Malnutrition

Malnutrition is described as loss of greater than 10% of body weight or a BMI lower than 18.5 kg/m ² , and both are considered negative predictors of survival in ALS patients. The prevalence of malnutrition in the ALS population varies among reports, from 16% to 53%. Malnutrition can initiate a vicious cycle for ALS patients, further compromising muscle strength and respiratory capacity due to weakening of both skeletal and respiratory muscles beyond that caused by motor neuron loss. The literature overwhelming shows that a low BMI and malnutrition negatively affect disease progression and thus the survival in ALS patients. Malnourished ALS patients have a 7.7-fold increased risk in mortality.

Anthropometrics

Malnutrition can be assessed using various methods, including anthropometric data, such as body weight, BMI, triceps skinfold thickness (TSF), and midarm muscle circumference (MAMC). It is believed that a sheer reduction in body weight of 5% to 10% from normal can suggest compromised nutritional status and be a prognostic factor for survival. Unfortunately, this range has not been validated in ALS patients. Studies have shown, however, BMI to be strongly associated with survival in ALS with malnutrition below 18.5 kg/m ² for all ages or less than 18.5 kg/m ² for ages 18 to 65 and below 20 kg/m ² for patients over 65 years old. A retrospective study of 427 ALS patients found a U-shaped relationship between BMI and survival with maximum survival observed in patients with BMI of 30 to 35, even when adjusting for FVC, bulbar onset, use of Rilutek, and duration of the disease. Paganoni and colleagues found patients with BMI greater than 35 had greater mortality due to higher frequency of cardiovascular disease (which was also a significant predictor of survival). The use of BMI, however, as a reliable assessment tool for the ALS population is questionable due to neurogenic atrophy, energy imbalance, and dependent edema caused by immobility.

Height and weight measurements are useful; however, they do not give information regarding the type of tissue gained or lost with changes in body weight. Changes in body composition can be assessed using other tools, such as TSF, which provide data regarding fat mass that can be followed over time. TSF is measured using Harpenden calipers, and these measures are compared with a reference table to determine leanness or excessive body fat. Unfortunately, fat distribution is not even; therefore, measuring skinfolds at multiple sites is believed to improve the accuracy of the assessment although no consensus exists as to which combination of sites is best for accurate measurement.

Additionally, there are tools designed to assess somatic protein (skeletal protein mass), which is the body’s major protein store and can be used to assess malnutrition. Measuring somatic protein using the following techniques can be used to track protein nutritional status and be quanitified using standardized tables by gender and age. MAMC gives information about lean body mass using TSF and midarm circumference (MAC) in a formula. The clinical status of ALS patients has been monitored using bone-free arm muscle area (AMA), which combines the TSF and MAMC measurements ( Box 1 ). AMA has been used for studies in the ALS population, providing serial assessment of muscle atrophy. AMA measures correlated significantly with body mass, FVC, and maximal voluntary ventilation. These measures are limited, however, in ALS due to upper limb dysfunction and muscle wasting. Despite their ease of use, the results from ALS patients compared with reference tables may not accurately depict patients’ nutrition status.

Body Composition

Body composition, the assessment of body fat and FFM, can additionally be used to track changes as the disease progresses. Various techniques can be used to measure body composition and each varies in cost and portability. A portable, inexpensive, and simple procedure is bioelectrical impedance analysis (BIA). BIA uses electrical current to measure resistance of body compartments to establish values for lean body mass, fat mass, and total body water.

There are 3 types of devices, 500 kHz monofrequency and 50-kHz and 100-kHz dual-frequency and multifrequency BIAs. BIA has been used in several ALS studies. In 2003, BIA was validated as an outcome measure for ALS studies for both longitudinal tracking and single examination measurements with the use of an adapted equation in conjunction with a frequency of 50 kHz.

