of weight, primarily due to loss of muscle tissue, are common and can have direct consequences on disease duration. The causes of malnutrition are multiple and include reduction in caloric and protein intake due to dysphagia or arm weakness and hypermetabolism, which leads to an increase in resting energy expenditure [2,3]. A more than seven-fold increased risk of death occurs in patients who become malnourished during the course of the disease [3]. Based on the results of experimental studies in animal models [4,5], altered lipid metabolism has been suspected to partially explain the observed hypermetabolism. In the ⁎ Corresponding author. Department of Neurology, CHRU, 2, boulevard Tonnellé, 37044 Tours Cedex, France. Tel.: +33 2 47 47 38 25; fax: +33 2 47 47 82 81. E-mail address: [email protected] (N. Limousin).
French ALS population, Dupuis et al. observed longer survivals in patients with hyperlipidemia [6], but this observation was not confirmed in an Italian cohort using a different method. However, Chio et al. found that respiratory impairment is related to lower blood lipid levels [7]. Thus, nutritional assessment is an important component of patient management. The body mass index (BMI), body weight and percentage of premorbid weight loss are all used to assess nutritional status [8]. The BMI has been used in large-scale nutrition surveys and epidemiologic studies of adults because it is easily administered and non-invasive. Recent data suggest that a single measure of BMI does not capture the significance of weight loss or reveal body composition changes [9]. Alternative methods, such as Mildram anthropometry, bioelectrical impedance analysis and dual-energy X-ray absorptiometry, have been used to assess body composition, but these techniques are not always available in daily practice. The aim of our study was to test several clinical nutritional parameters available in daily practice to determine their importance as prognostic factors for ALS.
0022-510X/$ – see front matter. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.06.028
N. Limousin et al. / Journal of the Neurological Sciences 297 (2010) 36–39
2. Methods One author (NL) reviewed the database records of all cases discharged from our centre between January 2002 and January 2006 with a diagnosis of definite or probable ALS according to the El Escorial criteria [10]. Cases with no regular follow-up in our centre (less than 2 examinations) were excluded. All patients were treated with riluzole. Non-invasive ventilation (NIV) was used in symptomatic patients based on consensus recommendations [11]. Data on gender, age at symptom onset, site of onset, familial history of ALS, time between onset and diagnosis, duration of disease, use of NIV and use of percutaneous endoscopic gastrostomy (PEG) tube were abstracted from the database. Disease onset was recorded as the time when the patient or relatives first noticed weakness. Disease duration was measured in months from symptom onset to death or tracheostomy. Because this study was retrospective, an ethical approval was not sought according to the French legislation. Data collected included self-reported body weight and BMI two years before diagnosis (t0), at diagnosis (t1) and at the final examination (t2). BMI was calculated according to the formula BMI=weight (kg)/height2 (m2) [3]. We determined the percentage change in weight and BMI between t0, t1 and t2. We examined subgroups of patients determined by premorbid weight loss exceeding 10% or BMI b 18.5 kg/m2 at t1 and t2. We compared differences in weights and BMI between time intervals using t-tests. A percentage of weight loss greater than 10% between t0 and t1 or a BMI b 18.5 kg/m2 defined malnutrition. We evaluated the relationship between disease duration and nutritional parameters (body weight, BMI, percentage of body weight loss and BMI variation at the different time points) using linear regression. We compared disease duration for subgroups of patients defined by premorbid weight loss exceeding 10% or BMI b 18.5 kg/m2 at t1 and at t2 with the others using Mann–Whitney tests. In order to determine the potential role of other factors on disease duration, we tested the association between disease duration and clinical characteristics (gender, age at onset, site of onset, use of NIV and use of PEG) using Mann–Whitney tests. Disease duration was compared between patients divided into two groups based on median age at onset. We tested the association between time between onset and diagnosis and the duration of disease using linear regression. Secondarily, in order to detect confounding factors in the two groups of patients defined by premorbid weight loss exceeding 10% at t1, we tested several parameters in each group using Mann–Whitney tests (age at onset and time between onset and diagnosis) and chi-square tests (gender, distribution of site of onset, use of PEG and use of NIV). The data were analyzed in a retrospective design. Data were stored in a computerized database, allowing for organized retrieval of data. Statistical significance was indicated by a p value b 0.05. 3. Results A total of 63 patients matching inclusion criteria were identified from our database. Diagnostic certainty was definite in 67% and probable in 33% of cases [10]. The clinical characteristics of our population are shown in Table 1. Five patients had missing data for time between onset and diagnosis. Six patients had a familial history of ALS. None had mutations of the SOD1 gene. Four patients had tracheostomies. Fifteen patients refused NIV and fifteen others refused PEG. Nutritional data are summarized in Table 1. Mean percentage of premorbid weight loss at t1 and at t2 was −3.93 ± 6.33% (95% confidence interval (CI) −2.36 to −5.49) and −8.94 ± 10.09% (95% CI −6.45 to −11.43), respectively. Mean percentages of premorbid BMI variation at the time of diagnosis and at final examination were +1.01 ± 1.65 (95% CI 0.6 to 1.42) and −3.28± 2.69% (95% CI − 2.62 to −3.95), respectively.
