An integrative approach to amyotrophic lateral sclerosis

Photo Cred: Harrison Broadbent/Unsplash

By Ken Sharlin

The earliest description of amyotrophic lateral sclerosis (ALS) goes back to 1869, and is attributed to the father of neurology, Jean-Martin Charcot. Most famously in the United States, ALS is referred to as Lou Gehrig’s disease. The New York Yankees first baseman died of the condition at the young age of 37, but many other icons of the American cultural landscape, including jazz virtuoso Charles Mingus, playwright and actor Sam Shephard, and perhaps most interesting to integrative practitioners, Roy Walford, MD. The story of Walford sets the stage for an integrative practitioner’s approach to ALS.

Walford, a physician and pathologist by training, and pioneering researcher in the biology of aging, was emeritus professor at the University of California in Los Angeles, when he died of the disease at the age of 79. Perhaps most notably, he wrote the 120 Year Diet, based on the principle that a nutrient-dense diet consisting of about a third calories typically recommended by the United States Department of Agriculture had the potential to extend life expectancy by several decades.

His approach became known as the Calorie Restriction with Optimal Nutrition (CRON) diet. Evidence to support his idea was based on studies going back to the 1930s, which demonstrated the benefit of a calorie-restricted diets in rodents. It made sense that the same principles should hold true in humans, but it had never been studied. In 1991, Walford had the opportunity to become the inside physician of the Biosphere 2 Project in the Arizona desert. The Biosphere, a self-contained ecosystem, was created to explore how humans might support and maintain life in outer space. Unexpectedly, the Biosphere could only produce about 83 percent of the total diet needed to support the scientist inhabitants. This shortage provided an opportunity to see his experiments play out in humans. In fact, the diet did show improvements comparable to what Walford had found in his experiments, reflected by changes in physiological, hematologic, hormonal, and biochemical parameters.    

On the surface, it would seem like a success, but it was not all good for Walford. As an unexpected consequence of the design, while living in Biosphere 2, he was subject to toxic levels of carbon monoxide and nitrous oxide. In addition, he and the rest of the crew suffered periods when the oxygen level in the structure was dangerously low. Walford was observed at times to have slurred speech or bump into things while walking. Initially, it was through that these changes were a transient state of delirium and would reverse with rebalancing of the gases in the atmosphere. But Walford’s speech and gait never recovered. Although initially thought to have an atypical parkinsonism, Walford was ultimately diagnosed with ALS and died of respiratory failure in 2004.

According to the ALS Association, every 90 minutes, someone is diagnosed with and someone passes away from ALS. It is estimated to affect at least 16,000 people in the U.S. Half of all people affected live at least three or more years after the diagnosis, but only about 20 percent live five years or more, and only 10 percent will live more than 10 years.

ALS is characterized by progressive deterioration of the neurons that give muscles their power the so-called upper motor neurons (UMNs) that begin in the cerebral cortex and extend their long axons all the way down to the spinal cord and lower motor neurons (LMNs) that synapse with the UMNs and comprise the motor portion of the peripheral nerves. Formally, the diagnosis of ALS is made using the World Federation of Neurology El Escorial Criteria that divides the likelihood of disease into categories based on available evidence—suspected, possible, probable, and definite. The history is that of progressive weakness, unexplained falls, difficulty swallowing or changes in speech, cramping or spasm of muscles that can be painful, and sometimes with cognitive impairment or  inappropriate crying and laughing. In my experience, rapid weight loss early in the disease is common.  

A careful physical exam is critical. The patient should be gowned or wear clothing that can be pushed aside for inspection of the upper arms, chest, back including paraspinal muscles, thighs, and calves. These areas and the tongue should be screened carefully for visible fasciculations and atrophy. Strength testing in the arms and legs will reveal multifocal weakness. Reflexes can sometimes be brisk while at other times diminished, depending on whether lower motor neuron pathology predominates, which will always result in diminished deep tendon reflexes. Sensation changes are not part of ALS, and, if identified, must be explained as a separate problem, or the diagnosis of ALS may be incorrect.