Dual-energy x-ray absorptiometry (DXA) directly measures the body’s absorption of x-rays at 2 energy levels, which allows for the direct measurement of body compartments. It is more expensive to use and less portable than BIA. DXA has been used as a measure in the ALS population and studies have found a reduction in fat mass, muscle mass, and bone mass with a fat mass/muscle mass ratio that was low or normal compared with myogenic atrophy patients and control patients. Kanda and colleagues additionally found that DXA provided a clearer distinction between myogenic atrophy and neurogenic atrophy due to increased fat infiltration in the myogenic atrophied skeletal muscle. DXA has provided confirmatory data that ALS patients lose lean body mass over time despite normal or elevated calorie intake. Therefore, weight maintenance or gain in this population, as disease progresses, is likely a reflection of change in body composition with an increase in fat stores. In another study by Tandan and colleagues that followed patients over 1 year, reduced lean body mass occurred over time that correlated with the ALS functional rating scale but not with total body weight, BMI, or FVC.

Both of these tools, BIA and DXA, can track body composition change over time, but each presents a different challenge related to cost, availability, and patient comfort. No definitive studies using either BIA or DXA have demonstrated that the observed changes in tissue distribution are a prognostic factor for survival. It has been argued, however, that a higher fat mass is beneficial for survival in the ALS population due to an observed progressive reduction in body fat stores associated with proximity to death. Additionally, knowledge of a patient’s fat-free mass (FFM) weight, as determined by BIA or DXA, can assist in estimating energy needs in relation to ALS-associated hypermetabolism (discussed later).

Biochemical Indices

Serum markers are useful for different purposes when assessing the nutritional status of ALS patients. Certain serum markers provide information regarding the current nutritional state of patients, whereas others correlate with disease progression and survival. Serum markers used for the assessment of malnutrition in ALS patients include serum albumin, prealbumin, hemoglobin, magnesium, calcium (total and ionized), phosphorous, serum zinc and copper, and retinol-binding protein whereas the creatinine height index (CHI) has been used as a marker of disease progression and survival. CHI is a ratio of a patient’s 24-hour creatinine excretion and the expected normal creatinine excretion for a given height. CHI has been shown to correlate with the degree of muscle depletion in ALS patients. A drop in CHI, with a corresponding elevation in serum calcium, has been observed in close proximity to death in ALS patients. The other markers remain within normal limits, with no gender differences or changes related to time to death.

These tests have been validated as markers of nutritional status in other disease populations but have not been well researched in ALS. Furthermore, these values can be altered by hydration status, inflammation, hepatic failure, or catabolism at the level of the muscle and intestine, and the body often compensates to maintain normal values with slowly progressive malnutrition. Other micronutrients, such as B vitamins, vitamin D, antioxidant vitamins, and minerals, have not been well researched due to the poor correlation of blood values with intracellular stores. Thus, biochemical markers used to assess malnutrition are often less reliable then anthropometric assessments, such as monitoring body weight, BMI, and FFM.

Studies have suggested a positive correlation of hyperlipidemia and diabetes mellitus type 2 in relation to ALS disease onset and prolonged survival time. Hyperlipidemia, obesity, and diabetes mellitus type 2 were found in one study to possibly delay the onset of motor symptoms. Multiple studies evaluating more than 300 subjects have found that patients with hyperlipidemia and elevated fasting total cholesterol and triglycerides as well as elevated low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio had significantly increased survival by nearly 12 months compared with subjects with normal serum lipid levels. Additionally, low levels of LDL and total cholesterol have been associated with lower percent predicted FVC. In a cross-sectional study by Ikeda and colleagues, an inverse relationship was observed between both total cholesterol and LDL values, when compared to the annual decline of the ALS functional rating scale and FVC.

Contrary to these findings, an earlier study of more than 600 subjects found the exact opposite, with no correlation in lipid values with survival time. The investigators observed a significant decrease in lipid levels in those patients with an FVC of less than 70% predicted and interpreted this finding as a indicator that respiratory impairment is related to a decrease in blood lipids. Another study similarly found no changes in length of survival in patients with hyperlipidemia compared with patients with normal lipid values. It has been argued that BMI may be a confounding factor when evaluating the effects of lipid levels in ALS. In 427 ALS patients from 3 clinical trials assessing serum lipids, the LDL/HDL ratio was shown to not be associated with survival after adjusting for BMI. As discussed previously, higher BMIs, between 30 and 35, have been associated with longer survival time in ALS. In spite of the controversy, changes in lipid metabolism with lowering of serum lipid levels is considered one possible sign consistent with hypermetabolism in ALS and may be a sufficient argument against the appropriateness of statin use in this population.

