Nuedexta has plausible mechanisms for improving bulbar function in PALS. Some PALS reported concomitant improvement in bulbar function for at least a short period when taking Nuedexta for PBA. A well-designed phase II trial in PALS demonstrated the efficacy of Nuedexta in patient-reported bulbar function, and the preliminary result of another trial showed improvement in bulbar physiology. However, its long-term effect on bulbar function is unclear, and one open-label study showed a lack of benefit in one year. There is no evidence suggesting Nuedexta slows down progression or prolongs survival. Nuedextacauses mild to moderate side effects, but severe side effects directly caused by Nuedexta have not been reported. It should be avoided in patients with a known history of prolonged QT interval. Given all this, we feel there is sufficient evidence to consider Nuedexta treatment for bulbar dysfunction in ALS patients with and without PBA. Financial burden and periodic assessment of its efficacy should be considered for the latter.
Patient case reports
Anti-Mycobacterial Antibiotics
There is a theorized association between MAP and ALS, and two published case reports described improvements in ALS-like conditions (both with atypical features) after treatment with antimycobacterial antibiotics. Based on these, we believe it would be reasonable to perform chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between MAP and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.
Ketogenic Diets
Ketogenic diets have plausible mechanisms for treating ALS. One flawed preclinical study and two PatientsLikeMe participants reported benefits; these were not independently verified. Two other PatientsLikeMe participants and one patient under
the care of an ALSUntangled investigator did not show benefits. A trial of a ketogenic diet was only able to enroll a single patient and their experience cannot be interpreted due to the lack of any control group. We hope to see another trial of a ketogenic diet in people with ALS. Until then, given the frequent side effects, we do not advise such diets for the treatment of ALS
Azathioprine
As an immunosuppressant drug, AZA has a plausible mechanism for slowing the progression of ALS. However, there is no pre-clinical data to support its use and two clinical trials did not support efficacy. There are 2 published cases in which
ALS reversals occurred on AZA, but it is not clear to us that the AZA actually contributed to the ALS improvements. One of these patients also had myasthenia gravis, which is known to cause reversible weakness and therefore complicates the measurement of ALS. The other patient was taking many different medications and supplements along with AZA. AZA has very serious, potentially fatal, both short and long-term risks associated with its use and requires medical monitoring. Based on the
available data, we do not advise the use of AZA as an ALS treatment
Acetyl-L-Carnitine
There are good theoretical mechanisms for carnitines, some pre-clinical evidence for LC and ALCAR, and a single clinical trial that suggested ALCAR could slow disease progression in PALS. All three carnitines appear to be well-tolerated, generally safe, and inexpensive. We believe that there is a need for future clinical trials of carnitines in PALS to further elucidate their efficacy. Until there is further data, we cannot endorse any of these supplements as a definite way to slow ALS progression; however, oral ALCAR at 1000mg three times daily (3000 mg total daily dose) appears to be a theoretically promising supplement available for PALS whom would like to self-experiment.
Vitamin E
Vitamin E (a-tocopherol) is perhaps the most studied supplement in the history of ALS and was taken by one of the most famous ALS patients. Vitamin E has mechanistic potential in ALS as an antioxidant but appears in the SOD1 mutant mouse model to only have an effect on delaying disease onset. This bears out in human populations as large prospective cohorts show that long-duration vitamin E supplementation may decrease the risk of ALS, but randomized clinical trials show that even high dose vitamin E does not benefit the disease once ALS has been diagnosed. Although it is inexpensive and safe, we do not recommend vitamin E to slow, stop or reverse ALS
based on the lack of efficacy in clinical trials.
Glutathione
As an ALS treatment, glutathione and cysteine-containing supplements that increase glutathione appear reasonably safe, and they have a plausible mechanism, positive preclinical data and 2 interesting case reports. Unfortunately small clinical trials of glutathione itself and of acetylcysteine showed no significant benefit. Given these negative clinical trials, we do not advise PALS to take glutathione or cysteine-containing supplements for their ALS at this time.
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Gluten-Free Diet
Theoretically, gluten-induced autoimmunity could trigger ALS. However, the data supporting this link are weak, consisting of two association studies and a single case-report. Further studies are needed to confirm the relationship between GRDs and ALS, and the utility of the GFD in patients with both conditions. In spite of the fact that GFD is reasonably safe, it is a complex undertaking and is more expensive than a standard diet. While we wait for better data, it would be reasonable to screen PALS who have GI symptoms, iron-deficiency anemia, or an abnormal brain MRI for the antibodies associated with GFDs. Those with elevated antibodies could be referred to a gastroenterologist for further work-up, and if this is consistent with a GRD, then GFD could be tried under the guidance and monitoring of a dietician.
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