- Email: [email protected]
Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients
Accepted Manuscript Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients Yongsoon Park, Jinhee Park, Yeonsun Kim, Heejoon Baek, Seung Hyun Kim PII:
S0899-9007(15)00244-0
DOI:
10.1016/j.nut.2015.05.025
Reference:
NUT 9553
To appear in:
Nutrition
Received Date: 27 January 2015 Revised Date:
8 April 2015
Accepted Date: 27 May 2015
Please cite this article as: Park Y, Park J, Kim Y, Baek H, Kim SH, Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients, Nutrition (2015), doi: 10.1016/j.nut.2015.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Association between nutritional status and disease severity using the amyotrophic
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lateral sclerosis (ALS) functional rating scale in ALS patients
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Yongsoon Park1*, Jinhee Park1†, Yeonsun Kim1, Heejoon Baek2, Seung Hyun Kim3*
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Department of Food and Nutrition, Hanyang University, Seoul, Korea
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Department of Food and Nutrition Services, Hanyang University Hospital, Seoul, Korea
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Department of Neurology, Hanyang University Hospital, Seoul, Korea
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This author contributed equally to this work as the first author.
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*Correspondence to: Professor Yongsoon Park; Department of Food and Nutrition, College
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of Human Ecology, Hanyang University, Wangsimni-ro 222, Seongdong-gu, Seoul 133-791,
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South Korea; (Tel) +82-2-2220-1205; (Fax) +82-2-2220-1856; (E-mail)
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[email protected]; Seung Hyun Kim, Department of Neurology, Hanyang University
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Hospital, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-792, South Korea; (Email)
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[email protected]
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ACCEPTED MANUSCRIPT Abstract
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Objective: The nutritional status of patients with amyotrophic lateral sclerosis (ALS) has
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been shown to be associated with mortality. However, there have not been any studies on the
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association between nutritional status and disease severity. The present study investigated the
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hypothesis that nutritional status was negatively associated with disease severity using the
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ALS functional rating scale (ALSFRS-R).
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Methods: One hundred ninety-three Korean ALS patients were divided into tertiles based on
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their ALSFRS-R score. Dietary intake was measured using 24-h recall and nutritional status
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was determined by body mass index (BMI) and geriatric nutritional risk index (GNRI).
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Results: BMI and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-
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R. BMI and GNRI also correlated with ALSFRS-R score, bulbar score, albumin levels, total
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lymphocyte count, and total daily energy expenditure. Intakes of energy and most nutrients
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were significantly lower in patients in the lowest tertiles of ALSFRS-R, but significances
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disappeared after adjusting for energy intake. Intakes of vegetables, grains, seasonings, and
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oils were also significantly lower in patients in the lowest tertile of ALSFRS-R. In addition,
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patients in the lowest tertile of ALSFRS-R were significantly younger at the disease onset,
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had a longer duration of ALS, less regular exercise, and less sun exposure.
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Conclusion: Nutritional status, as assessed by BMI and GNRI, was negatively associated with
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disease severity using ALSFRS-R. The present study suggested that intake of nutrients
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decreases with disease progression in ALS patients.
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Keywords: Amyotrophic lateral sclerosis, Revised ALS functional rating scale, Body mass
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index, Geriatric nutritional risk index, Dietary intake
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Introduction Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), is a fatal
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neurodegenerative disease which progressively impairs motor neurons in the brain and spinal
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cord by unknown molecular mechanisms [1]. The severity of ALS can be assessed using the
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revised ALS functional rating scale (ALSFRS-R), which reflects the degree of neurological
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deficit [2]. ALS progresses at different rates among patients who have had ALS for a similar
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duration or exhibit similar ALSFRS-R scores. However, age at onset, onset site, time
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between onset and diagnosis, sex, nutritional state, and respiratory functions may all be
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factors that affect disease progression [3-5].
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Despite numerous clinical trials and advances in our understanding of ALS [6], there
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has been no reliable pharmacologic treatments to stop or reverse its course. Riluzol, the only
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Food and Drug Administration (FDA) approved drug for ALS, has no effect on disease onset
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but prolongs survival by 2 to 3 months [7].
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On the other hand, nutritional management constitutes an important therapeutic
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strategy to retard ALS progress, mortality, and improve the patient’s quality of life [8, 9].
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ALS patients with active disease status commonly experience altered nutritional status
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mainly due to difficulty swallowing by muscle atrophy, placing them at high risk of
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malnutrition [10, 11]. The increased nutritional needs by hyper-metabolism that often
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accompany ALS with unknown reason exacerbate the often already poor nutritional status
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[12]. Malnutrition, described as body mass index (BMI) lower than 18.5 kg/m2, was observed
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in 8-19% of ALS patients. A low BMI increases the risk of death up to 7.7-fold [13, 14].
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Previous studies have suggested a role of nutrient intake on the risk of ALS onset and
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the mortality due to ALS. However, there has not been a study on the association between
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nutritional status and disease severity. The present study investigated the hypothesis that
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nutritional status was negatively associated with disease severity using the ALSFRS-R score
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in Korean ALS patients.
3 Patients and Methods
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Patients
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One hundred ninety-three patients were recruited from the ALS outpatient clinic at
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Hanyang University Hospital between October 2012 and December 2013. ALS was defined
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and confirmed by a neurologist according to the revised El Escorial criteria [15]. Patients
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with a nasogastric tube or percutaneous endoscopic gastrostomy (PEG) were excluded. This
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study was conducted according to guidelines laid out in the Declaration of Helsinki and all
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procedures involving human subjects were approved by the Institutional Review Board of
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Hanyang University (HYI-12-036). Written informed consent was obtained from all patients
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prior to enrollment in the study.
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Disease severity
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Patients were interviewed to collect the information such as exercise habits, frequency of sun exposure, smoking status, drinking status, supplement intake and family
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medical history. Medical charts of patients were reviewed to obtain the ALSFRS-R score, age
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at onset, time between onset and diagnosis, duration of the disease, and onset site. Severity of
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the disease was quantitatively assessed by ALSFRS-R, which consists of 12 questions that
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evaluates the ability of performing activities of daily living of ALS patients ranging from 0
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(total limitation) to 48 points (normal) [2, 3]. The bulbar score was calculated as a subscale as
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the mean score of the 3 questions in the ALSFRS-R that correspond to bulbar function
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(speaking, salivation, and swallowing).
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Biochemical and anthropometric measurements Height was obtained from medical charts. Weight was measured using an InBody 720 (Biospace Corporation, Seoul, Korea). Fasting blood sugar, total protein, albumin, urea
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nitrogen (BUN), creatinine and total cholesterol levels were measured using the Hitachi 7600
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automatic biochemical analyzer (Hitachi Ltd., Tokyo, Japan). Albumin was measured by
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bromocresol green method. Hemoglobin, hematocrit, and total lymphocyte count (TLC) were
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analyzed using the Sysmex XE-2100 automated blood cell counter (Sysmex, Kobe, Japan).