Other biochemical indices studied include uric acid levels. High uric acid levels have been previously linked to a reduced risk of developing Parkinson disease and slower rates of decline as well as slower progression in Huntington disease, multiple system atrophy, and mild cognitive impairment. The mechanism remains unclear but the theory involves its antioxidant properties and its protective influence on neuronal cell death. There have been a few studies showing reduced uric acid levels in the ALS population in comparison with healthy controls and one study found higher baseline uric acid values associated with increased survival in men with levels of 4.8 mg/dL or greater. These same uric acid levels, however, did not show an increase survival for women and only 22% had a level greater than 4.8 mg/dL. Uric acid levels are notoriously higher in men than women complicating the utility of this serum marker.

Often the relevance of common biochemical indices associated with malnutrition in ALS is of questionable value and should be assessed in conjunction with anthropometric measurements. Biomarker research is ongoing and will uncover more accurate and reliable indices to assess nutrition status in patients with ALS. Two recent cross-sectional studies found 23 metabolites related to neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction that were significantly altered in plasma from ALS patients compared with healthy volunteers.

Hypermetabolism

Most ALS patients suffer from hypermetabolism. Reports suggest nearly 100% of patients with familial ALS and 52% of patients with sporadic ALS suffer from hypermetabolism. Hypermetabolism is a strange paradoxic occurrence in the ALS population given denervation, reduced physical activity, and muscle atrophy. It is expected that energy requirements decline under these circumstances. This phenomenon, in conjunction with poor energy intake and swallowing difficulties, is an additional contributor to malnutrition and poor survival in the ALS population.

Hypermetabolism has most commonly been confirmed using the ratio of measured REE (mREE) to calculated REE (cREE). Findings in the ALS population often reveal a ratio greater than 1.1, or 110% of normal. The mREE is obtained by calorimetry whereas cREE is calculated using an established energy equation. Calorimetry is a measurement of the amount of heat eliminated or stored in a system. Direct calorimetry is the measurement of the amount of heat produced by a patient while housed for a certain amount of time within a small chamber. Access to equipment allowing direct calorimetry measurement is limited and often impractical.

Indirect calorimetry is a more often used measure of energy expenditure. This technique uses gas exchange measurements, oxygen consumption, and CO ₂ output to determine the amount of heat produced by patients indirectly. Patients are typically evaluated in a seated position for 20 to 30 minutes and asked to breathe normally under a transparent canopy. Indirect calorimetry is noninvasive and simple to perform but not regularly used to due the cost, availability of equipment, and patient tolerance. Ultimately, indirect calorimetry can be used to help assess energy expenditure and allow for customized recommendations for nutritional support to meet a patient’s mREE and minimize weight loss.

Many studies have evaluated ALS patients comparing indirect calorimetry with calculated energy expenditure equations. The Harris-Benedict and the Mifflin–St Jeor equations have both been recommended for use when estimating energy requirements for ALS patients ( Box 2 ). The Harris-Benedict equation is the most commonly used in these comparison studies, which have found an increase in mREE on average of 14% to 20% beyond that predicted by the Harris-Benedict–derived cREE. One study reported using the Harris-Benedict equation and overestimating patient needs; however, the study cohort included patients with mechanical ventilation, and 11 of the 34 had not fasted overnight before indirect calorimetry testing. Both of these factors compromise the data and thus the interpretation of results. Current thinking supports the addition of a 10% increase in calories beyond the cREE values when providing nutritional recommendations for patients with ALS.

The mREE represents the energy requirement necessary for homeostasis of normal bodily functions, including the cardiorespiratory, cerebral, and nervous systems as well as biochemical reactions to sustain organ function. It does not include the energy expenditure associated with physical activity or that due to the thermic effect of food. The most metabolically active tissues are the FFM, viscera, and muscle tissue. Visceral organs are responsible for 70% to 80% of the daily REE in comparison to 22% by muscle mass. In ALS, it might be assumed that resultant muscle atrophy, and reduced calorie intake, with its related reduction from the thermic effect of food, would result in decreased mREE. This is not the case, however.