37
Table 1 Demographic, clinical characteristics, technical supports and nutritional data of ALS patients. Characteristic Demographic data Sex male (%) Age at symptoms onset (years) Bulbar onset (%) Clinical data Time between onset to diagnosis (months) Duration of the disease (months) Technical supports Use of NIV (%) Use of PEG (%) Nutritional data Premorbid body weight (kg) Premorbid BMI (kg/m2) Body weight at the time of diagnosis (kg) BMI at the time of diagnosis (kg/m2) Body weight at final examination (kg) BMI at final examination (kg/m2)
Total group 51 66 (12) 44 11 (10) 32 (25) 38 49 69 (12) 25 (4) 66 (12) 24 (4) 60 (12) 22 (6)
NIV, non-invasive ventilation; PEG, percutaneous endoscopic gastrostomy; BMI, body mass index. Data are expressed as mean (SD).
Thirteen (21%) patients (8 men and 5 women) had lost 10% of their premorbid weight at t1 (mean percentage weight loss: 14.53±3.84% (95% CI 12.45 to 16.62); mean variation BMI: −3.82±1.04 (95% CI −3.25 to −4.38)). At t2, 30 (48%) patients (12 men and 18 women) presented weight loss exceeding 10% of their premorbid weight (mean percentage weight loss: −17.55±5.73% (95% CI −15.50 to −19.60); mean variation BMI: −5.24±1.96 (95% CI −4.54 to −5.94)). At t1, no patient had a BMIb 18.5 kg/m2. At t2, nine patients had a BMIb 18.5 kg/m2. Mean weights significantly differed between t0 and t2 (p=4.7× 10− 5) and between t1 and t2 (p=4.1×10− 3) but not between t0 and t1 (p=0.19). Mean BMIs significantly differed at the same times (between t0 and t2 (p=1.9×10− 6) and between t1 and t2 (p=7.8×10− 4) but not between t0 and t1 (p=0.13)). There was no association between disease duration and body weight, BMI, the percentage of body weight and BMI variation between t0 and t1 or the percentage of body weight and BMI variation between t0 and t2 (p N 0.05). The mean disease duration was significantly shorter in the subgroup of patients with weight loss exceeding 10% at t1 than in other patients (p = 0.002). No significant difference was found for disease duration between the subgroup of patients with BMI b 18.5 kg/ m2 at t2 and other patients (Table 2). ALS patients using PEGs had longer disease durations than other patients (Table 2). Duration of disease was significantly longer (Mann– Whitney test, p = 0.02) in the subgroup of patients not malnourished at t1 using PEG but not in the subgroup of those malnourished at t1 (Mann–Whitney test, p = 0.52). A linear correlation was found between mean disease duration and time between onset and diagnosis (p b 0.0001). Clinical and demographic features (including gender, bulbar onset, age at onset, time from onset to diagnosis and use of PEG and NIV) of patients with weight loss exceeding 10% at t1 were similar to those features in other patients (data not shown). 4. Discussion We aimed to evaluate several available nutritional parameters as prognostic factors in ALS patients. Use of PEG and weight loss exceeding 10% at the time of diagnosis were associated with a shortened lifespan. In ALS, malnutrition is an independent factor for worse prognosis [3]. Usually, malnutrition is defined by one of the two following criteria: weight loss exceeding 10% or BMI b 18.5 kg/m2. Occurrence of malnutrition at all stages of the disease was similar in our population
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N. Limousin et al. / Journal of the Neurological Sciences 297 (2010) 36–39
Table 2 Results of Mann–Whitney test analyses of prognostic variables. Numbers of patients Disease duration, months P value Gender Male Female Age at onset N67 years b67 years Site of onset Bulbar onset Limb onset Nutritional status at t1 Loss weight N 10% Loss weight b 10% Nutritional status at t2 Loss weight N 10% Loss weight b 10% BMI b 18.5 kg/m2 BMI N 18.5 kg/m2 Technical supports Use of PEG Without PEG Use of NIV Without NIV
32 31
25 (13) 38 (31)
0.08
33 30
36 (31) 26 (13)
0.39
28 35
26 (14) 36 (30)
0.13
13 50
17 (6) 35 (26)
0.002
30 33 9 54
34 29 27 32
(22) (27) (11) (26)
0.054
33 30 38 25
38 24 28 36
(30) (13) (19) (32)
0.91
0.02 0.34
NIV, non-invasive ventilation; PEG, percutaneous endoscopic gastrostomy; BMI, body mass index. Data are expressed as mean (SD).