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Nutritional status measurements
BMI was categorized into four groups based on Western Pacific Region of WHO
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criteria: <18.5, underweight; 18.5 to 22.9, normal; 23.0 to 24.9, overweight; and ≥25, obese
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[16]. Underweight patients were considered to be exhibiting malnutrition [10]. Geriatric
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nutritional risk index (GNRI) was also used to assess nutritional status because ALS patients
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have similar difficulties in chewing and swallowing as the elderly population [17]. GNRI was
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categorized into four groups of malnutrition risk: <82, high risk; 82 to <92, moderate risk; 92
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to 98, low risk; >98, no risk. GNRI was calculated by [1.489 × albumin (g/L)] + [41.7 ×
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(weight/ideal weight)]. Ideal weight (in kg) was calculated from the equations of Lorentz:
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height (cm) - 100 - [(height (cm) - 150)/4] for a man and height (cm) - 100 - [(Height (cm) -
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150)/2.5] for a woman. Weight/ideal weight was set to 1 when the ratio was over 1 [18, 19].
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Dietary intake was obtained by a registered dietitian using 24-h recall from patients
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or caregivers preparing meals if a patient was unable to speak. Nutrients evaluated were
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chosen in reference to the Dietary Reference Intakes (DRIs) and analyzed by Can-Pro version
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4.0 (Computer Aided Nutritional analysis Program for professionals, Korean Nutrition
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Society, Seoul, Korea).
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expenditure [20], but has not been satisfactory for ALS patients mainly due to the hyper-
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metabolism of ALS patients [21]. Thus, total daily energy expenditure (TDEE) was
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calculated by combined use of the Harris-Benedict equation and the total score of the 6
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questions in the ALSFRS-R that related to physical activity (speech, handwriting, dressing
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and hygiene, turning in bed and adjusting bed clothes, walking, dyspnea) [22].
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7 Statistical analysis
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Data analysis was performed using the statistical software package SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables are presented as the mean ±
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standard error of mean (SEM) and differences were verified with Duncan’s multiple range
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test after running a one-way ANOVA test. Qualitative variables were presented as number of
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patients and percentage of distribution and differences were determined by a chi-square test.
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For dietary intake evaluation, an ANCOVA test was run after adjusting for sex, age at onset,
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BMI, duration of the disease, exercise habits, and sun exposure. Pearson’s correlation was
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calculated to determine the relationship between variables. A p value of <0.05 was regarded
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as significant.
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Results
Characteristics of patients according to tertiles of ALSFRS-R are shown in Table 1.
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Total and bulbar scores were significantly different among the tertiles of ALSFRS-R. Patients
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in the lowest tertile of ALSFRS-R were significantly younger at onset, had ALS for a longer
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duration, exercises less regularly, and had less sun exposure compared with those in the
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middle and highest tertile of ALSFRS-R. Blood albumin level and total lymphocyte count
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were also significantly lower in patients in the lowest tertile of ALSFRS-R. Although there 6
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supplements (Table 1). Types of dietary supplements were following: multivitamins (21.2%),
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vitamin C (14.5%), vitamin E (6.2%), Ca (6.2%), vitamin B complex (5.7%), vitamin A
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(1.6%), vitamin D (1.6%), Zn (1.0%), and Se (1.0%) in the entire ALS patients. There were
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no significant differences in regard to sex, age, time between onset and diagnosis, site of
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onset, family history of ALS, smoking, drinking, or other biochemical parameters.
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Body weight, BMI, and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-R, but height did not differ (Table 2). Consistently, there were more
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patients with underweight and moderate risk of malnutrition in the lowest tertile of ALSFRS-
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R as compared with the middle and/or highest tertile of ALSFRS-R. BMI was significantly
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correlated with ALSFRS-R (r=0.330, P<0.001), bulbar score (r=0.291, P<0.001), albumin
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(r=0.150, P<0.05), creatinine (r=0.206, P<0.01), BUN (r=0.239, P<0.01), TLC (r=0.250,
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P<0.01), and TDEE (r=0.620, P<0.001) after adjusting for sex, age at ALS onset, site of
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onset, duration of disease, exercise, exercise time, and sun exposure (Data not shown). In
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addition, GNRI was significantly correlated with ALSFRS-R (r=0.421, P<0.001), bulbar
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score (r=0.368, P<0.001), BMI (r=0.775, P<0.001), blood total protein (r=0.485, P<0.001),
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albumin (r= 0.737, P<0.001), total cholesterol (r=0.218, P<0.01), hemoglobin (r=0.294,
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P<0.001), hematocrit (r=0.268, P<0.001), TLC (r=0.298, P<0.001), and TDEE (r=0.588,
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P<0.001).
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Intakes of vegetables, grains, seasonings, and oils were significantly lower in patients
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in the lowest tertile (Fig 1). However, intakes of fruits, beans, meats, seafood, seaweeds, eggs,
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dairy products, mushrooms, and seeds did not significantly differ among groups. Intakes of
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energy, carbohydrates, fat, protein, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B6,
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niacin, folate, calcium, phosphorus, sodium, potassium, iron, zinc, copper, and manganese
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were significantly lower in patients in the lowest tertiles compared with patients in the 7
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disappeared after adjusting for energy intake. There were significantly more patients in the
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lowest tertile of ALSFRS-R consuming less than 75% of the KDRIs for energy, protein, fiber,
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vitamin K, vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folate, phosphorus,
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sodium, potassium, iron, zinc, copper, manganese, and selenium.
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Discussion
This was the first study to show that nutritional status was negatively associated with
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disease severity using ALSFRS-R in Korean patients with ALS. In the present study, nutritional status was evaluated by BMI and GNRI, which was significantly lower in the
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patients in lowest tertile (based on ALSFRS-R score). Patients with underweight and
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malnutrition were observed more frequently in the lowest tertile of ALSFRS-R as compared
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with middle and highest tertiles. Both BMI and GNRI were significantly correlated with
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ALSFRS-R, biochemical parameters, and daily energy expenditure in the present study,
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suggesting that nutritional status decline as ALS progressed.
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Our study suggested that GNRI is a helpful tool to assess nutritional status in ALS patients. GNRI is a predictor of nutritional-related complications and muscle dysfunction in
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elderly people [19, 23].
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Patients with ALS were observed to experience a progressive reduction in BMI as
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the time of death approached [30]. In addition, underweight ALS patients were reported to
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have a higher mortality [13, 14]. In the present study, underweight patients were only 1-3% in
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the middle and highest tertiles of ALSFRS-R, but comprised 21% in the tertile with the most
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severe ALS. Dysphagia is a well-known symptom of the illness and a decline of food intake
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might be anticipated in ALS patients with progressive oropharyngeal weakness [1]. In close
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agreement with previous studies [24, 25], our results also showed that most of ALS patients 8
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recommended to consume more energy than their estimated needs due to hyper-metabolism
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[26]. Patients who consumed less than the recommended intake for energy increased from 54%
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in the tertile of patients with the least severe ALS to 79% in the tertile of patients with the
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most severe ALS. In addition, intake of most nutrients decreased as the disease progressed,
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but a lower intake of nutrients was likely due to the less intake energy because significances
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disappeared after adjusting for energy intake. Enteral nutrition resulted in an increase in the
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weight in ALS patients who underwent percutaneous endoscopic gastrostomy [11] and tube
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feeding of a hypercaloric formula [27]. In ALS animal models, a caloric dense diet promotes
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mitochondrial function, survival, and delay of disease onset, suggesting that higher caloric
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diets may help retard the progression of ALS [26, 28, 29].