Each organ has its own energy expenditure rate that is dependent on its weight. As muscle mass is lost in an ALS patient, the patient’s proportion of organ mass to muscle mass increases, shifting caloric needs due to greater calories required per kilogram of FFM. Given this shift, there have been REE equations derived for use in ALS, adjusting for these changes in FFM, using 34 kcal/kg to 35 kcal/kg of FFM. When indirect calorimetry is not available, these energy equations can be used to predict energy requirements (cREE) with expected error of approximately 150 to 250 calories.

It has been argued that mREE can be used as a prognostic factor for survival. Measured REE has been followed longitudinally through the course of disease, with REE levels remaining high until the late terminal stage of disease, when a decrease is observed in mREE just before death. Measured REE has been positively correlated with BMI, FFM, energy, protein intakes, and albumin levels. The mREE has been shown to remain higher than calculated with a slight decrease at proximity of death whereas FFM remained stable. This suggests REE is a prognostic factor for survival. mREE and mREE/cREE, however, have shown stable despite deterioration of the disease, thus making mREE questionable as a predictor of survival. For hypermetabolism to occur in the ALS population while in the midst of decreasing physical activity and increased denervation with muscle atrophy necessarily suggests the presence of an underlying metabolic derangement.

Several hypotheses have been developed to explain the increase in mREE. One proposed mechanism is that the increased work required for functional skeletal and respiratory muscles activity in the setting of progressive loss caused by denervation results in increased energy expenditure. Another proposed mechanism is termed, the respiratory hypothesis— that increased mREE is due to increased respiratory muscular expenditures. The respiratory hypothesis seems an inadequate explanation because FVC has not been associated with mREE, and although FVC decreases with disease progression and proximity to death, mREE/cREE and mREE remain stable.

In addition, it has been postulated that fasciculations, spasticity, or both contribute to hypermetabolism because they theoretically increase basic muscular tone and thus REE. No correlation between fasciculation or spasticity and REE, however, has been identified. Genetics may play a role in hypermetabolism because familial ALS patients consistently have higher mREE compared with sporadic ALS patients. But the biologic mechanism responsible for this difference remains unknown. Lastly, the increased proportion of calorically demanding visceral tissue in the setting of reduced metabolically active muscle tissue may contribute to hypermetabolism because these organs can become metabolic sinks.

Animal models of ALS, in particular mutant SOD1 and TDP-43 mice, have contributed to understanding of ALS and its pathologic processes. Both models have provided evidence in support of the hypothesis that abnormalities in muscle energy metabolism and mitochondrial function create the energy deficit and hypermetabolism seen in ALS. Animal studies evaluating energy dysmetabolism in ALS have identified defects involving decreased production of ATP, expression of mitochondrial uncoupling proteins, increased concentrations of markers of carbohydrate and lipid metabolism, unspecified mitochondrial defect, and mutant gene expression in muscle and nonmuscle tissues.

Further research is needed to determine the role of each of these potential contributors. ALS murine models, however, have convincingly shown that energy metabolism is impaired and is likely a major factor in creating the hypermetabolism observed in ALS patients.

Muscle Atrophy, Dysphagia, and Their Influence on Nutrition

Muscle mass and contractility are dependent on chemical stimulation from motor neurons. The loss of motor neurons and associated neuromuscular junctions in ALS reduce neuronal signaling to the muscle, leading to mitochondrial dysfunction with mishandling of calcium. The mishandling of calcium in turn leads to the initiation of denervation-induced muscle atrophy, which is further complicated by the altered function of mitochondria, resulting in increased production of reactive oxygen species and overall oxidative stress. The increased oxidative stress can potentiate further muscle atrophy through muscle cell apoptosis and muscle protein degradation.

