Should patients with ALS gain weight during their follow-up?

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Article

Reference

Should patients with ALS gain weight during their follow-up?

HERITIER BARRAS, Anne-Chantal, et al.

Abstract

It was recently postulated that a nutritional intervention aiming at achieving weight gain might increase survival in ALS patients. This article discusses the effect of nutritional status and weight gain on survival, respiratory status and physical function. Based on the available literature, it remains unknown whether weight gain during the progression of the disease improves survival whatever the baseline body weight is. A high body mass index may impair respiratory muscle function and passive mobilization of paretic patients. Future research should evaluate the effect of changes in weight and body composition on clinical outcome while taking into account respiratory muscle strength and physical function

HERITIER BARRAS, Anne-Chantal, et al . Should patients with ALS gain weight during their follow-up? Nutrition , 2015, vol. 31, no. 11-12, p. 1368-1371

DOI : 10.1016/j.nut.2015.06.005 PMID : 26429657

Available at:

http://archive-ouverte.unige.ch/unige:88220

Disclaimer: layout of this document may differ from the published version.

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Applied nutritional investigation

Should patients with ALS gain weight during their follow-up?

Anne-Chantal H eritier M.D.

^a

, Jean-Paul Janssens M.D.

^b

, Dan Adler M.D.

^b

, Ruxandra Iancu Ferfoglia M.D.

^a

, Laurence Genton M.D.

^c^,^*

aDivision of Neurology, Geneva University Hospitals, Geneva, Switzerland

bDivision of Pulmonary Diseases, Geneva University Hospitals, Geneva, Switzerland

cClinical Nutrition, Geneva University Hospitals, Geneva, Switzerland

a r t i c l e i n f o

Article history:

Received 30 January 2015 Accepted 7 June 2015

Keywords:

ALS Weight Body composition Fat-free mass Fat mass Mortality

Respiratory function

a b s t r a c t

It was recently postulated that a nutritional intervention aiming at achieving weight gain might increase survival in ALS patients. This article discusses the effect of nutritional status and weight gain on survival, respiratory status and physical function. Based on the available literature, it remains unknown whether weight gain during the progression of the disease improves survival whatever the baseline body weight is. A high body mass index may impair respiratory muscle function and passive mobilization of paretic patients. Future research should evaluate the effect of changes in weight and body composition on clinical outcome while taking into account respiratory muscle strength and physical function.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a life expectancy of 2 to 5 y. Effective treatment for ALS is lacking. A multidisciplinary approach [1], non-invasive ventilation[2], riluzole, and enteral nutrition via percutaneous endoscopic gastrostomy have been shown to improve survival and quality of life to some extent [1]. In a recently published article, it was postulated that a nutritional intervention, aiming at achieving weight gain, might be a therapeutic option for patients with ALS[3]. These assumptions relied on the increased survival with a high-calorie diet in an ALS mouse model[4]and on the lower risk for ALS in overweight or obese individuals[5].

Here we summarize the effect of initial nutritional status and weight gain during follow-up on survival and respiratory and physical function to explore whether weight gain is beneﬁcial for patients with ALS.

Weight and body mass index at diagnosis and survival

Few studies related baseline weight to survival in ALS. In clinical routine, weight often is expressed as body mass index (BMI). A BMI <18.5 kg/m² deﬁnes underweight and a BMI 30 kg/m²deﬁnes obesity[6].

A study of 92 patients with ALS demonstrated that a history of weight loss at diagnosis was signiﬁcantly associated with survival[7]. After adjustment for age, sex, bulbar versus non-bulbar onset, ALS functional rating scale (ALSFRS), manual muscular testing, forced vital capacity, and diagnostic delay, the study found a 30% increase in risk for death for each 5% weight loss and a 20% increase in risk for death for each BMI unit loss.

In the same study population, undernutrition at diagnosis, deﬁned as a BMI<18.5 kg/m²if<70 y or<21 kg/m²if70 y (n¼8), was not associated with survival, after the aforementioned adjustments[7]. Effect of obesity was not assessed. A larger study stratiﬁed 285 patients with ALS according to BMI categories at baseline[8]. BMI categories were not predictive of survival or rate of progression. However, only 3 patients were undernourished and 65 were obese. A shorter survival in patients with ALS and a baseline BMI<18.5 kg/m²(n¼9) than in those with a higher BMI was reported in univariate Cox re- gressions[9]. One group of researchers studied 427 patients with ALS[10]. A decreased survival was seen in patients with a BMI

>35 or<18.5 kg/m²at diagnosis; thus a U-shaped relationship between BMI and survival was established. This ﬁnding was conﬁrmed in the PRO-ACT (Pooled Resources Open Access ALS Clinical Trial) database, which pooled data from 16 Phase II/III trials and 1 observational study (n ¼ 8635) [11]. Obese and overweight patients with ALS, respectively, showed a 54% and

*Corresponding author. Tel.:þ41-22-3729-344; fax:þ41-22-3729-363.

E-mail address:laurence.genton@hcuge.ch(L. Genton).

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Nutrition

jo u rn a l h o m e p a g e :w w w . n u t r i t i o n j r n l . c o m

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35% lower risk for dying compared with those with a BMI

<25 kg/m².