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Consistent with the decreased intake of energy and nutrients, patients in the lowest tertile of ALSFRS-R consumed fewer vegetables, grains, seasonings, oils and meats than
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medium or highest tertiles, but higher amounts of fruits and beans. ALS patients may modify
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their eating pattern because they need to eat cautiously and slowly. Modifying the texture of
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the food to yield soft, semisolid, or semiliquid states with a high water content, such as
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jellified water or sucking cubes, are suggested as better alternative to thinner liquids and can
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help alleviate aspiration [30]. In the present study, bean intake was mostly due to tofu, which
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has soft texture and is easy to chew.
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In the present study, intake of vitamin D was less than recommended in patients in all
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ALSFRS-R score tertiles, and was the lowest in the lowest tertile. Vitamin D deficiency has
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been shown to accelerate functional decline and has been associated with a greater incidence
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of fractures and mortality in ALS patients [31, 32].
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This study had a few limitations. Because of the cross-sectional study design, we were unable to establish a cause-effect relationship between the risk of malnutrition and 9
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ALSFRS-R score. Second, a number of potential confounders were adjusted for statistically;
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however, there is a possibility that other factors affecting the risk of malnutrition and
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ALSFRS-R score exists. Last, only mild to moderate stage of patients were enrolled in the
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present study.
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Nutritional status, evaluated by BMI and GNRI, was worst in patients in the lowest tertile of ALSFRS-R and correlated with ALSFRS-R, bulbar score, albumin, total
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lymphocyte count, and total daily energy expenditure. Intakes of total energy and most
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nutrients were also lower in patients in the lowest tertiles of ALSFRS-R. However, future
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clinical trials are necessary to confirm whether the prevention of malnutrition slows the
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progression of ALS.
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Acknowledgements
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This work was supported by the Korea Research Foundation (2012R1A2040553) and the Center for Women in Science, Engineering and Technology (WISET) Grant (KW-2014-
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PPD-0056) funded by the Ministry of Science, ICT & Future Planning of Korea (MSIP).
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ACCEPTED MANUSCRIPT Table 1 Characteristics of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)1 Tertile of ALSFRS-R score Lowest (n=65)
Middle (n=61)
≤36
37-41
29.40 ± 0.78a
39.31 ± 0.19b
8.94 ± 0.27a
ALSFRS-R score
Highest (n=67)
P-value
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≥42
<0.0012
10.54 ± 0.17b
11.36 ± 0.15c
<0.001
53.91 ± 1.34
57.44 ± 1.26
53.75 ± 1.29
0.085
Sex, Male, n (%)
42 (64.6)
36 (59.0)
42 (62.7)
0.806
Age at onset (y)
50.52 ± 1.34a
55.30 ± 1.30b
51.82 ± 1.31ab
0.035
Onset to diagnosis (mon)
17.29 ± 2.85
11.08 ± 1.22
11.83 ± 1.40
0.056
Duration of ALS (mon)
39.33 ± 3.61a
22.75 ± 1.85b
22.14 ± 2.28b
<0.001
14 (21.5)
9 (14.8)
13 (19.4)
0.6093
1(1.5)
0 (0.0)
1 (1.5)
0.627
22 (33.8)
36 (59.0)
52 (77.6)
<0.001
33 (50.8)
43 (70.5)
60 (89.6)
<0.001
Smoking, n (%)
7 (10.8)
2 (3.3)
7 (10.4)
0.212
Drinking, n (%)
11 (16.9)
7 (11.5)
14 (20.9)
0.451
Dietary supplement, n (%)
34 (52.3)
44 (72.1)
45 (67.2)
0.053
Glucose (mmol/L)
6.63 ± 0.22
6.30 ± 0.19
6.56 ± 0.26
0.5662
41.86 ± 0.51a
43.52 ± 0.47b
44.93 ± 0.47c
<0.001
5.13 ± 0.30
5.21 ± 0.19
5.23 ± 0.17
0.953
65.37 ± 1.96
66.79 ± 1.62
0.636
Bulbar (range 0-12)
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Age (y)
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ALS family history, n (%) Exercise, n (%)4
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Sun exposure, n (%)
Albumin (g/L) Urea nitrogen (mmol/L) Creatinine (µmol/L)
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44.10 ± 0.20c
Total (range 0-48)
61.20 ± 7.03
ACCEPTED MANUSCRIPT Hemoglobin (g/L)
140.91 ± 2.16
138.34 ± 1.54
141.43 ± 1.94
0.484
Hematocrit (%)
42.15 ± 0.60
40.93 ± 0.43
41.82 ± 0.53
0.254
Cholesterol (mmol/L)
4.84 ± 0.13
4.89 ± 0.10
4.98 ± 0.12
0.669
TLC5 (×109/L)
2.02 ± 0.08a
2.00 ± 0.08a
2.28 ± 0.08b
0.031
Values are presented as the mean ± SEM or number of patients (percentage distribution), as
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appropriate. 2Values with different superscripts in the same row are significantly different at P<0.05 by one way ANOVA followed by Duncan's multiple range test. 3Differences were
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analyzed using chi-square test at P<0.05. 4> 1 time/week. 5Total lymphocyte count
ACCEPTED MANUSCRIPT Table 2 Nutritional status of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)1 Tertile of ALSFRS-R score P-value
Middle (n=61)
Highest (n=67)
≤36
37≤to≤41
≥42
Height (cm)
165.78 ± 0.89
162.80 ± 1.20
164.41 ± 0.930
0.1212
Weight (kg)
58.46 ± 1.29b
60.70 ± 1.36ab
63.45 ± 1.23a
0.0232
BMI (kg/m2)3
21.22 ± 0.40b
22.84 ± 0.44a
23.38 ± 0.33a
<0.0012
14 (21.5)
Normal, n (%)
36 (55.4)
Overweight, n (%)
7 (10.8)
Obese, n (%)
8 (12.3)
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1(1.6)
2(3.0)
35(57.4)
31(46.3) <0.0014
12(19.7)
15(22.4)
13(21.3)
19(28.4)
102.10 ± 1.19a
107.54 ± 1.09b
110.64 ± 0.94c
39 (60.0)
52(85.2)
63(94.0)
17 (26.2)
8(13.1)
4(6.0)
Moderate risk, n (%)
8(12.3)
1(1.6)
0
High risk, n (%)
1(1.5)
0
0
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<0.0012
<0.0014
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Low risk, n (%)
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Underweight, n (%)
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Lowest (n=65)
Values are presented as the mean ± SEM or number of patients (percentage distribution), as
appropriate. 2Values with different superscripts in the same row are significantly different at P<0.05 by one way ANOVA followed by Duncan's multiple range test. 3Body mass index was categorized into four groups based on Western Pacific Region of WHO criteria; <18.5, underweight; 18.5 to 22.9, normal; 23 to 24.9, overweight; ≥25, obese. 4Differences were analyzed using chi-square test at P<0.05.
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Geriatric nutritional risk index; < 82, high risk; 82 to < 92, moderate risk; 92 to 98, low
risk; >98, no risk. GNRI was calculated by [1.489 × albumin (g/L)] + [41.7 × (weight/ideal weight)]. Ideal weight was calculated with the equations of Lorentz: height (cm) - 100 [(height (cm) - 150)/4] for man and height (cm) - 100 - [(Height (cm) - 150)/2.5] for
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woman.
