Why is nutrition vital for advancing ALS care and clinical research?

Abstract

Objective: We endeavor to draw attention to what appears to be a gap in the management of ALS patients and the potential uncertainty of clinical drug trial research results in the absence of a structured approach to ensure nutritional adequacy.

Methods: A selective literature review was curated to focus on the barriers to measure the adequacy of daily nutritional intake in the context of physical challenges and functional impairments facing ALS patients. The consequences of a negative energy (calorie) balance are highlighted and discussed from the perspective of clinical drug trials and daily ALS care.

Conclusion: We propose that by redirecting the emphasis away from the exclusive focus on symptoms to the fundamental principles of maintaining adequate nutritional intake, we will mitigate the consequences of nutrition as an uncontrolled variable to improve global efforts in battling ALS.

Keywords:

• Nutrition
• body composition
• gastrostomy tube
• clinical trials

ALS reveals itself as a multifaceted challenge on many levels. Patients are eager to realize advances in therapy, a sentiment shared by the ALS research community, albeit with cautious optimism. To achieve this goal, we must reevaluate our approach to delivering care and conducting clinical trials.

The mnemonic “FFA” may help. In the context of ALS, FFA signifies “Food—Fluid—Air,” or nutrition, hydration and ventilation, the very foundations of life. These realities must be addressed early and stabilized continually throughout the progressive disease course. This challenge dominates ALS management, and the failure to optimize nutrition could mask the potential effectiveness of research interventions. Frequently, patients or their families are distracted by collateral issues such as the severity of dysphagia or whether they may have completed a meal. The central question, however, is whether oral intake is adequate to meet the requirements for basic nutrition and hydration. Securing energy (calorie) intake to achieve energy balance on a daily basis is THE fundamental goal. This is often not clearly addressed, nor are the negative consequences of failing to sustain energy balance fully appreciated. We must have a laser focus on this from the beginning.

So, why is there a disconnect between medical recommendations based on scientific research and the acceptance by patients? It might be that we do not use the correct vocabulary to explain the basis for our recommendations in clear, unambiguous terms. We do not understand how often, and to what extent, an intervention becomes an ever-present symbol of disease progression in the minds of patients rather than being the “right tool for the job” to preserve independence and function. In this regard, a recommendation for gastrostomy might have a symbolic value of “giving in.” Continued eating by mouth also has symbolic value, as does food itself.

Undoubtedly, one of the biggest unmet needs in ALS is more effective drug therapy. This is not from lack of effort, with over 70 failed drug trials since the 1980s (1). We need to examine the alternative causes for this failure, and many possibilities present themselves. It is likely that we have incomplete or faulty understanding of the basic pathogenesis of sporadic ALS, and that the drug candidates may be off target or underdosed. Much is written about the limitations of different trial designs and the outcome measures. One glaring deficiency is the lack of control and standardization of the basic necessities of life ― nutrition, hydration and to a lesser extent, ventilation. We need look no further than to compare a basic animal study with the typical ALS clinical drug trial. The typical animal study using a monogenic rodent ALS model is highly controlled compared (2) to a human ALS drug trial, as depicted in the Table 1.

Table 1 Comparison of paradigms for ALS interventional studies.

Aspect	ALS Rodent Study	Human ALS Clinical Drug Trial
Genetics	Inbred; genotype known	Outbred
Temperature/Humidity	Controlled; no variation	Variable
Light/Dark Cycle	12 hrs light; 12 hrs dark	Self-choice; variable
Nutrition	Controlled and standardized; no variation; ad libitum access	Not standardized but ad libitum access; use of a PEG tube variable; nutritional status not measured
Hydration	Ad libitum access	Ad libitum access; may be limited by dysphagia
Alcohol/Recreational Drugs	No exposure	Self-choice; variable
Smoking	No exposure	Self-choice; variable
Drug Intervention: Active vs Placebo	Controlled administration Exposure to single drug	Multiple prescribed medications and over-the-counter nutraceuticals Single experimental intervention

Then we pose the identical question to both experimental systems: is the drug safe and effective? Many of the dissimilarities are intrinsic to the differences between the confined, inbred, monogenic experimental animals and the free-living, genetically diverse humans. But, in contrast to the animal studies, we fail to control for (or even measure) the nutritional and hydration status in human studies for ALS neurotherapeutics; this may have contributed to failed trials. For example, a well-nourished ALS participant on placebo may progress more slowly than a malnourished ALS participant assigned to the active drug arm, a circumstance which could obscure a potential positive drug effect (3,4).