As ALS progresses, denervation of muscle tissue spreads beyond the region of first symptom, to affect other regions of the body. In spinal-onset ALS, muscle atrophy begins in the upper and/or lower limbs, eventually having an impact on a patient’s ability to self-feed and maintain a seated position with head upright to facilitate a good swallow. The time it takes to independently complete a meal increases in parallel to a patient’s increasing disability. Eventually, ALS patients become dependent on caregivers for feeding, which often results in further reduction of intake from early cessation of meals in an attempt by patients to avoid caregiver burden. Bulbar-onset ALS, affecting the muscles of the tongue, oropharynx, and mastication, creates nutritional challenges for patients due to progressive impairment of chewing and swallowing with resultant dysphagia. In all cases of ALS, inadequate nutrition, whatever the cause, has the potential to worsen muscle atrophy.

Dysphagia, or difficulty swallowing, is a major cause of malnutrition in ALS patients. In cases of bulbar ALS, dysphagia can result from the involvement of the trigeminal, facial, hypoglossal, glossopharyngeal, or vagus cranial nerves. In the early stages of ALS associated dysphagia, lingual dysfunction results in poor food bolus control, uncontrolled loss of the bolus over the back of the tongue, and delayed transition of the bolus from the oral cavity to the pharynx. In the later stages of disease, the mechanisms that cause dysphagia expand to include impaired constriction of the pharynx and decreased elevation of the larynx, resulting in bolus residue in the pyriform sinuses. These complications, compounded by ALS patients’ declining respiratory status, place these individuals at high risk for aspiration and nutritional compromise.

Dysphagia is present in 45% of patients with bulbar onset at diagnosis, and irrespective of onset, nearly 81% of all ALS patients experience dysphagia. Bulbar-onset disease progresses more rapidly to dysphagia compared with spinal onset, which develops later and more slowly. These statistics emphasize the importance of having a speech therapist as a member of a multidisciplinary team or available to provide care for ALS patients.

There are several techniques available to evaluate swallow function, ranging from a simple test of observing patients consume water and assessing for salivary pooling, dysarthria, or speech abnormalities to more complex evaluations that include the use of modalities, such as videofluoroscopy and flexible fiberoptic laryngoscopy. Patients should be asked at each regularly scheduled follow-up evaluation if they are having problems swallowing, have experienced choking episodes, or are coughing while drinking thin liquids, such as water or coffee—often the earliest sign of dysphagia. If symptoms are present, a formal evaluation by a speech therapist should be performed, a referral placed for an evaluation by a registered dietician, and conversations should begin addressing the use of gastrostomy tube in ALS. Early conversation regarding this simple procedure allows patients time to adjust to the idea of having a gastrostomy tube inserted before their swallowing and respiratory status become too impaired. These delayed and weakened oral activities ultimately result in reduced calorie and fluid intake for fear of coughing or choking and/or because of the length of time it takes to complete a meal. Over time and without intervention, dysphagia in ALS patients often results in dehydration, weight loss, and malnutrition.

Dietary Recall and Dietary Modifications

A 24-hour dietary recall and dietary logs are useful tools for registered dietitians and speech therapists. The information gathered through interviews can allow for assessment of progressive changes in dysphagia and overall intake over time. It can be a struggle, however, for patients to provide this information depending on their communication status and familiarity with quantification of portion size. It is not uncommon for overestimation to occur. Gathering of information, such as foods that trigger choking, foods that a patient purposefully avoids, and foods that are difficult to swallow, however, can be ascertained. Determining the length it takes for a typical meal and relating it to a patient’s fatigue can also provide important information regarding calorie intake and hydration because some patients require at least 60 minutes to consume adequate calories during a meal.

Dysphagic patients often benefit from calorie dense foods to help reduce total volume necessary for adequate intake, especially given the trend of mild to moderate energy deficiency. Many ALS patients have been found to consume only 70% of the recommended dietary allowance for energy. Often patients focus on consumption of a high-protein diet because they believe this may ameliorate the reduction of muscle mass due to atrophy. High-energy diets, however, with more calories coming from fat to support fat stores, have been shown to modify energy metabolism, reverse expression of markers associated with muscle denervation, and reduce weight loss, all important for survival in ALS patients.

To accommodate changes in swallowing and chewing and to avoid choking and aspiration, soft, moist, and thickened foods are often recommended. Additives are available that increase the viscosity of beverages and there are beverages that are naturally thicker or prethickened commercially for use. Some supplemental nutrition drinks served chilled are thicker than if served warm or at room temperature. ALS patients benefit from proper instruction provided by a speech therapist on postures that improve swallowing and reduce aspiration risk.