Thus, studies generally agree that undernutrition at diagnosis decreases survival, whereas a BMI of 25 to 35 kg/m² may be protective in this patient population.

Weight change and survival

Several studies highlighted that weight loss increases the risk for mortality in patients with ALS [7–9,12–14]. As a corollary, interventions aiming at preventing weight loss, such as hypercaloric nutrition, should be beneﬁcial. The tolerance and safety of such an intervention was tested in 24 patients under enteral nutrition, randomized to hypercaloric high-carbohydrate (HC) nutrition, hypercaloric high-fat nutrition, or isocaloric (C) nutrition, for 4 mo and followed up to 5 mo[3]. At baseline, patients had a BMI in the normal range but a body weight loss of almost 20%. Patients on the HC diet had fewer adverse events (e.g., dyspepsia, bloating, diarrhea, etc.), fewer serious adverse events (e.g., hypoxia, dyspnea, bronchoaspiration, etc.) and a higher ALSFRS after the intervention than controls. Weight gain and mortality were not signiﬁcantly different between groups.

The authors suggested that HC nutrition might be a therapeutic option in patients with ALS, although they could not highlight a difference in weight gain, probably because of difﬁculties in determining energy balance.

From the aforementioned studies, it is uncertain whether weight loss increases the risk for mortality independently of baseline body weight. It is possible that weight loss is not as detrimental in obese patients as it is in lean patients because it improves mobilization and ventilation and thus quality of life.

Additionally, the timing of nutritional support is still unclear.

Should health care providers wait until patients with ALS have lost 10% of their body weight before providing nutritional support by percutaneous endoscopic gastrostomy [15], or aim at increasing weight as of initial follow-up evaluation? Health care providers also must realize that achieving weight gain in a patient with ALS may be difﬁcult because of large variations in energy expenditure[16].

Thus, weight gain during follow-up may decrease mortality;

however, the effect of changes in body composition, physical activity, and timing and composition of nutritional support remains largely unknown.

Body weight versus body composition

Body composition measurements allow separating body mass into fat mass (FM) and fat-free mass (FFM), which includes muscle mass. Because low FFM, a hallmark of undernutrition, has been related to several negative outcomes (increased hospital length of stay, mortality)[17], assessment of body composition, in addition to BMI, may provide useful information for treatment and follow-up, as suggested elsewhere[18].

A low FFM has been linked to mortality in older and obese patients[19,20]. Thus, it would seem logical to consider that FFM at diagnosis may predict survival. As physical activity is among the main anabolic drives, individuals who are physically active at baseline may have a higher muscle mass and function and may survive longer than those who already have physical limitations.

If baseline FFM is a key factor for estimating survival, the best methodology for body composition assessment must be deter- mined. Because ALS generally does not affect the limbs sym- metrically, methodologies that do not rely on assumptions

integrating a symmetrical distribution, such as dual energy x-ray absorptiometry (DXA), may be the most appropriate.

Changes in body composition may, in fact, be better pre- dictors of mortality than body weight changes. An increase in FM predicts a better survival[7]. Using DXA, one study showed that patients who gained weight increased FM and FFM, whereas those who lost weight lost FFM but increased FM[3]. This sug- gests that loss of FFM may be a better predictor of mortality than loss of FM. Recently, one study demonstrated the negative effect of FFM loss on mortality[21]. Consequently, every effort should be directed toward maintaining FFM. This may be achieved to some extent through physical activity, if feasible for the patient, or by increasing intake of energy (Fig. 1). In healthy individuals, a positive energy balance leads to an increase of both FM and FFM.

In patients with ALS, gain in FFM seems unlikely due to the disease, but weight gain could offset loss of FFM.

However, the advice to maintain FFM through weight gain probably should take into account the patient’s BMI. It likely applies to patients with ALS who have a low or normal BMI but not to those with a BMI in the overweight or obese range. In the latter group, weight gain may worsen physical and respiratory function, and passive mobilization, as detailed later.

To summarize, in ALS, an increase in FM predicts a longer survival. The increase in FM may just reﬂect a better preservation of FFM.

Nutritional status and respiratory function

Progressive loss of upper and lower motor neurons involving respiratory muscles in ALS leads to respiratory failure and is a major determinant of prognosis. Nutritional status may affect respiratory function in ALS through several pathways.

In patients with non-bulbar onset of ALS, hypercapnic respiratory failure occurs relatively late in the course of the disease.

Decrease in peripheral muscle strength and FFM is associated with a simultaneous loss in inspiratory muscle strength. Longi- tudinal noninvasive follow-up of inspiratory muscle strength using Sniff nasal inspiratory pressure[22]shows a linear slope of decline that may be a better predictor of the need for ventilator support than conventional parameters such as forced vital capacity or PaCO2[23]. The relationship between peripheral muscle mass, muscle strength, and respiratory muscle mass (mainly the diaphragm) has been well established in healthy individuals [21]and in patients with chronic hypercapnic respiratory failure.

In a descriptive study, hypercapnic patients with restrictive or obstructive lung disease were more likely to have a low FFM index when compared with age- and sex-matched controls[24].