(48%) to other series that have ranged from 15 to 55% [12]. We did not find any correlation between reduced BMI and shortened survival; our data suggest that BMI cannot be used to predict the course of the disease. BMI may not be as good of an indicator of nutritional status in neuromuscular disease as weight loss [13–15]. Because patients with neuromuscular disease can be underweight due to muscle atrophy from the primary disease processes and from decreased food intake secondary to dysphagia, changes in the compartmentalized distribution of muscle and fat may not be reflected in the BMI [9]. Percentage weight loss is typically used to graphically translate weight changes in relation to premorbid body weight [9]. Previous studies have reported that a loss in weight exceeding 10% after PEG or during the course of the disease is a negative predictive factor in ALS but none had taken weight loss at the time of diagnosis into consideration [12,13]. The most powerful indicator of shortened disease duration in our study was weight loss exceeding 10% at the time of diagnosis. Time between onset of symptoms and diagnosis in these patients was not significantly different than in other patients. The simplicity of measuring body weight and its ability to assess nutritional status makes the measure of weight an important assessment of prognosis and guide for treatment decisions. These findings also support the hypothesis of early increased energy expenditure in some ALS patients who need special care and follow-up [4]. Among all patients in our study, prognosis was better in those who used a PEG than in those who did not, as previously shown in other studies [16]. This benefit was only seen in the subgroup of patients not malnourished at the time of diagnosis and not in the subgroup of patients malnourished at the time of diagnosis. This result was not our primary outcome measure and should be interpreted with caution. This result might be also due to some confounding factors like time to PEG placement or reasons for PEG placement. Some retrospective studies suggest that PEG placement might be performed too late in the course of the disease to be helpful [17]. Although practice parameters exist in the United States and Europe, the optimal timing for PEG placement is not yet known [18]. We did not find any effect of NIV on survival. Use of NIV usually improves the survival and quality of life of ALS patients [19]. Our negative results may result from poor compliance with NIV or from a small sample size that rendered the study under-powered to detect a small benefit of NIV.
A shorter delay from symptom onset to diagnosis was associated with a worse prognosis, a finding that is consistent with the results of other studies [17,20,21] and probably reflects a more aggressive course and thus a disease that is easier to diagnose. The main limitations of this study are its retrospective nature and a reporting system that lacked standardization of premorbid weight and height assessments. However, in previous studies, self-reports of weight and height have been highly correlated with measured values [22]. In our ALS centre, all patients are asked to recall their weight two years prior the diagnosis at admission to assess premorbid weight. The second important limitation is the small sample of patients and their enrollment in a clinic rather than in a population-based manner. In addition, our database did not include patients with possible or suspected ALS and the study considered only patients followed in our centre. Nevertheless, our sample seems to be representative of the general ALS population. Age at onset, disease duration, and time between onset and diagnosis were comparable to these characteristics in other series. The percentage of bulbar-onset patients (44%) was slightly higher than the ratio with bulbar onset reported elsewhere in the published literature [17,21,23,24], and there is no explanation for this high number. Patients with bulbar onset had poorer survival and more swallowing problems than those with spinal onset [20,21,25]. This high rate of bulbar-onset patients did not affect our results because among malnourished patients at the time of diagnosis, there were no more patients with bulbar onset than limb onset. Our study suggested that premorbid weight loss exceeding 10% at the time of diagnosis is related to a poor prognosis in patients with ALS. This measure was more sensitive than the BMI in this study. A positive effect of PEG was seen in the whole group, but we did not find this result in the subgroup of patients with weight loss exceeding 10% at the time of diagnosis. 