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Table 3
Tertile of ALSFRS-R score Middle (n=61)
Highest (n=67)
Variables 37≤to≤41
≤36 Intakes1
N (%)
Intakes
Energy (Kcal/d)
1229±54
51(78.5)2
1475±53
Carbohydrate (g/d)
195.0±9.1
-
240.6±8.9
Lipid (g/d)
28.5±2.5
-
31.7±2.4
Protein (g/d)
49.1±3.3
39(60.0)3
Fiber (g/d)
16.2±1.1 688.0±73.9
Vitamin D (µg/d)
3.9±0.8
Vitamin E (mg/d)
9.4±0.9
Vitamin K (µg/d)
149.2±27.3
P-value5
P-value6
≥42
N (%)
N (%)
37(60.7)
1621±51
36(53.7)
<0.001
0.010
-
251.3±8.6
-
<0.001
-
-
39.0±2.1
-
0.008
-
57.8±3.2
25(41.0)
68.3±3.1
27(40.3)
<0.001
0.039
39(60.0)4
19.6±1.0
25(41.0)
20.6±1.0
27(40.3)
0.278
0.039
34(52.3)3
696.4±72.0
25(41.0)
759.7±69.4
24(35.8)
0.741
0.149
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Vitamin A (µg RE/d)
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Lowest (n=65)
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Dietary intake of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)
53(81.5)4
2.5±0.9
51(83.6)
4.1±0.8
51(76.1)
0.011
0.542
30(46.2)4
11.6±0.8
17(27.9)
13.6±0.8
20(29.9)
0.003
0.057
19(29.2)4
219.7±26.6
6(9.8)
213.9±25.6
9(13.4)
0.151
0.009
35(53.8)3
1.1±0.1
23(37.7)
1.4±0.1
21(31.3)
0.004
0.026
Vitamin B2 (mg/d)
0.8±0.2
48(73.8)3
1.04±0.2
38(62.3)
1.6±0.2
30(44.8)
0.010
0.003
Niacin (mg NE/d)
11.1±0.9
39(60.0)3
13.4±0.9
21(34.4)
16.1±0.9
23(34.3)
<0.001
0.003
Vitamin B6 (mg/d)
1.1±0.1
31(47.7)3
1.5±0.1
15(24.6)
1.7±0.6
17(25.4)
0.004
0.006
Folate (µg DFE/d)
388.2±31.1
26(40.0)3
477.1±30.4
11(18.0)
515.8±29.3
0.017
0.004
Vitamin B12 (µg/d)
7.6±1.3
20(30.8)3
8.8±1.3
5(8.2)
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12(17.9)
9.7±1.3
6(9.0)
0.511
<0.001
Vitamin C (mg/d)
80.8±10.2
41(63.1)3
94.3±9.9
31(50.8)
97.6±9.5
33(49.3)
0.500
0.223
Calcium (mg/d)
348.7±35.1
52(80.0)3
421.9±34.2
47(77.0)
497.7±32.9
46(68.7)
0.013
0.294
Phosphorus (mg/d)
774.1±50.3
17(26.2)3
940.5±49.1
6(9.8)
1064.3±47.3
3(4.5)
<0.001
0.001
Sodium (g/d)
2.8±2.4
8(12.3)4
3.8±2.3
1(1.6)
4.1±0.2
0(0)
<0.001
0.001
Potassium (g/d)
2.1±0.1
51(78.5)4
2.5±0. 1
32(52.5)
2.74±0.13
35(52.2)
0.006
0.002
Magnesium (mg/d)
71.5±7.0
64(98.5) 3
63.8±6. 8
61(100.0)
77.2±6.5
67(100)
0.353
0.372
Iron (mg/d)
11.3±0.9
Zinc (mg/d)
7.5±0.5
Copper (mg/d)
0.9±0.1
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0.8±0.1
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Vitamin B1 (mg/d)
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ACCEPTED MANUSCRIPT
19(29.2)3
13.8±0.9
5(8.2)
15.5±0.9
2(3.0)
0.007
<0.001
26(40.0)3
9.1±0.5
11(18.0)
10.4±0.4
13(19.4)
<0.001
0.006
17(26.2)3
1.1±0.1
9(14.8)
1.2±0.1
5(7.5)
0.014
0.013
ACCEPTED MANUSCRIPT
Iodine (µg /d) Selenium (µg/d)
2.9±0.2
35(53.8)4
106.1±224.1
43(66.2)3
87.5±5.2
16(24.6)3
3.6±0.2 533.8±218. 75.2±5.4
19(31.1)
3.92±0.20
19(28.4)
0.007
0.005
41(67.2)
665.4±119.5
39(58.2)
0.204
0.504
8(13.1)
87.5±5.2
0.066
0.038
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Manganese (mg/d)
6(9.0)
Values are presented as the mean ± SEM. 2Number of patients (%) consuming less than 75% of the Korean estimated energy requirement.
3
Number of patients (%) consuming less than 75% of the Korean estimated average requirement. 4Number of patients (%) consuming less than
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75% of the Korean adequate intake. 5Differences were calculated by ANCOVA after adjusting for sex, age at ALS onset, body mass index,
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duration of the disease, exercise and sun exposure at P<0.05. 6Differences were analyzed using chi-square test at P<0.05.
ACCEPTED MANUSCRIPT
350
70
p=0.013
300
60
p=0.012
50 40
150
30 p=0.314
100
20
50
10
0 Grains
M AN U
0
Vegetables
Fruits
Beans
p=0.404
Beverages
Potatoes
Seasonings
Sugars
10
p=0.776
9
p=0.057
100 80 60
p=0.224
20 0 Meats
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40
Sea foods
p=0.663
7 p=0.419
6 5 4
EP
P=057
p=0.007
8
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p=0.683
Dairy products
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p=0.02
p=0.490
200
g/d
p=0.457
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g/d
250
120
p=0.482
p=0.228
3 2 1 0 Eggs
Oils
Seeds
Seaweeds
Mushrooms
Fig. 1 Daily intake of food in patients with myotophic lageral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R). Differences were calculated by ANCOVA after adjusting for sex, age at ALS onset, body mass index and duration of the disease at P<0.05; Highest tertile;
Medium tertile;
Lowest tertile
ACCEPTED MANUSCRIPT Highlights Nutritional status, evaluated by BMI and GNRI, was worst in the lower score of amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) in Korean ALS
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patients. Nutritional status correlated with ALSFRS-R, bulbar score, albumin, total lymphocyte count, and total daily energy expenditure in Korean ALS patients.
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Intakes of total energy and most nutrients were decreased in Korean ALS patients with
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lower score of ALSFRS-R.