No commercially available biomarkers of the disease exist. Confirmation of the diagnosis depends largely upon the use of electromyography-nerve conduction studies with exclusion of other disorders based on clinical suspicion or reasonable possibility, and the use of imaging modalities such as MRI, spinal fluid examination, and serology for investigation of these other disorders. The differential diagnosis includes pathology affecting the spinal cord (compressive myelopathy or syringomyelia) or peripheral nerves (B12 deficiency, multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy), toxicity such as with lead or mercury, copper deficiency, infections such as Lyme disease, and certain types of cancers.

Since I am a neurologist whose approach is integrative, I still believe the cornerstone of a solid clinical approach is to identify the correct diagnosis before investigating contributing root causes. Taking this a step further, if diseases are a result of a combination of genetic susceptibility, lifestyle, and environmental insults, then my strategy is largely focused on integrating lifestyle and environmental modification to reduce inflammation and oxidative stress. This approach, in turn, influences gene expression, including susceptibility genes, in such a way that health, rather than disease, is promoted at the level of the cell and the organism as a whole.

While cases of familial ALS do exist, about 90 percent ALS sufferers are considered sporadic. Among sporadic cases, two investigative approaches have yielded contrasting estimates as to the impact of genes on the risk of ALS. Genome-wide association studies have identified the heritability of sporadic ALS to be between 12 and 21 percent while one twin study found the heritability to be about 61 percent. Although a handful of gene variants are more common, particularly the Chromosome 9 open reading frame 72 triple repeat expansion (C9orf72), and superoxide dismutase 1 (SOD1) the risk of sporadic ALS is associated with mutations in over 25 genes. C9orf72 triple repeat expansions are responsible for RNA gain-of function toxicity. Similarly, the SOD1 mutation seems to trigger a toxic gain-of-function by altering mitochondrial protein composition and decreasing protein import, ultimately damaging mitochondria. These genetic vulnerabilities are not enough, however, to trigger ALS. Instead, it is apparent that multiple environmental triggers over time, combined with genetic susceptibility, turns healthy motor neurons into degenerating ones.

Based on this information the principles and practices of integrative medicine are equally suited to help the patient with ALS as they are for other neurological conditions we treat. A deep dive investigation into the triggers of inflammation and oxidative stress is required, including micronutrient imbalances, fatty acid imbalances, chemical and heavy metal toxin exposure or impaired toxin clearance, microbial infections, food allergies and food sensitivities, environmental triggers of the cellular inflammatory response, gut barrier disruption, blood-brain barrier disruption, microvascular changes, EMF exposure, and hormone imbalances including cortisol, thyroid, and gonadal. Gathering patient information on how their lifestyle factors act as both triggers and mediators of inflammation and oxidative stress is also critical.

Returning to Walford’s case, beyond his known toxic exposures to nitrous oxide, carbon monoxide, and the chronic hypoxia, his diet as a Biosphere physician consisted of 10 percent fat, 15 percent protein, and 75 percent carbohydrate. The calorie restriction caused him to lose 25 pounds. ALS patients have abnormally high energy demands. Weight loss is strongly associated with shorter survival in ALS. In addition, individuals who have a lower weight prior to the diagnosis also appear to have a worse prognosis. Whether the high carbohydrate diet, at one point consuming as many as 471 grams of carbohydrates per day, also played a role in triggering or mediating his disease is unknown, but interestingly a ketogenic diet may slow the progression of disease, as long as calorie needs are met and body weight is maintained. The two years of confinement in the Biosphere were characterized by heated arguments and warring between the inhabitants suggesting chronic emotional stress may have contributed to the pathogenesis of his disease.

Finally, from a structured effort to understand documented cases of ALS reversal, it is possible to gain greater insight into specific nutraceutical supplementation that may assist the integrative practitioner. Interim research from the Pooled Research Open-Access ALS Clinical Trials Consortium has been published, and further research is ongoing. While a discussion of the individual mechanisms of action are beyond the scope of this article, the investigators found the odds of taking curcumin, luteolin, cannabidiol, copper, glutathione, vitamin D, and fish oil were higher for reversal cases than controls. While they offered the caveat that these therapies should be further evaluated in clinical trials in the meantime, they represent additional tools available when approaching the patient with ALS.