5. Conclusions Few studies have examined ALS patients' weight over the course of their illness. ALS patients with weight loss exceeding 10% at the time of diagnosis seem to have shorter disease duration in our preliminary retrospective study. A more detailed, larger, longitudinal study might be warranted to confirm our results and to determine causes of weight loss and the effect of specific nutritional management in those patients. Disclosure The authors have reported no conflict of interest. References [1] Mitsumoto H, Chad DA, Pioro EP. Course and prognosis. Amyotrophic lateral sclerosis. Philadelphia, PA: Davis; 1998. [2] Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr 1996;63:130–7. [3] Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Nutritional status is a prognostic factor for survival in ALS patients. Neurology 1999;53: 1059–63. [4] Dupuis L, Oudart H, René F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a highenergy diet in a transgenic mouse model. Proc Natl Acad Sci USA 2004;101: 11159–64. [5] Mattson MP, Cutler RG, Camandola S. Energy intake and amyotrophic lateral sclerosis. Neuromolecular Med 2007;9:17–20. [6] Dupuis L, Corcia P, Fergani A, Gonzalez De Aguilar JL, Bonnefont-Rousselot D, Bittar R, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004–9. [7] Chiò A, Calvo A, Ilardi A, Cavallo E, Moglia C, Mutani R, Palmo A, Galletti R, Marinou K, Papetti L, Mora G. Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology 2009;73:1681–5. [8] Kasarskis EJ, Neville HE. Management of ALS: nutritional care. Neurology 1996;47: S118–20. [9] Rio A, Cawadias E. Nutritional advice and treatment by dietitians to patients with amyotrophic lateral sclerosis/motor neurone disease: a survey of current practice in England, Wales, Northern Ireland and Canada. J Hum Nutr Diet 2007;20:3–13.
N. Limousin et al. / Journal of the Neurological Sciences 297 (2010) 36–39 [10] Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 1994;124 S:96–107. [11] Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, et al. 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 2009;73:1218–26. [12] Mazzini L, Corrà T, Zaccala M, Mora G, Del Piano M, Galante M. Percutaneous endoscopic gastrostomy and enteral nutrition in amyotrophic lateral sclerosis. J Neurol 1995;242:695–8. [13] Chiò A, Finocchiaro E, Meineri P, Bottacchi E, Schiffer D. Safety and factors related to survival after percutaneous endoscopic gastrostomy in ALS. ALS Percutaneous Endoscopic Gastrostomy Study Group. Neurology 1999;53:1123–5. [14] Kasarskis EJ, Scarlata D, Hill R, Fuller C, Stambler N, Cedarbaum JM. A retrospective study of percutaneous endoscopic gastrostomy in ALS patients during the BDNF and CNTF trials. J Neurol Sci 1999;169:118–25. [15] Pessolano FA, Súarez AA, Monteiro SG, Mesa L, Dubrovsky A, Roncoroni AJ, De Vito EL. Nutritional assessment of patients with neuromuscular diseases. Am J Phys Med Rehabil 2003;82:182–5. [16] Chiò A, Mora G, Leone M, Mazzini L, Cocito D, Giordana MT, et al. Piemonte and Valle d'Aosta Register for ALS (PARALS). Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 2002;59:99–103. [17] Czaplinski A, Yen AA, Simpson EP, Appel SH. Slower disease progression and prolonged survival in contemporary patients with amyotrophic lateral sclerosis: is
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the natural history of amyotrophic lateral sclerosis changing? Arch Neurol 2006;63:1139–43. Ludolph AC. 135th ENMC International Workshop: nutrition in amyotrophic lateral sclerosis 18–20 of March 2005, Naarden, The Netherlands. Neuromuscul Disord 2006;16:530–8. Piepers S, van den Berg JP, Kalmijn S, van der Pol WL, Wokke JH, Lindeman E, van den Berg LH. Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature. Amyotroph Lateral Scler 2006;7:195–200. del Aguila MA, Longstreth Jr WT, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003;60: 813–9. Zoccolella S, Beghi E, Palagano G, Fraddosio A, Guerra V, Samarelli V, et al. SLAP Registry. Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 2008;79:33–7. Stevens J, Keil JE, Waid LR, Gazes PC. Accuracy of current, 4-year, and 28-year selfreported body weight in an elderly population. Am J Epidemiol 1990;132: 1156–63. Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996–2000. J Neurol Neurosurg Psychiatry 2003;74:1258–61. Mandrioli J, Faglioni P, Nichelli P, Sola P. Amyotrophic lateral sclerosis: prognostic indicators of survival. Amyotroph Lateral Scler 2006;7:211–20. Forbes RB, Colville S, Cran GW. Scottish Motor Neurone Disease Register. Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease. J Neurol Neurosurg Psychiatry 2004;75:1753–5.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Malnutrition at the time of diagnosis is associated with a shorter disease duration in ALS Nadège Limousin a,⁎, Hélène Blasco b,c, Philippe Corcia a,b, Paul H. Gordon d, Bertrand De Toffol a, Christian Andres b,c, Julien Praline a,b a