S0899-9007(15)00244-0
DOI:
10.1016/j.nut.2015.05.025
Reference:
NUT 9553
To appear in:
Nutrition
Received Date: 27 January 2015 Revised Date:
8 April 2015
Accepted Date: 27 May 2015
Please cite this article as: Park Y, Park J, Kim Y, Baek H, Kim SH, Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients, Nutrition (2015), doi: 10.1016/j.nut.2015.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 2
Association between nutritional status and disease severity using the amyotrophic
3
lateral sclerosis (ALS) functional rating scale in ALS patients
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Yongsoon Park1*, Jinhee Park1†, Yeonsun Kim1, Heejoon Baek2, Seung Hyun Kim3*
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Department of Food and Nutrition, Hanyang University, Seoul, Korea
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2
Department of Food and Nutrition Services, Hanyang University Hospital, Seoul, Korea
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3
Department of Neurology, Hanyang University Hospital, Seoul, Korea
†
This author contributed equally to this work as the first author.
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*Correspondence to: Professor Yongsoon Park; Department of Food and Nutrition, College
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of Human Ecology, Hanyang University, Wangsimni-ro 222, Seongdong-gu, Seoul 133-791,
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South Korea; (Tel) +82-2-2220-1205; (Fax) +82-2-2220-1856; (E-mail)
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[email protected]; Seung Hyun Kim, Department of Neurology, Hanyang University
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Hospital, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-792, South Korea; (Email)
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[email protected]
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ACCEPTED MANUSCRIPT Abstract
2
Objective: The nutritional status of patients with amyotrophic lateral sclerosis (ALS) has
3
been shown to be associated with mortality. However, there have not been any studies on the
4
association between nutritional status and disease severity. The present study investigated the
5
hypothesis that nutritional status was negatively associated with disease severity using the
6
ALS functional rating scale (ALSFRS-R).
7
Methods: One hundred ninety-three Korean ALS patients were divided into tertiles based on
8
their ALSFRS-R score. Dietary intake was measured using 24-h recall and nutritional status
9
was determined by body mass index (BMI) and geriatric nutritional risk index (GNRI).
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Results: BMI and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-
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R. BMI and GNRI also correlated with ALSFRS-R score, bulbar score, albumin levels, total
12
lymphocyte count, and total daily energy expenditure. Intakes of energy and most nutrients
13
were significantly lower in patients in the lowest tertiles of ALSFRS-R, but significances
14
disappeared after adjusting for energy intake. Intakes of vegetables, grains, seasonings, and
15
oils were also significantly lower in patients in the lowest tertile of ALSFRS-R. In addition,
16
patients in the lowest tertile of ALSFRS-R were significantly younger at the disease onset,
17
had a longer duration of ALS, less regular exercise, and less sun exposure.
18
Conclusion: Nutritional status, as assessed by BMI and GNRI, was negatively associated with
19
disease severity using ALSFRS-R. The present study suggested that intake of nutrients
20
decreases with disease progression in ALS patients.
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Keywords: Amyotrophic lateral sclerosis, Revised ALS functional rating scale, Body mass
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index, Geriatric nutritional risk index, Dietary intake
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ACCEPTED MANUSCRIPT 1
Introduction Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), is a fatal
3
neurodegenerative disease which progressively impairs motor neurons in the brain and spinal
4
cord by unknown molecular mechanisms [1]. The severity of ALS can be assessed using the
5
revised ALS functional rating scale (ALSFRS-R), which reflects the degree of neurological
6
deficit [2]. ALS progresses at different rates among patients who have had ALS for a similar
7
duration or exhibit similar ALSFRS-R scores. However, age at onset, onset site, time
8
between onset and diagnosis, sex, nutritional state, and respiratory functions may all be
9
factors that affect disease progression [3-5].
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Despite numerous clinical trials and advances in our understanding of ALS [6], there
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has been no reliable pharmacologic treatments to stop or reverse its course. Riluzol, the only
12
Food and Drug Administration (FDA) approved drug for ALS, has no effect on disease onset
13
but prolongs survival by 2 to 3 months [7].
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On the other hand, nutritional management constitutes an important therapeutic
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strategy to retard ALS progress, mortality, and improve the patient’s quality of life [8, 9].
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ALS patients with active disease status commonly experience altered nutritional status
17
mainly due to difficulty swallowing by muscle atrophy, placing them at high risk of
18
malnutrition [10, 11]. The increased nutritional needs by hyper-metabolism that often
19
accompany ALS with unknown reason exacerbate the often already poor nutritional status
20
[12]. Malnutrition, described as body mass index (BMI) lower than 18.5 kg/m2, was observed
21
in 8-19% of ALS patients. A low BMI increases the risk of death up to 7.7-fold [13, 14].
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Previous studies have suggested a role of nutrient intake on the risk of ALS onset and
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the mortality due to ALS. However, there has not been a study on the association between
24
nutritional status and disease severity. The present study investigated the hypothesis that
3
ACCEPTED MANUSCRIPT 1
nutritional status was negatively associated with disease severity using the ALSFRS-R score
2
in Korean ALS patients.
3 Patients and Methods
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Patients
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One hundred ninety-three patients were recruited from the ALS outpatient clinic at
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Hanyang University Hospital between October 2012 and December 2013. ALS was defined
8
and confirmed by a neurologist according to the revised El Escorial criteria [15]. Patients
9
with a nasogastric tube or percutaneous endoscopic gastrostomy (PEG) were excluded. This
10
study was conducted according to guidelines laid out in the Declaration of Helsinki and all
11
procedures involving human subjects were approved by the Institutional Review Board of
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Hanyang University (HYI-12-036). Written informed consent was obtained from all patients
13
prior to enrollment in the study.
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Disease severity
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Patients were interviewed to collect the information such as exercise habits, frequency of sun exposure, smoking status, drinking status, supplement intake and family
18
medical history. Medical charts of patients were reviewed to obtain the ALSFRS-R score, age
19
at onset, time between onset and diagnosis, duration of the disease, and onset site. Severity of
20
the disease was quantitatively assessed by ALSFRS-R, which consists of 12 questions that
21
evaluates the ability of performing activities of daily living of ALS patients ranging from 0
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(total limitation) to 48 points (normal) [2, 3]. The bulbar score was calculated as a subscale as
23
the mean score of the 3 questions in the ALSFRS-R that correspond to bulbar function
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(speaking, salivation, and swallowing).
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Biochemical and anthropometric measurements Height was obtained from medical charts. Weight was measured using an InBody 720 (Biospace Corporation, Seoul, Korea). Fasting blood sugar, total protein, albumin, urea
4
nitrogen (BUN), creatinine and total cholesterol levels were measured using the Hitachi 7600
5
automatic biochemical analyzer (Hitachi Ltd., Tokyo, Japan). Albumin was measured by
6
bromocresol green method. Hemoglobin, hematocrit, and total lymphocyte count (TLC) were
7
analyzed using the Sysmex XE-2100 automated blood cell counter (Sysmex, Kobe, Japan).
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Nutritional status measurements
BMI was categorized into four groups based on Western Pacific Region of WHO
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criteria: <18.5, underweight; 18.5 to 22.9, normal; 23.0 to 24.9, overweight; and ≥25, obese
12
[16]. Underweight patients were considered to be exhibiting malnutrition [10]. Geriatric
13
nutritional risk index (GNRI) was also used to assess nutritional status because ALS patients
14
have similar difficulties in chewing and swallowing as the elderly population [17]. GNRI was
15
categorized into four groups of malnutrition risk: <82, high risk; 82 to <92, moderate risk; 92
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to 98, low risk; >98, no risk. GNRI was calculated by [1.489 × albumin (g/L)] + [41.7 ×
17
(weight/ideal weight)]. Ideal weight (in kg) was calculated from the equations of Lorentz:
18
height (cm) - 100 - [(height (cm) - 150)/4] for a man and height (cm) - 100 - [(Height (cm) -
19
150)/2.5] for a woman. Weight/ideal weight was set to 1 when the ratio was over 1 [18, 19].
