People with ALS now have more options to deal with a distressing set of symptoms called bulbar signs. These include difficulties with speech, swallowing, and salivation that result from neurodegeneration of the bulb-shaped brainstem. The brainstem gives rise to motor neurons controlling head, neck, and facial muscles. At the International ALS/MND Symposium December 11-13 in Orlando, Florida, scientists presented promising results from two clinical studies. Richard Smith of the Center for Neurologic Study in La Jolla, California, shared how a drug called AVP-923, trade named Nuedexta, improved bulbar symptoms compared to a placebo. Edward Kasarskis of the University of Kentucky in Lexington offered another option to deal with excess saliva. He reported that radiation therapy to fry salivary glands proved effective and, importantly, safe.

When ALS attacks the brainstem, it causes facial muscles such as the tongue to atrophy. A person’s speech becomes hoarse or wheezy, making him or her difficult to understand, and many patients lose the ability to speak altogether. It can become hard to swallow not only food but also saliva. That, combined with trouble holding one’s head up and mouth closed, often results in drooling, too, even though people with ALS do not make more saliva than others. People find this distressing, Kasarskis noted; they may have to use a bib. Plus, not swallowing one’s saliva means losing up to 1.5 liters of water a day, risking dehydration.

Smith found a potential solution to the three bulbar signs—speech, swallowing, and saliva—in a medication used to treat another symptom of brainstem motor neuron disease, pseudobulbar affect. This occurs in ALS and other conditions when the neural circuits that control emotional response break down. People laugh or cry involuntarily, sometimes even if they are not feeling amused or sad. Nuedexta was approved in 2010 to treat pseudobulbar symptoms (Cruz, 2013). The main ingredient is dextromethorphan, an activator of the sigma-1 receptor and antagonist of NMDA receptors. The same stuff is commonly added to cold medicine because it suppresses the brain pathways that trigger coughing. Nuedexta also contains quinidine, which slows breakdown of dextromethorphan so it remains active in the bloodstream. Scientists are also testing Nuedexta for agitation in people with Alzheimer’s disease (see Sep 2015 news). 

Scientists are not sure how dextromethorphan works against pseudobulbar symptoms, but the sigma-1 receptor prevents protein aggregation in the endoplasmic reticulum, protecting cells from apoptosis due to protein stress. Mutations in the sigma-1 gene are implicated in both juvenile ALS and motor neuron disease associated with frontotemporal dementia (see Aug 2011 newsLuty et al., 2010). 

Smith initially prescribed Nuedexta for people with ALS who had emotional symptoms. He noticed that they reported bulbar improvements, too. To assess this objectively, Smith and colleagues recruited 60 people with ALS for a Phase 2 trial. Half received Nuedexta for a month, and the other half placebo. Then, after a couple of weeks to allow any drug to leave their systems, participants switched to the other treatment arm for a second month.

To evaluate the drug, the researchers came up with a 21-item scale, the Center for Neurologic Study-Bulbar Function Scale, by which people with ALS could rate their bulbar symptoms. They specified how often they experienced items such as difficulty making themselves understood, indicating they had trouble speaking clearly. A person with no problems would score a 21, and the worst possible score was 105. On this subjective scale, people on Nuedexta averaged significantly better (54) than the placebo group (59).

The drug worked regardless of whether people had emotional symptoms. However, about a quarter of the participants did not respond to the drug. Smith was unsure why. He also does not know how Nuedexta worked against bulbar symptoms, though he suspects the benefits resulted from its action on sigma-1 receptors.

Merit Cudkowicz of Massachusetts General Hospital in Boston, a co-principal investigator on the study, was pleased to see positive results from an ALS trial, where good news is rare. Cudkowicz has already started prescribing Nuedexta for her patients with bulbar symptoms. She predicted it could benefit many more since most people with ALS develop bulbar problems sooner or later.