Centre SLA, Service de Neurologie et de Neurophysiologie Clinique, CHRU, Tours, France INSERM UMR 930, Université François-Rabelais, Tours, France Laboratoire de Biochimie et Biologie Moléculaire, CHRU, Tours, France d Centre SLA, Fédération des Maladies du Système Nerveux, Hôpital de la Salpétrière, Paris, France b c
a r t i c l e
i n f o
Article history: Received 28 April 2010 Received in revised form 24 June 2010 Accepted 30 June 2010 Available online 31 July 2010 Keywords: Amyotrophic lateral sclerosis Malnutrition Gastrostomy Body mass index Body weight
a b s t r a c t Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. During the course of the illness, malnutrition can occur and may shorten survival. The aim of our study was to determine whether clinical nutritional parameters that are used in daily practice are associated with prognosis and whether they can help guide therapeutic decisions. Methods: We retrospectively reviewed a cohort of ALS patients in our institution between January 2002 and January 2006. Clinical and demographic outcomes were compiled. To evaluate predictors of survival, we analyzed several clinical nutritional parameters available in daily practice (body mass index, weight loss exceeding 10% of premorbid weight at the time of diagnosis and during the course of the disease and the use of technical supports such as percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation). Results: Sixty-three patients were retrospectively studied. Thirteen patients had weight loss exceeding 10% of premorbid weight at the time of diagnosis and thirty patients had weight loss meeting this criterion at final examination. Weight loss exceeding 10% at the time of diagnosis was associated with a shorter duration of disease (17 ± 6 months versus 35± 26 months; p = 0.002). A linear correlation was found between mean disease duration and time between onset and diagnosis (p b 0.0001). The subgroup of patients with a PEG had a longer survival time than the other subgroup of patients (p = 0.02). Conclusions: In ALS patients, early and marked weight loss significantly predicts a worse prognosis. The percentage of premorbid weight loss is a suitable and useful measure that can be used in daily practice to identify patients with a poor prognosis. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by progressive degeneration of upper and lower motor neurons that has a median survival of approximately 36 months [1]. During the course of ALS, malnutrition and loss of weight, primarily due to loss of muscle tissue, are common and can have direct consequences on disease duration. The causes of malnutrition are multiple and include reduction in caloric and protein intake due to dysphagia or arm weakness and hypermetabolism, which leads to an increase in resting energy expenditure [2,3]. A more than seven-fold increased risk of death occurs in patients who become malnourished during the course of the disease [3]. Based on the results of experimental studies in animal models [4,5], altered lipid metabolism has been suspected to partially explain the observed hypermetabolism. In the ⁎ Corresponding author. Department of Neurology, CHRU, 2, boulevard Tonnellé, 37044 Tours Cedex, France. Tel.: +33 2 47 47 38 25; fax: +33 2 47 47 82 81. E-mail address: [email protected] (N. Limousin).
French ALS population, Dupuis et al. observed longer survivals in patients with hyperlipidemia [6], but this observation was not confirmed in an Italian cohort using a different method. However, Chio et al. found that respiratory impairment is related to lower blood lipid levels [7]. Thus, nutritional assessment is an important component of patient management. The body mass index (BMI), body weight and percentage of premorbid weight loss are all used to assess nutritional status [8]. The BMI has been used in large-scale nutrition surveys and epidemiologic studies of adults because it is easily administered and non-invasive. Recent data suggest that a single measure of BMI does not capture the significance of weight loss or reveal body composition changes [9]. Alternative methods, such as Mildram anthropometry, bioelectrical impedance analysis and dual-energy X-ray absorptiometry, have been used to assess body composition, but these techniques are not always available in daily practice. The aim of our study was to test several clinical nutritional parameters available in daily practice to determine their importance as prognostic factors for ALS.