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Dietary intake was obtained by a registered dietitian using 24-h recall from patients
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or caregivers preparing meals if a patient was unable to speak. Nutrients evaluated were
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chosen in reference to the Dietary Reference Intakes (DRIs) and analyzed by Can-Pro version
23
4.0 (Computer Aided Nutritional analysis Program for professionals, Korean Nutrition
24
Society, Seoul, Korea).
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2
expenditure [20], but has not been satisfactory for ALS patients mainly due to the hyper-
3
metabolism of ALS patients [21]. Thus, total daily energy expenditure (TDEE) was
4
calculated by combined use of the Harris-Benedict equation and the total score of the 6
5
questions in the ALSFRS-R that related to physical activity (speech, handwriting, dressing
6
and hygiene, turning in bed and adjusting bed clothes, walking, dyspnea) [22].
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7 Statistical analysis
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Data analysis was performed using the statistical software package SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables are presented as the mean ±
11
standard error of mean (SEM) and differences were verified with Duncan’s multiple range
12
test after running a one-way ANOVA test. Qualitative variables were presented as number of
13
patients and percentage of distribution and differences were determined by a chi-square test.
14
For dietary intake evaluation, an ANCOVA test was run after adjusting for sex, age at onset,
15
BMI, duration of the disease, exercise habits, and sun exposure. Pearson’s correlation was
16
calculated to determine the relationship between variables. A p value of <0.05 was regarded
17
as significant.
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Results
Characteristics of patients according to tertiles of ALSFRS-R are shown in Table 1.
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Total and bulbar scores were significantly different among the tertiles of ALSFRS-R. Patients
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in the lowest tertile of ALSFRS-R were significantly younger at onset, had ALS for a longer
23
duration, exercises less regularly, and had less sun exposure compared with those in the
24
middle and highest tertile of ALSFRS-R. Blood albumin level and total lymphocyte count
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were also significantly lower in patients in the lowest tertile of ALSFRS-R. Although there 6
ACCEPTED MANUSCRIPT was no significant difference, patients in the most severe group consumed fewer dietary
2
supplements (Table 1). Types of dietary supplements were following: multivitamins (21.2%),
3
vitamin C (14.5%), vitamin E (6.2%), Ca (6.2%), vitamin B complex (5.7%), vitamin A
4
(1.6%), vitamin D (1.6%), Zn (1.0%), and Se (1.0%) in the entire ALS patients. There were
5
no significant differences in regard to sex, age, time between onset and diagnosis, site of
6
onset, family history of ALS, smoking, drinking, or other biochemical parameters.
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Body weight, BMI, and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-R, but height did not differ (Table 2). Consistently, there were more
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patients with underweight and moderate risk of malnutrition in the lowest tertile of ALSFRS-
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R as compared with the middle and/or highest tertile of ALSFRS-R. BMI was significantly
11
correlated with ALSFRS-R (r=0.330, P<0.001), bulbar score (r=0.291, P<0.001), albumin
12
(r=0.150, P<0.05), creatinine (r=0.206, P<0.01), BUN (r=0.239, P<0.01), TLC (r=0.250,
13
P<0.01), and TDEE (r=0.620, P<0.001) after adjusting for sex, age at ALS onset, site of
14
onset, duration of disease, exercise, exercise time, and sun exposure (Data not shown). In
15
addition, GNRI was significantly correlated with ALSFRS-R (r=0.421, P<0.001), bulbar
16
score (r=0.368, P<0.001), BMI (r=0.775, P<0.001), blood total protein (r=0.485, P<0.001),
17
albumin (r= 0.737, P<0.001), total cholesterol (r=0.218, P<0.01), hemoglobin (r=0.294,
18
P<0.001), hematocrit (r=0.268, P<0.001), TLC (r=0.298, P<0.001), and TDEE (r=0.588,
19
P<0.001).
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Intakes of vegetables, grains, seasonings, and oils were significantly lower in patients
21
in the lowest tertile (Fig 1). However, intakes of fruits, beans, meats, seafood, seaweeds, eggs,
22
dairy products, mushrooms, and seeds did not significantly differ among groups. Intakes of
23
energy, carbohydrates, fat, protein, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B6,
24
niacin, folate, calcium, phosphorus, sodium, potassium, iron, zinc, copper, and manganese
25
were significantly lower in patients in the lowest tertiles compared with patients in the 7
ACCEPTED MANUSCRIPT highest tertiles of ALSFRS-R (Table 3). However, significances of all nutrient intakes
2
disappeared after adjusting for energy intake. There were significantly more patients in the
3
lowest tertile of ALSFRS-R consuming less than 75% of the KDRIs for energy, protein, fiber,
4
vitamin K, vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folate, phosphorus,
5
sodium, potassium, iron, zinc, copper, manganese, and selenium.
6
8 9
Discussion
This was the first study to show that nutritional status was negatively associated with
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disease severity using ALSFRS-R in Korean patients with ALS. In the present study, nutritional status was evaluated by BMI and GNRI, which was significantly lower in the
11
patients in lowest tertile (based on ALSFRS-R score). Patients with underweight and
12
malnutrition were observed more frequently in the lowest tertile of ALSFRS-R as compared
13
with middle and highest tertiles. Both BMI and GNRI were significantly correlated with
14
ALSFRS-R, biochemical parameters, and daily energy expenditure in the present study,
15
suggesting that nutritional status decline as ALS progressed.
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Our study suggested that GNRI is a helpful tool to assess nutritional status in ALS patients. GNRI is a predictor of nutritional-related complications and muscle dysfunction in
18
elderly people [19, 23].
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Patients with ALS were observed to experience a progressive reduction in BMI as
20
the time of death approached [30]. In addition, underweight ALS patients were reported to
21
have a higher mortality [13, 14]. In the present study, underweight patients were only 1-3% in
22
the middle and highest tertiles of ALSFRS-R, but comprised 21% in the tertile with the most
23
severe ALS. Dysphagia is a well-known symptom of the illness and a decline of food intake
24
might be anticipated in ALS patients with progressive oropharyngeal weakness [1]. In close
25
agreement with previous studies [24, 25], our results also showed that most of ALS patients 8
ACCEPTED MANUSCRIPT consumed less than the recommended intake for energy, despite that ALS patients were
2
recommended to consume more energy than their estimated needs due to hyper-metabolism
3
[26]. Patients who consumed less than the recommended intake for energy increased from 54%
4
in the tertile of patients with the least severe ALS to 79% in the tertile of patients with the
5
most severe ALS. In addition, intake of most nutrients decreased as the disease progressed,
6
but a lower intake of nutrients was likely due to the less intake energy because significances
7
disappeared after adjusting for energy intake. Enteral nutrition resulted in an increase in the
8
weight in ALS patients who underwent percutaneous endoscopic gastrostomy [11] and tube
9
feeding of a hypercaloric formula [27]. In ALS animal models, a caloric dense diet promotes
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mitochondrial function, survival, and delay of disease onset, suggesting that higher caloric
11
diets may help retard the progression of ALS [26, 28, 29].