Richard Bedlack of the Duke ALS Clinic in Durham, North Carolina, said he also has started to prescribe Nuedexta to many more of his patients since learning about the trial results. “It is very exciting,” he said, noting that previously physicians had no treatments to relieve difficulty with speech and swallowing.

“These results are quite promising and deserve further research,” added Kasarskis. He focused his presentation on just one of those bulbar issues, salivation. Cudkowicz, who did not participate in Kasarskis’ study, said it can be one of the hardest ALS symptoms to treat. Usually, physicians prescribe anticholinergic drugs, but they do not work for everyone and can have unpleasant side effects such as dizziness and constipation. As a second option, doctors can inject botulinum toxin into the salivary gland. Both methods work by interfering with acetylcholine signaling at synapses in the glands. However, using too much of the botulinum toxin could make swallowing even more difficult, and Cudkowicz said doctors often under-dose for fear of that. The notion of using radiation therapy for excess salivation has been around for decades, but neurologists worried that it was irreversible, and that if it worked too well a person would have a perpetually dry mouth. Cudkowicz said she has only prescribed it once.

Kasarskis and colleagues dared to give it a go. In 2011, they reported on 10 people who received radiation therapy (Kasarskis et al., 2011); at the meeting, he presented retrospective data from a total of 32. In total, his clinic has treated about 50 people with radiation, he said. They signed on because the salivation bothered them, or anticholinergic medications had failed.

Radiologists focused an electron beam at the parotid salivary gland in just one side of the mouth, through the skin of the outer cheek, leaving the other gland alone. People who received the therapy noted less saliva flow within weeks. To measure salivation objectively, the researchers placed cotton wads in each person’s cheeks for five minutes. Participants found it more comfortable to do both cheeks at once. The scientists weighed the cotton before and after, to calculate saliva production. Before radiation treatment, the average person produced about 2.5 grams of saliva in five minutes. After treatment, this dropped to about half a gram. The benefit lasted for at least two years, Kasarskis said, leading him to postulate it was “probably permanent.”

Importantly, the treatment was safe. One person suffered a bit of reddening skin at the radiation site, but this was temporary. No one developed dry mouth. Some people were able to stop taking the anticholinergic drugs; others found the medication more effective after radiation therapy.

“I was impressed not only by how effective this is for drooling (a very common and difficult-to-treat problem), but also how safe,” commented Bedlack. “I do plan to start offering this to patients who do not have a good response to medications.” Cudkowicz said that based on Kasarskis’ results, she would consider radiation the second line of treatment for salivation problems, ahead of botulinum toxin.

Kasarskis noted that researchers still need to work out the ideal dosing schedule. The University of Kentucky center administers a total of 1,500 centigray—a measure of how much radiation matter absorbs—over three different days to minimize adverse reactions to the radiation, such as skin blistering or nausea. That dose is low in terms of traditional radiotherapy, but may not be the ideal approach, Kasarskis said.—Amber Dance

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References

Therapeutics Citations

  1. AVP-923

News Citations

  1. Paper Alert: Promising Phase 2 Results for Agitation Drug Published
  2. New ALS Genes Implicate Protein Degradation, Endoplasmic Reticulum

Paper Citations

  1. . Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. P T. 2013 Jun;38(6):325-8. PubMed.
  2. . Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann Neurol. 2010 Nov;68(5):639-49. PubMed.
  3. . Unilateral parotid electron beam radiotherapy as palliative treatment for sialorrhea in amyotrophic lateral sclerosis. J Neurol Sci. 2011 Sep 15;308(1-2):155-7. Epub 2011 Jul 2 PubMed.

External Citations

  1. Phase 2 trial

Further Reading

Papers

  1. . The evidence for symptomatic treatments in amyotrophic lateral sclerosis. Curr Opin Neurol. 2014 Oct;27(5):524-31. PubMed.
  2. . A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014 Mar;21(3):529-36. Epub 2014 Jan 21 PubMed.
  3. . Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2013 Nov;12(11):1059-67. Epub 2013 Sep 23 PubMed.