Constipation is a common problem due primarily to a low-fiber diet, dehydration, and minimal physical activity. Unfortunately, this can further contribute to poor appetite. Extra fluids and a mild laxative should be offered. At some point, however, these recommendations no longer support adequate calorie intake because the dysphagia becomes so severe that the need for enteral nutrition becomes the next step.

Malnutrition

Malnutrition is described as loss of greater than 10% of body weight or a BMI lower than 18.5 kg/m ² , and both are considered negative predictors of survival in ALS patients. The prevalence of malnutrition in the ALS population varies among reports, from 16% to 53%. Malnutrition can initiate a vicious cycle for ALS patients, further compromising muscle strength and respiratory capacity due to weakening of both skeletal and respiratory muscles beyond that caused by motor neuron loss. The literature overwhelming shows that a low BMI and malnutrition negatively affect disease progression and thus the survival in ALS patients. Malnourished ALS patients have a 7.7-fold increased risk in mortality.

Anthropometrics

Malnutrition can be assessed using various methods, including anthropometric data, such as body weight, BMI, triceps skinfold thickness (TSF), and midarm muscle circumference (MAMC). It is believed that a sheer reduction in body weight of 5% to 10% from normal can suggest compromised nutritional status and be a prognostic factor for survival. Unfortunately, this range has not been validated in ALS patients. Studies have shown, however, BMI to be strongly associated with survival in ALS with malnutrition below 18.5 kg/m ² for all ages or less than 18.5 kg/m ² for ages 18 to 65 and below 20 kg/m ² for patients over 65 years old. A retrospective study of 427 ALS patients found a U-shaped relationship between BMI and survival with maximum survival observed in patients with BMI of 30 to 35, even when adjusting for FVC, bulbar onset, use of Rilutek, and duration of the disease. Paganoni and colleagues found patients with BMI greater than 35 had greater mortality due to higher frequency of cardiovascular disease (which was also a significant predictor of survival). The use of BMI, however, as a reliable assessment tool for the ALS population is questionable due to neurogenic atrophy, energy imbalance, and dependent edema caused by immobility.

Height and weight measurements are useful; however, they do not give information regarding the type of tissue gained or lost with changes in body weight. Changes in body composition can be assessed using other tools, such as TSF, which provide data regarding fat mass that can be followed over time. TSF is measured using Harpenden calipers, and these measures are compared with a reference table to determine leanness or excessive body fat. Unfortunately, fat distribution is not even; therefore, measuring skinfolds at multiple sites is believed to improve the accuracy of the assessment although no consensus exists as to which combination of sites is best for accurate measurement.

Additionally, there are tools designed to assess somatic protein (skeletal protein mass), which is the body’s major protein store and can be used to assess malnutrition. Measuring somatic protein using the following techniques can be used to track protein nutritional status and be quanitified using standardized tables by gender and age. MAMC gives information about lean body mass using TSF and midarm circumference (MAC) in a formula. The clinical status of ALS patients has been monitored using bone-free arm muscle area (AMA), which combines the TSF and MAMC measurements ( Box 1 ). AMA has been used for studies in the ALS population, providing serial assessment of muscle atrophy. AMA measures correlated significantly with body mass, FVC, and maximal voluntary ventilation. These measures are limited, however, in ALS due to upper limb dysfunction and muscle wasting. Despite their ease of use, the results from ALS patients compared with reference tables may not accurately depict patients’ nutrition status.

Body Composition

Body composition, the assessment of body fat and FFM, can additionally be used to track changes as the disease progresses. Various techniques can be used to measure body composition and each varies in cost and portability. A portable, inexpensive, and simple procedure is bioelectrical impedance analysis (BIA). BIA uses electrical current to measure resistance of body compartments to establish values for lean body mass, fat mass, and total body water.

There are 3 types of devices, 500 kHz monofrequency and 50-kHz and 100-kHz dual-frequency and multifrequency BIAs. BIA has been used in several ALS studies. In 2003, BIA was validated as an outcome measure for ALS studies for both longitudinal tracking and single examination measurements with the use of an adapted equation in conjunction with a frequency of 50 kHz.