0022-510X/$ – see front matter. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.06.028
N. Limousin et al. / Journal of the Neurological Sciences 297 (2010) 36–39
2. Methods One author (NL) reviewed the database records of all cases discharged from our centre between January 2002 and January 2006 with a diagnosis of definite or probable ALS according to the El Escorial criteria [10]. Cases with no regular follow-up in our centre (less than 2 examinations) were excluded. All patients were treated with riluzole. Non-invasive ventilation (NIV) was used in symptomatic patients based on consensus recommendations [11]. Data on gender, age at symptom onset, site of onset, familial history of ALS, time between onset and diagnosis, duration of disease, use of NIV and use of percutaneous endoscopic gastrostomy (PEG) tube were abstracted from the database. Disease onset was recorded as the time when the patient or relatives first noticed weakness. Disease duration was measured in months from symptom onset to death or tracheostomy. Because this study was retrospective, an ethical approval was not sought according to the French legislation. Data collected included self-reported body weight and BMI two years before diagnosis (t0), at diagnosis (t1) and at the final examination (t2). BMI was calculated according to the formula BMI=weight (kg)/height2 (m2) [3]. We determined the percentage change in weight and BMI between t0, t1 and t2. We examined subgroups of patients determined by premorbid weight loss exceeding 10% or BMI b 18.5 kg/m2 at t1 and t2. We compared differences in weights and BMI between time intervals using t-tests. A percentage of weight loss greater than 10% between t0 and t1 or a BMI b 18.5 kg/m2 defined malnutrition. We evaluated the relationship between disease duration and nutritional parameters (body weight, BMI, percentage of body weight loss and BMI variation at the different time points) using linear regression. We compared disease duration for subgroups of patients defined by premorbid weight loss exceeding 10% or BMI b 18.5 kg/m2 at t1 and at t2 with the others using Mann–Whitney tests. In order to determine the potential role of other factors on disease duration, we tested the association between disease duration and clinical characteristics (gender, age at onset, site of onset, use of NIV and use of PEG) using Mann–Whitney tests. Disease duration was compared between patients divided into two groups based on median age at onset. We tested the association between time between onset and diagnosis and the duration of disease using linear regression. Secondarily, in order to detect confounding factors in the two groups of patients defined by premorbid weight loss exceeding 10% at t1, we tested several parameters in each group using Mann–Whitney tests (age at onset and time between onset and diagnosis) and chi-square tests (gender, distribution of site of onset, use of PEG and use of NIV). The data were analyzed in a retrospective design. Data were stored in a computerized database, allowing for organized retrieval of data. Statistical significance was indicated by a p value b 0.05. 3. Results A total of 63 patients matching inclusion criteria were identified from our database. Diagnostic certainty was definite in 67% and probable in 33% of cases [10]. The clinical characteristics of our population are shown in Table 1. Five patients had missing data for time between onset and diagnosis. Six patients had a familial history of ALS. None had mutations of the SOD1 gene. Four patients had tracheostomies. Fifteen patients refused NIV and fifteen others refused PEG. Nutritional data are summarized in Table 1. Mean percentage of premorbid weight loss at t1 and at t2 was −3.93 ± 6.33% (95% confidence interval (CI) −2.36 to −5.49) and −8.94 ± 10.09% (95% CI −6.45 to −11.43), respectively. Mean percentages of premorbid BMI variation at the time of diagnosis and at final examination were +1.01 ± 1.65 (95% CI 0.6 to 1.42) and −3.28± 2.69% (95% CI − 2.62 to −3.95), respectively.
37
Table 1 Demographic, clinical characteristics, technical supports and nutritional data of ALS patients. Characteristic Demographic data Sex male (%) Age at symptoms onset (years) Bulbar onset (%) Clinical data Time between onset to diagnosis (months) Duration of the disease (months) Technical supports Use of NIV (%) Use of PEG (%) Nutritional data Premorbid body weight (kg) Premorbid BMI (kg/m2) Body weight at the time of diagnosis (kg) BMI at the time of diagnosis (kg/m2) Body weight at final examination (kg) BMI at final examination (kg/m2)
Total group 51 66 (12) 44 11 (10) 32 (25) 38 49 69 (12) 25 (4) 66 (12) 24 (4) 60 (12) 22 (6)
NIV, non-invasive ventilation; PEG, percutaneous endoscopic gastrostomy; BMI, body mass index. Data are expressed as mean (SD).