In this report, estimation of nutritional status by BMI alone clearly underestimated the prevalence of FFM index depletion.

Furthermore, correlation between respiratory muscle strength and FFM was stronger than with BMI. A positive association between Sniff nasal inspiratory pressure and BMI also was reported in patients with chronic hypercapnic respiratory failure who survived an episode of respiratory failure in the intensive care unit[25]. The authors hypothesized that higher BMI values were associated with increases in FM and FFM. Theseﬁndings provide a possible explanation for the prevailing opinion that prognosis may be better in critically ill patients with obesity (“obesity paradox”).

Based on these observations, it is logical to surmise that in ALS, progressive peripheral muscle wasting assessed by FFM depletiondrelated or not with changes in BMIdmay be associated with a proportional and simultaneous decrease in respiratory muscle strength, leading to dyspnea and respiratory failure.

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A recent review reported that energy intakes are often low in patients with ALS, which may contribute to FFM depletion[26].

Because ALS is not a homogeneous disease and does not affect all peripheral muscles simultaneously, this relationship is difﬁcult to establish and may not be linear. Longitudinal relationship between FFM, peripheral muscle mass assessed by DXA, peripheral muscle strength tested bilaterally, and inspiratory muscle strength should be further explored. The clinical rele- vance of studying the relationship between peripheral muscle mass and inspiratory muscle strength is further supported by the direct relationship between dyspnea and reduced diaphragmatic function tests (i.e., pulmonary function tests, static pressures, mouth twitch pressures, cortical magnetic stimulation)[27].

In patients with major diaphragmatic impairment, recruitment of accessory muscles (mainly cervical muscles) may partially compensate for diaphragmatic weakness. Efﬁciency of these accessory muscles, however, is lower than that of the diaphragm, resulting in an increased caloric expenditure for a given respiratory workload (Fig. 1). A recent study of 10 patients with ALS who had signs of respiratory failure and diaphragmatic dysfunction showed that although resting energy expenditure was below predicted values while breathing spontaneously, noninvasive ventilation (NIV) induced a further median decrease of resting energy expenditure by 7%. The transfer of the respiratory burden from the diaphragm to the accessory inspiratory muscles may be a potent contributor to weight loss, reversible by NIV[28].

Inspiratory muscle function in ALS also can be affected by increased body weight, per se. Higher BMI values increase the likelihood of obstructive sleep apneas and hypopneas, with a higher inspiratory burden placed on inspiratory muscles and an

increased risk for nocturnal hypoventilation. Higher BMIs also can affect chest wall and respiratory system compliance and contribute to hypercapnic respiratory failure. Therefore, there could be a U- shaped relationship between BMI and respiratory muscle function in ALS, with both lower and higher values being detrimental.

These observations and hypotheses suggest that an appropriate longitudinal follow-up of FFM may be relevant to adjust caloric intake, with a possible effect on inspiratory muscle strength, dyspnea, and requirement for ventilator support.

Conversely, NIV may positively affect energy balance[28], with a possible protective effect on peripheral muscle mass.

Nutritional status and physical function

For patients with ALS, progression of motor dysfunction im- plies a loss of physical function with an increasing level of dependence. There are little data concerning nutritional status as prognostic factor for physical function in ALS. Results of one study found a signiﬁcant nonlinear association of initial BMI with changes in ALSFRS, the smallest decline being in patients with BMI 30 kg/m²[29]. In patients with BMI<30 kg/m², a higher initial BMI was associated with a slower functional decline. A recent systematic review aimed at determining factors predictive of ALSFRS decline. Only one study evaluated the relationship between initial BMI and progression of ALSFRS, which was the aforementioned study[29]. Thus, the level of evidence for an effect of initial BMI on progression of ALSFRS was considered very low[30].

In addition to a potential effect of BMI on active mobilization, BMI likely affects passive mobilization of paretic patients because they are obviously more difﬁcult for caregivers to mobilize.

Fig. 1.The effect of amyotrophic lateral sclerosis (ALS), nutrition, and ventilation on body weight and fat-free mass (FFM). ALS leads to a loss of motoneurones, which results in a decrease in FFM and body weight. The loss of FFM impairs respiratory function and peripheral muscle function, leading to a functional impairment and a further decrease in FFM and body weight, creating a vicious circle. Nutritional support and noninvasive ventilation may, to some extent, counteract the decrease in FFM occurring naturally in ALS, which is represented by the minus sign.

eritier et al. / Nutrition 31 (2015) 1368–1371 1370

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Conclusions

Based on the available literature, it is not clear whether patients with ALS should gain weight during their follow-up. It is likely that this recommendation should be adapted to the patient’s nutritional status, respiratory function, and physical abilities.

Nutritional status and support appear to be related to prognosis, functional status, and respiratory involvement in ALS. FFM may prove to better predict nutritional requirements, prognosis, and respiratory involvements than BMI or body weight. This requires assessing body composition through methods taking into account the often asymmetrical amyotrophy. Furthermore, the effect of weight gain and FFM maintenance on clinical outcomes should be further studied.

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