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Consistent with the decreased intake of energy and nutrients, patients in the lowest tertile of ALSFRS-R consumed fewer vegetables, grains, seasonings, oils and meats than
14
medium or highest tertiles, but higher amounts of fruits and beans. ALS patients may modify
15
their eating pattern because they need to eat cautiously and slowly. Modifying the texture of
16
the food to yield soft, semisolid, or semiliquid states with a high water content, such as
17
jellified water or sucking cubes, are suggested as better alternative to thinner liquids and can
18
help alleviate aspiration [30]. In the present study, bean intake was mostly due to tofu, which
19
has soft texture and is easy to chew.
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In the present study, intake of vitamin D was less than recommended in patients in all
21
ALSFRS-R score tertiles, and was the lowest in the lowest tertile. Vitamin D deficiency has
22
been shown to accelerate functional decline and has been associated with a greater incidence
23
of fractures and mortality in ALS patients [31, 32].
24 25
This study had a few limitations. Because of the cross-sectional study design, we were unable to establish a cause-effect relationship between the risk of malnutrition and 9
ACCEPTED MANUSCRIPT 1
ALSFRS-R score. Second, a number of potential confounders were adjusted for statistically;
2
however, there is a possibility that other factors affecting the risk of malnutrition and
3
ALSFRS-R score exists. Last, only mild to moderate stage of patients were enrolled in the
4
present study.
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Nutritional status, evaluated by BMI and GNRI, was worst in patients in the lowest tertile of ALSFRS-R and correlated with ALSFRS-R, bulbar score, albumin, total
9
lymphocyte count, and total daily energy expenditure. Intakes of total energy and most
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nutrients were also lower in patients in the lowest tertiles of ALSFRS-R. However, future
11
clinical trials are necessary to confirm whether the prevention of malnutrition slows the
12
progression of ALS.
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Acknowledgements
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This work was supported by the Korea Research Foundation (2012R1A2040553) and the Center for Women in Science, Engineering and Technology (WISET) Grant (KW-2014-
17
PPD-0056) funded by the Ministry of Science, ICT & Future Planning of Korea (MSIP).
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ACCEPTED MANUSCRIPT Table 1 Characteristics of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)1 Tertile of ALSFRS-R score Lowest (n=65)
Middle (n=61)
≤36
37-41
29.40 ± 0.78a
39.31 ± 0.19b
8.94 ± 0.27a
ALSFRS-R score
Highest (n=67)
P-value
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Variables
≥42
<0.0012
10.54 ± 0.17b
11.36 ± 0.15c
<0.001
53.91 ± 1.34
57.44 ± 1.26
53.75 ± 1.29
0.085
Sex, Male, n (%)
42 (64.6)
36 (59.0)
42 (62.7)
0.806
Age at onset (y)
50.52 ± 1.34a
55.30 ± 1.30b
51.82 ± 1.31ab
0.035
Onset to diagnosis (mon)
17.29 ± 2.85
11.08 ± 1.22
11.83 ± 1.40
0.056
Duration of ALS (mon)
39.33 ± 3.61a
22.75 ± 1.85b
22.14 ± 2.28b
<0.001
14 (21.5)
9 (14.8)
13 (19.4)
0.6093
1(1.5)
0 (0.0)
1 (1.5)
0.627
22 (33.8)
36 (59.0)
52 (77.6)
<0.001
33 (50.8)
43 (70.5)
60 (89.6)
<0.001
Smoking, n (%)
7 (10.8)
2 (3.3)
7 (10.4)
0.212
Drinking, n (%)
11 (16.9)
7 (11.5)
14 (20.9)
0.451
Dietary supplement, n (%)
34 (52.3)
44 (72.1)
45 (67.2)
0.053
Glucose (mmol/L)
6.63 ± 0.22
6.30 ± 0.19
6.56 ± 0.26
0.5662
41.86 ± 0.51a
43.52 ± 0.47b
44.93 ± 0.47c
<0.001
5.13 ± 0.30
5.21 ± 0.19
5.23 ± 0.17
0.953
65.37 ± 1.96
66.79 ± 1.62
0.636
Bulbar (range 0-12)
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Onset site (Bulbar), n (%)
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ALS family history, n (%) Exercise, n (%)4
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Sun exposure, n (%)
Albumin (g/L) Urea nitrogen (mmol/L) Creatinine (µmol/L)
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44.10 ± 0.20c
Total (range 0-48)
61.20 ± 7.03
ACCEPTED MANUSCRIPT Hemoglobin (g/L)
140.91 ± 2.16
138.34 ± 1.54
141.43 ± 1.94
0.484
Hematocrit (%)
42.15 ± 0.60
40.93 ± 0.43
41.82 ± 0.53
0.254
Cholesterol (mmol/L)
4.84 ± 0.13
4.89 ± 0.10
4.98 ± 0.12
0.669
TLC5 (×109/L)
2.02 ± 0.08a
2.00 ± 0.08a
2.28 ± 0.08b
0.031
Values are presented as the mean ± SEM or number of patients (percentage distribution), as
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appropriate. 2Values with different superscripts in the same row are significantly different at P<0.05 by one way ANOVA followed by Duncan's multiple range test. 3Differences were
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analyzed using chi-square test at P<0.05. 4> 1 time/week. 5Total lymphocyte count
ACCEPTED MANUSCRIPT Table 2 Nutritional status of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)1 Tertile of ALSFRS-R score P-value
Middle (n=61)
Highest (n=67)
≤36
37≤to≤41
≥42
Height (cm)
165.78 ± 0.89
162.80 ± 1.20
164.41 ± 0.930
0.1212
Weight (kg)
58.46 ± 1.29b
60.70 ± 1.36ab
63.45 ± 1.23a
0.0232
BMI (kg/m2)3
21.22 ± 0.40b
22.84 ± 0.44a
23.38 ± 0.33a
<0.0012
14 (21.5)
Normal, n (%)
36 (55.4)
Overweight, n (%)
7 (10.8)
Obese, n (%)
8 (12.3)
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1(1.6)
2(3.0)
35(57.4)
31(46.3) <0.0014
12(19.7)
15(22.4)
13(21.3)
19(28.4)
102.10 ± 1.19a
107.54 ± 1.09b
110.64 ± 0.94c
39 (60.0)
52(85.2)
63(94.0)
17 (26.2)
8(13.1)
4(6.0)
Moderate risk, n (%)
8(12.3)
1(1.6)
0
High risk, n (%)
1(1.5)
0
0
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<0.0012
<0.0014
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Low risk, n (%)
1
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Underweight, n (%)
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Lowest (n=65)
Values are presented as the mean ± SEM or number of patients (percentage distribution), as
appropriate. 2Values with different superscripts in the same row are significantly different at P<0.05 by one way ANOVA followed by Duncan's multiple range test. 3Body mass index was categorized into four groups based on Western Pacific Region of WHO criteria; <18.5, underweight; 18.5 to 22.9, normal; 23 to 24.9, overweight; ≥25, obese. 4Differences were analyzed using chi-square test at P<0.05.