Thirteen (21%) patients (8 men and 5 women) had lost 10% of their premorbid weight at t1 (mean percentage weight loss: 14.53±3.84% (95% CI 12.45 to 16.62); mean variation BMI: −3.82±1.04 (95% CI −3.25 to −4.38)). At t2, 30 (48%) patients (12 men and 18 women) presented weight loss exceeding 10% of their premorbid weight (mean percentage weight loss: −17.55±5.73% (95% CI −15.50 to −19.60); mean variation BMI: −5.24±1.96 (95% CI −4.54 to −5.94)). At t1, no patient had a BMIb 18.5 kg/m2. At t2, nine patients had a BMIb 18.5 kg/m2. Mean weights significantly differed between t0 and t2 (p=4.7× 10− 5) and between t1 and t2 (p=4.1×10− 3) but not between t0 and t1 (p=0.19). Mean BMIs significantly differed at the same times (between t0 and t2 (p=1.9×10− 6) and between t1 and t2 (p=7.8×10− 4) but not between t0 and t1 (p=0.13)). There was no association between disease duration and body weight, BMI, the percentage of body weight and BMI variation between t0 and t1 or the percentage of body weight and BMI variation between t0 and t2 (p N 0.05). The mean disease duration was significantly shorter in the subgroup of patients with weight loss exceeding 10% at t1 than in other patients (p = 0.002). No significant difference was found for disease duration between the subgroup of patients with BMI b 18.5 kg/ m2 at t2 and other patients (Table 2). ALS patients using PEGs had longer disease durations than other patients (Table 2). Duration of disease was significantly longer (Mann– Whitney test, p = 0.02) in the subgroup of patients not malnourished at t1 using PEG but not in the subgroup of those malnourished at t1 (Mann–Whitney test, p = 0.52). A linear correlation was found between mean disease duration and time between onset and diagnosis (p b 0.0001). Clinical and demographic features (including gender, bulbar onset, age at onset, time from onset to diagnosis and use of PEG and NIV) of patients with weight loss exceeding 10% at t1 were similar to those features in other patients (data not shown). 4. Discussion We aimed to evaluate several available nutritional parameters as prognostic factors in ALS patients. Use of PEG and weight loss exceeding 10% at the time of diagnosis were associated with a shortened lifespan. In ALS, malnutrition is an independent factor for worse prognosis [3]. Usually, malnutrition is defined by one of the two following criteria: weight loss exceeding 10% or BMI b 18.5 kg/m2. Occurrence of malnutrition at all stages of the disease was similar in our population
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N. Limousin et al. / Journal of the Neurological Sciences 297 (2010) 36–39
Table 2 Results of Mann–Whitney test analyses of prognostic variables. Numbers of patients Disease duration, months P value Gender Male Female Age at onset N67 years b67 years Site of onset Bulbar onset Limb onset Nutritional status at t1 Loss weight N 10% Loss weight b 10% Nutritional status at t2 Loss weight N 10% Loss weight b 10% BMI b 18.5 kg/m2 BMI N 18.5 kg/m2 Technical supports Use of PEG Without PEG Use of NIV Without NIV
32 31
25 (13) 38 (31)
0.08
33 30
36 (31) 26 (13)
0.39
28 35
26 (14) 36 (30)
0.13
13 50
17 (6) 35 (26)
0.002
30 33 9 54
34 29 27 32
(22) (27) (11) (26)
0.054
33 30 38 25
38 24 28 36
(30) (13) (19) (32)
0.91
0.02 0.34
NIV, non-invasive ventilation; PEG, percutaneous endoscopic gastrostomy; BMI, body mass index. Data are expressed as mean (SD).