So, what should our approach be to standardize nutrition and hydration in the clinic and in the research setting? ALS care providers have an organized approach for detecting ventilatory weakness and are adept at proactively intervening with respiratory support (5). In contrast, the basic principles of nutrition and the negative consequences of energy insufficiency and dehydration are less well-appreciated. The recommendation for gastrostomy is conflated either with the severity of dysphagia or with end-of-life discussions. However, there needs to be a clear-eyed focus on the central issue of adequacy of energy intake versus energy expenditure, i.e. energy balance. The emphasis on daily nutritional sufficiency to maintain energy balance is paramount, via the oral route if safely possible, or via gastrostomy.

How can we practically achieve this in the clinic and in the research setting? We developed a simple approach to serially measure body fat (6) and provide guidelines for maintaining energy balance (7) and hydration (8). Why is fat an important measure of nutritional adequacy? Body fat has been termed a “precious resource” when viewed from the perspective of its primary purpose, namely, ensuring survival during times of nutritional inadequacy such as war, famine or disaster. This is usually considered in the context of malnutrition of an entire population. However, in ALS net energy insufficiency in the face of abundant available calories is primarily the end result of weakness of the upper extremities and bulbar musculature. Hence, serial measurement of body fat is an indicator of the success of current nutritional approaches adopted by patients. Stable or increasing body fat provides prima facie evidence for adequate energy intake. Whereas decreasing body fat indicates that, however valiant the effort, energy intake is outpaced by energy expenditure, resulting in chronic energy inadequacy. Simply put: this is starvation and in ALS results in more severe disease (9), rapid progression (6), and earlier death (6). As with caloric deficiency, dehydration in ALS shortens survival (8). We must move beyond the outdated concept that merely getting through a meal without choking equates with adequate nutritional and water intake. It does not. This concept is a recipe for starvation and dehydration, and all their negative consequences.

Results of the historic Minnesota Experiment of human starvation demonstrate that chronic energy insufficiency decreases body fat as an adaptive survival response, but importantly, when viewed from the perspective of ALS also causes catabolism of functioning skeletal muscle and nutritional muscle atrophy (10,11). Skeletal muscle catabolism is the body’s last resort to make-up for a chronic deficit of oral energy intake and is completely avoidable. Cannibalizing one’s own functioning skeletal muscle is the last thing an ALS patient needs. In ALS, muscle weakness is THE impediment to safely accessing sufficient energy via the oral route, and this energy deficit results in accelerated muscle loss to compensate for preventable malnutrition! Such ALS patients desperately need nutritional intervention to receive adequate energy via gastrostomy (12,13). The breakdown of functioning skeletal muscle to make up for the lack of calories by the oral route is an inescapable biological reality.

Now we get back to the very foundations of life ― nutrition, hydration and ventilation ― FFA if you will, for the management of ALS in the clinic and for human drug trials going forward. The implementation involves recursive measurement of body fat as an index of adequate energy intake (6), in addition to ALSFRS-R to indicate disease severity and progression (14), and %FVC/MIP/MEP as indices of ventilatory status (5). Based on recent research, we developed an app (ALSNutrCalc.ukhc.org) to facilitate the easy implementation of these nutritional principles for ALS management. The interventions are clear and incontrovertible: adequate daily nutrition and hydration via gastrostomy when these needs are unmet orally. By doing so, we will improve not only patient care but also the design of clinical drug trials. We cannot continue to do the same old thing and expect a different result (with all due respect to Albert Einstein’s wisdom).

Declaration of interest

The authors report that there are no competing interests to declare.

Additional information

Funding

Original research was supported by National Institute of Neurological Disorders and Stroke under Grant Ro1 NS045087 and the Cynthia Shaw Crispen Endowment.