Dual-energy x-ray absorptiometry (DXA) directly measures the body’s absorption of x-rays at 2 energy levels, which allows for the direct measurement of body compartments. It is more expensive to use and less portable than BIA. DXA has been used as a measure in the ALS population and studies have found a reduction in fat mass, muscle mass, and bone mass with a fat mass/muscle mass ratio that was low or normal compared with myogenic atrophy patients and control patients. Kanda and colleagues additionally found that DXA provided a clearer distinction between myogenic atrophy and neurogenic atrophy due to increased fat infiltration in the myogenic atrophied skeletal muscle. DXA has provided confirmatory data that ALS patients lose lean body mass over time despite normal or elevated calorie intake. Therefore, weight maintenance or gain in this population, as disease progresses, is likely a reflection of change in body composition with an increase in fat stores. In another study by Tandan and colleagues that followed patients over 1 year, reduced lean body mass occurred over time that correlated with the ALS functional rating scale but not with total body weight, BMI, or FVC.

Both of these tools, BIA and DXA, can track body composition change over time, but each presents a different challenge related to cost, availability, and patient comfort. No definitive studies using either BIA or DXA have demonstrated that the observed changes in tissue distribution are a prognostic factor for survival. It has been argued, however, that a higher fat mass is beneficial for survival in the ALS population due to an observed progressive reduction in body fat stores associated with proximity to death. Additionally, knowledge of a patient’s fat-free mass (FFM) weight, as determined by BIA or DXA, can assist in estimating energy needs in relation to ALS-associated hypermetabolism (discussed later).

Biochemical Indices

Serum markers are useful for different purposes when assessing the nutritional status of ALS patients. Certain serum markers provide information regarding the current nutritional state of patients, whereas others correlate with disease progression and survival. Serum markers used for the assessment of malnutrition in ALS patients include serum albumin, prealbumin, hemoglobin, magnesium, calcium (total and ionized), phosphorous, serum zinc and copper, and retinol-binding protein whereas the creatinine height index (CHI) has been used as a marker of disease progression and survival. CHI is a ratio of a patient’s 24-hour creatinine excretion and the expected normal creatinine excretion for a given height. CHI has been shown to correlate with the degree of muscle depletion in ALS patients. A drop in CHI, with a corresponding elevation in serum calcium, has been observed in close proximity to death in ALS patients. The other markers remain within normal limits, with no gender differences or changes related to time to death.

These tests have been validated as markers of nutritional status in other disease populations but have not been well researched in ALS. Furthermore, these values can be altered by hydration status, inflammation, hepatic failure, or catabolism at the level of the muscle and intestine, and the body often compensates to maintain normal values with slowly progressive malnutrition. Other micronutrients, such as B vitamins, vitamin D, antioxidant vitamins, and minerals, have not been well researched due to the poor correlation of blood values with intracellular stores. Thus, biochemical markers used to assess malnutrition are often less reliable then anthropometric assessments, such as monitoring body weight, BMI, and FFM.

Studies have suggested a positive correlation of hyperlipidemia and diabetes mellitus type 2 in relation to ALS disease onset and prolonged survival time. Hyperlipidemia, obesity, and diabetes mellitus type 2 were found in one study to possibly delay the onset of motor symptoms. Multiple studies evaluating more than 300 subjects have found that patients with hyperlipidemia and elevated fasting total cholesterol and triglycerides as well as elevated low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio had significantly increased survival by nearly 12 months compared with subjects with normal serum lipid levels. Additionally, low levels of LDL and total cholesterol have been associated with lower percent predicted FVC. In a cross-sectional study by Ikeda and colleagues, an inverse relationship was observed between both total cholesterol and LDL values, when compared to the annual decline of the ALS functional rating scale and FVC.