ACCEPTED MANUSCRIPT 5
Geriatric nutritional risk index; < 82, high risk; 82 to < 92, moderate risk; 92 to 98, low
risk; >98, no risk. GNRI was calculated by [1.489 × albumin (g/L)] + [41.7 × (weight/ideal weight)]. Ideal weight was calculated with the equations of Lorentz: height (cm) - 100 [(height (cm) - 150)/4] for man and height (cm) - 100 - [(Height (cm) - 150)/2.5] for
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woman.
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Table 3
Tertile of ALSFRS-R score Middle (n=61)
Highest (n=67)
Variables 37≤to≤41
≤36 Intakes1
N (%)
Intakes
Energy (Kcal/d)
1229±54
51(78.5)2
1475±53
Carbohydrate (g/d)
195.0±9.1
-
240.6±8.9
Lipid (g/d)
28.5±2.5
-
31.7±2.4
Protein (g/d)
49.1±3.3
39(60.0)3
Fiber (g/d)
16.2±1.1 688.0±73.9
Vitamin D (µg/d)
3.9±0.8
Vitamin E (mg/d)
9.4±0.9
Vitamin K (µg/d)
149.2±27.3
P-value5
P-value6
≥42
N (%)
N (%)
37(60.7)
1621±51
36(53.7)
<0.001
0.010
-
251.3±8.6
-
<0.001
-
-
39.0±2.1
-
0.008
-
57.8±3.2
25(41.0)
68.3±3.1
27(40.3)
<0.001
0.039
39(60.0)4
19.6±1.0
25(41.0)
20.6±1.0
27(40.3)
0.278
0.039
34(52.3)3
696.4±72.0
25(41.0)
759.7±69.4
24(35.8)
0.741
0.149
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Lowest (n=65)
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Dietary intake of patients with amyotrophic lateral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R)
53(81.5)4
2.5±0.9
51(83.6)
4.1±0.8
51(76.1)
0.011
0.542
30(46.2)4
11.6±0.8
17(27.9)
13.6±0.8
20(29.9)
0.003
0.057
19(29.2)4
219.7±26.6
6(9.8)
213.9±25.6
9(13.4)
0.151
0.009
35(53.8)3
1.1±0.1
23(37.7)
1.4±0.1
21(31.3)
0.004
0.026
Vitamin B2 (mg/d)
0.8±0.2
48(73.8)3
1.04±0.2
38(62.3)
1.6±0.2
30(44.8)
0.010
0.003
Niacin (mg NE/d)
11.1±0.9
39(60.0)3
13.4±0.9
21(34.4)
16.1±0.9
23(34.3)
<0.001
0.003
Vitamin B6 (mg/d)
1.1±0.1
31(47.7)3
1.5±0.1
15(24.6)
1.7±0.6
17(25.4)
0.004
0.006
Folate (µg DFE/d)
388.2±31.1
26(40.0)3
477.1±30.4
11(18.0)
515.8±29.3
0.017
0.004
Vitamin B12 (µg/d)
7.6±1.3
20(30.8)3
8.8±1.3
5(8.2)
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12(17.9)
9.7±1.3
6(9.0)
0.511
<0.001
Vitamin C (mg/d)
80.8±10.2
41(63.1)3
94.3±9.9
31(50.8)
97.6±9.5
33(49.3)
0.500
0.223
Calcium (mg/d)
348.7±35.1
52(80.0)3
421.9±34.2
47(77.0)
497.7±32.9
46(68.7)
0.013
0.294
Phosphorus (mg/d)
774.1±50.3
17(26.2)3
940.5±49.1
6(9.8)
1064.3±47.3
3(4.5)
<0.001
0.001
Sodium (g/d)
2.8±2.4
8(12.3)4
3.8±2.3
1(1.6)
4.1±0.2
0(0)
<0.001
0.001
Potassium (g/d)
2.1±0.1
51(78.5)4
2.5±0. 1
32(52.5)
2.74±0.13
35(52.2)
0.006
0.002
Magnesium (mg/d)
71.5±7.0
64(98.5) 3
63.8±6. 8
61(100.0)
77.2±6.5
67(100)
0.353
0.372
Iron (mg/d)
11.3±0.9
Zinc (mg/d)
7.5±0.5
Copper (mg/d)
0.9±0.1
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0.8±0.1
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Vitamin B1 (mg/d)
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19(29.2)3
13.8±0.9
5(8.2)
15.5±0.9
2(3.0)
0.007
<0.001
26(40.0)3
9.1±0.5
11(18.0)
10.4±0.4
13(19.4)
<0.001
0.006
17(26.2)3
1.1±0.1
9(14.8)
1.2±0.1
5(7.5)
0.014
0.013
ACCEPTED MANUSCRIPT
Iodine (µg /d) Selenium (µg/d)
2.9±0.2
35(53.8)4
106.1±224.1
43(66.2)3
87.5±5.2
16(24.6)3
3.6±0.2 533.8±218. 75.2±5.4
19(31.1)
3.92±0.20
19(28.4)
0.007
0.005
41(67.2)
665.4±119.5
39(58.2)
0.204
0.504
8(13.1)
87.5±5.2
0.066
0.038
RI PT
Manganese (mg/d)
6(9.0)
Values are presented as the mean ± SEM. 2Number of patients (%) consuming less than 75% of the Korean estimated energy requirement.
3
Number of patients (%) consuming less than 75% of the Korean estimated average requirement. 4Number of patients (%) consuming less than
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1
M AN U
75% of the Korean adequate intake. 5Differences were calculated by ANCOVA after adjusting for sex, age at ALS onset, body mass index,
AC C
EP
TE D
duration of the disease, exercise and sun exposure at P<0.05. 6Differences were analyzed using chi-square test at P<0.05.
ACCEPTED MANUSCRIPT
350
70
p=0.013
300
60
p=0.012
50 40
150
30 p=0.314
100
20
50
10
0 Grains
M AN U
0
Vegetables
Fruits
Beans
p=0.404
Beverages
Potatoes
Seasonings
Sugars
10
p=0.776
9
p=0.057
100 80 60
p=0.224
20 0 Meats
AC C
40
Sea foods
p=0.663
7 p=0.419
6 5 4
EP
P=057
p=0.007
8
TE D
p=0.683
Dairy products
RI PT
p=0.02
p=0.490
200
g/d
p=0.457
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g/d
250
120
p=0.482
p=0.228
3 2 1 0 Eggs
Oils
Seeds
Seaweeds
Mushrooms
Fig. 1 Daily intake of food in patients with myotophic lageral sclerosis (ALS) according to tertiles of the revised ALS functional rating scale (ALSFRS-R). Differences were calculated by ANCOVA after adjusting for sex, age at ALS onset, body mass index and duration of the disease at P<0.05; Highest tertile;
Medium tertile;
Lowest tertile
ACCEPTED MANUSCRIPT Highlights Nutritional status, evaluated by BMI and GNRI, was worst in the lower score of amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) in Korean ALS
RI PT
patients. Nutritional status correlated with ALSFRS-R, bulbar score, albumin, total lymphocyte count, and total daily energy expenditure in Korean ALS patients.
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Intakes of total energy and most nutrients were decreased in Korean ALS patients with
AC C
EP
TE D
M AN U
lower score of ALSFRS-R.