(48%) to other series that have ranged from 15 to 55% [12]. We did not find any correlation between reduced BMI and shortened survival; our data suggest that BMI cannot be used to predict the course of the disease. BMI may not be as good of an indicator of nutritional status in neuromuscular disease as weight loss [13–15]. Because patients with neuromuscular disease can be underweight due to muscle atrophy from the primary disease processes and from decreased food intake secondary to dysphagia, changes in the compartmentalized distribution of muscle and fat may not be reflected in the BMI [9]. Percentage weight loss is typically used to graphically translate weight changes in relation to premorbid body weight [9]. Previous studies have reported that a loss in weight exceeding 10% after PEG or during the course of the disease is a negative predictive factor in ALS but none had taken weight loss at the time of diagnosis into consideration [12,13]. The most powerful indicator of shortened disease duration in our study was weight loss exceeding 10% at the time of diagnosis. Time between onset of symptoms and diagnosis in these patients was not significantly different than in other patients. The simplicity of measuring body weight and its ability to assess nutritional status makes the measure of weight an important assessment of prognosis and guide for treatment decisions. These findings also support the hypothesis of early increased energy expenditure in some ALS patients who need special care and follow-up [4]. Among all patients in our study, prognosis was better in those who used a PEG than in those who did not, as previously shown in other studies [16]. This benefit was only seen in the subgroup of patients not malnourished at the time of diagnosis and not in the subgroup of patients malnourished at the time of diagnosis. This result was not our primary outcome measure and should be interpreted with caution. This result might be also due to some confounding factors like time to PEG placement or reasons for PEG placement. Some retrospective studies suggest that PEG placement might be performed too late in the course of the disease to be helpful [17]. Although practice parameters exist in the United States and Europe, the optimal timing for PEG placement is not yet known [18]. We did not find any effect of NIV on survival. Use of NIV usually improves the survival and quality of life of ALS patients [19]. Our negative results may result from poor compliance with NIV or from a small sample size that rendered the study under-powered to detect a small benefit of NIV.
A shorter delay from symptom onset to diagnosis was associated with a worse prognosis, a finding that is consistent with the results of other studies [17,20,21] and probably reflects a more aggressive course and thus a disease that is easier to diagnose. The main limitations of this study are its retrospective nature and a reporting system that lacked standardization of premorbid weight and height assessments. However, in previous studies, self-reports of weight and height have been highly correlated with measured values [22]. In our ALS centre, all patients are asked to recall their weight two years prior the diagnosis at admission to assess premorbid weight. The second important limitation is the small sample of patients and their enrollment in a clinic rather than in a population-based manner. In addition, our database did not include patients with possible or suspected ALS and the study considered only patients followed in our centre. Nevertheless, our sample seems to be representative of the general ALS population. Age at onset, disease duration, and time between onset and diagnosis were comparable to these characteristics in other series. The percentage of bulbar-onset patients (44%) was slightly higher than the ratio with bulbar onset reported elsewhere in the published literature [17,21,23,24], and there is no explanation for this high number. Patients with bulbar onset had poorer survival and more swallowing problems than those with spinal onset [20,21,25]. This high rate of bulbar-onset patients did not affect our results because among malnourished patients at the time of diagnosis, there were no more patients with bulbar onset than limb onset. Our study suggested that premorbid weight loss exceeding 10% at the time of diagnosis is related to a poor prognosis in patients with ALS. This measure was more sensitive than the BMI in this study. A positive effect of PEG was seen in the whole group, but we did not find this result in the subgroup of patients with weight loss exceeding 10% at the time of diagnosis. 5. Conclusions Few studies have examined ALS patients' weight over the course of their illness. ALS patients with weight loss exceeding 10% at the time of diagnosis seem to have shorter disease duration in our preliminary retrospective study. A more detailed, larger, longitudinal study might be warranted to confirm our results and to determine causes of weight loss and the effect of specific nutritional management in those patients. Disclosure The authors have reported no conflict of interest. References [1] Mitsumoto H, Chad DA, Pioro EP. Course and prognosis. Amyotrophic lateral sclerosis. Philadelphia, PA: Davis; 1998. [2] Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr 1996;63:130–7. [3] Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Nutritional status is a prognostic factor for survival in ALS patients. Neurology 1999;53: 1059–63. [4] Dupuis L, Oudart H, René F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a highenergy diet in a transgenic mouse model. Proc Natl Acad Sci USA 2004;101: 11159–64. [5] Mattson MP, Cutler RG, Camandola S. Energy intake and amyotrophic lateral sclerosis. Neuromolecular Med 2007;9:17–20. [6] Dupuis L, Corcia P, Fergani A, Gonzalez De Aguilar JL, Bonnefont-Rousselot D, Bittar R, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004–9. [7] Chiò A, Calvo A, Ilardi A, Cavallo E, Moglia C, Mutani R, Palmo A, Galletti R, Marinou K, Papetti L, Mora G. Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology 2009;73:1681–5. [8] Kasarskis EJ, Neville HE. Management of ALS: nutritional care. Neurology 1996;47: S118–20. [9] Rio A, Cawadias E. Nutritional advice and treatment by dietitians to patients with amyotrophic lateral sclerosis/motor neurone disease: a survey of current practice in England, Wales, Northern Ireland and Canada. J Hum Nutr Diet 2007;20:3–13.
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