Contrary to these findings, an earlier study of more than 600 subjects found the exact opposite, with no correlation in lipid values with survival time. The investigators observed a significant decrease in lipid levels in those patients with an FVC of less than 70% predicted and interpreted this finding as a indicator that respiratory impairment is related to a decrease in blood lipids. Another study similarly found no changes in length of survival in patients with hyperlipidemia compared with patients with normal lipid values. It has been argued that BMI may be a confounding factor when evaluating the effects of lipid levels in ALS. In 427 ALS patients from 3 clinical trials assessing serum lipids, the LDL/HDL ratio was shown to not be associated with survival after adjusting for BMI. As discussed previously, higher BMIs, between 30 and 35, have been associated with longer survival time in ALS. In spite of the controversy, changes in lipid metabolism with lowering of serum lipid levels is considered one possible sign consistent with hypermetabolism in ALS and may be a sufficient argument against the appropriateness of statin use in this population.

Other biochemical indices studied include uric acid levels. High uric acid levels have been previously linked to a reduced risk of developing Parkinson disease and slower rates of decline as well as slower progression in Huntington disease, multiple system atrophy, and mild cognitive impairment. The mechanism remains unclear but the theory involves its antioxidant properties and its protective influence on neuronal cell death. There have been a few studies showing reduced uric acid levels in the ALS population in comparison with healthy controls and one study found higher baseline uric acid values associated with increased survival in men with levels of 4.8 mg/dL or greater. These same uric acid levels, however, did not show an increase survival for women and only 22% had a level greater than 4.8 mg/dL. Uric acid levels are notoriously higher in men than women complicating the utility of this serum marker.

Often the relevance of common biochemical indices associated with malnutrition in ALS is of questionable value and should be assessed in conjunction with anthropometric measurements. Biomarker research is ongoing and will uncover more accurate and reliable indices to assess nutrition status in patients with ALS. Two recent cross-sectional studies found 23 metabolites related to neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction that were significantly altered in plasma from ALS patients compared with healthy volunteers.

Hypermetabolism

Most ALS patients suffer from hypermetabolism. Reports suggest nearly 100% of patients with familial ALS and 52% of patients with sporadic ALS suffer from hypermetabolism. Hypermetabolism is a strange paradoxic occurrence in the ALS population given denervation, reduced physical activity, and muscle atrophy. It is expected that energy requirements decline under these circumstances. This phenomenon, in conjunction with poor energy intake and swallowing difficulties, is an additional contributor to malnutrition and poor survival in the ALS population.

Hypermetabolism has most commonly been confirmed using the ratio of measured REE (mREE) to calculated REE (cREE). Findings in the ALS population often reveal a ratio greater than 1.1, or 110% of normal. The mREE is obtained by calorimetry whereas cREE is calculated using an established energy equation. Calorimetry is a measurement of the amount of heat eliminated or stored in a system. Direct calorimetry is the measurement of the amount of heat produced by a patient while housed for a certain amount of time within a small chamber. Access to equipment allowing direct calorimetry measurement is limited and often impractical.

Indirect calorimetry is a more often used measure of energy expenditure. This technique uses gas exchange measurements, oxygen consumption, and CO ₂ output to determine the amount of heat produced by patients indirectly. Patients are typically evaluated in a seated position for 20 to 30 minutes and asked to breathe normally under a transparent canopy. Indirect calorimetry is noninvasive and simple to perform but not regularly used to due the cost, availability of equipment, and patient tolerance. Ultimately, indirect calorimetry can be used to help assess energy expenditure and allow for customized recommendations for nutritional support to meet a patient’s mREE and minimize weight loss.

Many studies have evaluated ALS patients comparing indirect calorimetry with calculated energy expenditure equations. The Harris-Benedict and the Mifflin–St Jeor equations have both been recommended for use when estimating energy requirements for ALS patients ( Box 2 ). The Harris-Benedict equation is the most commonly used in these comparison studies, which have found an increase in mREE on average of 14% to 20% beyond that predicted by the Harris-Benedict–derived cREE. One study reported using the Harris-Benedict equation and overestimating patient needs; however, the study cohort included patients with mechanical ventilation, and 11 of the 34 had not fasted overnight before indirect calorimetry testing. Both of these factors compromise the data and thus the interpretation of results. Current thinking supports the addition of a 10% increase in calories beyond the cREE values when providing nutritional recommendations for patients with ALS.

Box 2

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