As mentioned in my primer page and capstone blog post, treatment for ALS is palliative, meaning it is not intended to cure or directly increase survivability in patients. ALS is still a terminal disease, so treatment is about improving quality of life, so people do not spend the last months or years of their life in pain and boredom. However, some progress has been made in increasing longevity to a marginal extent. I will begin with that, then go into the nonmedical ways to manage ALS symptoms. By the time people see symptoms, they have very similar cellular problems, so treatment and management for ALS usually does not depend on genetic or sporadic cause.
Quality of life and productivity-management treatments work by using physical and psychological assistance to sustain mental health and salvage some of the activities patients could engage in before paralysis. A multidisciplinary team of professionals is always helpful; the team can include neurologists, specially trained nurses, pulmonologists, speech therapists, occupational therapists, physical therapists, respiratory therapists, nutritionists, psychologists, a social worker, and a genetic counselor (in ALS1 cases) (Siddique and Siddique 1993). A part-time, in-home caregiver can be a boon for ALS patients, and they may be covered by insurance.
As paralysis progresses, new management strategies must be employed to deal with the new symptoms, some of which are not readily obvious. Feeding tubes or purees can help to maintain nutrition when swallowing becomes difficult. Losing control of your body can cause depression, so antidepressants are sometimes prescribed. Technology and analog tools can be of assistance, including alphabet boards for communication (only useful if patients can move their fingers), walkers, wheelchairs, stairlifts, ventilators (although patients usually decline this option), and bidets (Siddique and Siddique 1993). Digital alphabet boards controlled only by the eyes are in development as of 2020.
As mentioned in other pages, the two drugs approved for ALS treatment are riluzole and edaravone. Riluzole, approved in 1993, is thought to act as a glial glutamate transporter (Trotti et al. 1999), removing D-glutamate from the synapse, thereby reducing neuron stimulation and slowing disease progression (see Figure 3 in the Disease Mechanism page). Other studies consistently find that glial cells, especially microglia and astrocytes, play a major role in ALS (Mondola et al. 2016). There is variation in who benefits most, but on average riluzole increases lifespan by two months when taken regularly, compared to placebo (Bensimon et al. 1994). Edaravone was developed much more recently, with the drug thought to be a free radical collector, reducing the load on SOD1. It is used on a smaller subset of ALS patients, and often in conjunction with riluzole (Abe et al. 2007, Siddique and Siddique 1993).
Just as with any illness, such as COVID-19, alternative medicines are used by some patients. Patients often elect to take vitamin supplements, including vitamin E, vitamin C, B vitamins, selenium, zinc, coenzyme Q10, and herbal preparations such as ginseng, ginkgo biloba, and Maharishi Amrit Kalesh (Siddique and Siddique 1993). Most of these are antioxidants, which should reduce the existing oxidative stress. The placebo effect certainly helps in some of these homemade treatments, but there is reason to believe they are not inherently helpful. A Cochrane review (published before edaravone was approved) looked at various ways of treating ALS and separated anecdotal evidence from reputable trials. They found that only glutamate blocking agents (like riluzole) and enteral feeding tubes were effective at increasing longevity in ALS patients. Antioxidants, like the alternative medicine described above, were found ineffective, with vitamin E at higher doses having a toxic effect. However, several treatments were found to need more supporting data to be evaluated. These include insulin-like growth factor-1 (IGF-1), drugs prescribed for treating pain (including cannabis), and treatments for muscle spasticity. Moderate therapeutic exercise would be expected to hurt the already damaged neurons, but the normal benefits of exercise are already well-documented in healthy individuals, so it is not clear how moderate exercise would affect ALS patients; unsurprisingly, the Cochrane review found more data is needed (Orrell 2010).
An increasing number of researchers are speculating that the reason for the failure of so many ALS treatments is because patients in the trials are not separated by genetic cause. These researchers say that the heterogeneity in sample groups, including both ALS1 and sporadic ALS patients, masks the effectiveness of some drugs that only act on specific cases, skewing results away from statistical significance, especially with SOD1 FALS (Beghi et al. 2011). The Cochrane review had similar views on this. This might make sense when looking at the disease mechanism, since only SOD1 ALS1 directly increases ROS concentration by having a lower Km for hydrogen peroxide, which might make it more treatable by antioxidants and free radical scavengers, like edaravone. This will be a focus of ALS research in the twentieth century, though it mainly helps patients with ALS1, who are the minority.
Finally, I will discuss the preliminary and future research in ALS. Keep in mind that a lot of this is speculation, that’s why clinical trials are underway. The big question about ALS is why only motor neurons are affected, since SOD1 is necessarily present in all human cells. Although the high energy needs of neurons create more oxidative stress, which connects to ALS, researchers continue to look into what else is involved and why other high-consuming organs, like the kidney, are not affected. Researchers are looking into related defects in RNA processing, protein recycling, and associated glia and how they contribute to ALS, and for the possibility of a biomarker for different forms of the disease (ALS Fact Sheet 2013).
Less robust evidence has been found for a few other mechanisms of ALS, either adding to or kickstarting the central ROS/amyloid plaques pathway. The ALS Association recognizes four such mechanisms, none of which are specific to FALS or ALS1. Defects in axonal transport may be a mechanism, and it would be most noticed in spinal cord axons since they are so long. Cell death by necrosis or neurodegenerative apoptosis is another, vague mechanism, and this could be facilitated by glia. A third mechanism is overstimulation of the synapse by glutamate, previously mentioned in the context of riluzole. The most compelling mechanism is mitochondrial damage, especially to calcium transport, which is vital for neurons. Changes in motor neuron mitochondria can be observed before any clinical symptoms, which is a strong indicator that ALS begins in the mitochondria (Disease Mechanisms 2020), and which makes sense in the context of SOD1’s disease mechanism. These are the themes that will define ALS research in the mid-twentieth century.