Using alcohol as a tool to unravel laryngeal dystonia: The Vodka Trial

I am happy to welcome to the podcast the senior author on this paper, Professor Kristina Simonyan from the Department of Otolaryngology, Head and Neck Surgery, Harvard Medical School and Mass Eye and Ear and Department of Neurology at Massachusetts General Hospital. Welcome to the podcast, Professor Simon 

Prof. Kristina Simonyan: Thank you very much for the invitation. It's great to be here with you.

Dr. Divyani Garg: Laryngeal dystonia is a rare but life altering condition that disrupts a person's ability to [00:01:00] speak, and for years, patients and clinicians alike have noticed something remarkable that alcohol seems to improve symptoms for some people. But how much of this is anecdotal and how much is rooted in biology?

So this study brings objectivity to the question by combining a standardized alcohol challenge test with specific pathophysiology driven genetic analysis, we'll explore alcohol's role in dystonia, specifically in laryngeal dystonia, the genetic signatures that may predict responsiveness and what this could mean for the future of treatment of laryngeal dystonia specifically, but also dystonia in general.

To help us unpack these findings, we'll discuss the challenges of studying alcohol in a clinical setting, what the results reveal about the GABAergic pathways and how these insights could open the door to safer and more targeted therapies. So let me begin by asking you, professor, just as an introduction to our listeners, what is laryngeal dystonia?

How frequent is it among the dystonia, and why is it so challenging to treat?

Prof. Kristina Simonyan: Yes. Laryngeal dystonia is a form [00:02:00] of dystonia which causes uncontrollable spasms in the laryngeal muscle. It has an interesting phenomenology as these spasms predominantly occur during production of voiced speech. And they sound as breakages on vowels or voiceless consonants that are aced by strained struggled and near breathy quality of voice. In contrary to voiced speech production patients with laryngeal dystonia are nearly asymptomatic during production of other vocal tasks such as whispering, laughing, crying and so on. Laryngeal dystonia occurs in about 50,000 people in North America. It is a rough estimate as we do not know the exact incidence of this condition.

However, this number is likely to be [00:03:00] underestimated because, is quite challenging to diagnose this condition as it has features of other voice disorders such as voice tremor or non neurological condition, muscle tension, dysphonia, and the similarities between symptoms of this condition sometimes are misleading in the clinical setting, and they lead frequently, unfortunately, to misdiagnosis of laryngeal dystonia. The reason why it is difficult to treat because, on average patients are known to get their first diagnosis about five and a half years after the first onset of symptoms. So this misdiagnosis also leads to the delayed treatment. And in general dystonia are difficult to treat because there are no specifically designed therapies.

And we will talk [00:04:00] probably about botulinum toxin injections, which are the first line of care in this patient. However, there are mostly use for symptom management rather than the treatment of disorder. And that's why looking into the pathophysiology combined with symptomatology of this disorder is likely to lead to the identification of novel therapeutic options.

Dr. Divyani Garg: Speaking of botulinum toxin, what has been your experience with respect to the success of botulinum neurotoxin for laryngeal dystonia? Your experience as well as experience from other groups? Because for focal dystonia, botulinum neurotoxin is among the foremost therapies that is offered to patients.

Prof. Kristina Simonyan: Botulinum toxin injections, as I already mentioned, are known as the first line of symptom management for dystonia as well, this including laryngeal dystonia. [00:05:00] However, several studies especially the ones coming from large population studies such as Dystonia Coalition have shown that only about 60% of patients with dystonia receive injection.

The highest use has been noted in patients with laryngeal dystonia and blepharospasm, but only about half of these patients receive injections. So there is much larger population of patients who go untreated. The efficacy of botulinum toxin also is dependent on the clinical form of dystonia.

Even within laryngeal dystonia, it is well known that patients with adductor form of laryngeal dystonia get most of benefits. Benefits range between 70 and 90% of voice improvement while patients with abductor form of laryngeal [00:06:00] dystonia get much less benefits. And smaller number of patients with abductor laryngeal dystonia also gets treated. All together, n early one third of patients receive no treatment. Botulinum toxin injections have been also shown to have little to no effect on the pathophysiology of laryngeal dystonia. And this again brings me to the point that while it is the first line of treatment, currently, it is mostly managing symptoms rather than treating the disorder, treating the neural alterations known to be present in these patients.

Dr. Divyani Garg: Which brings me to the topic of the study. So historically, how have clinicians and patients noticed the effects of alcohol and dystonia symptoms, and specifically on laryngeal dystonia, and why was it important to move from anecdotal [00:07:00] reports to objective testing?

Prof. Kristina Simonyan: This is an interesting question because this knowledge of alcohol responsiveness was building up really gradually. I started noticing during research studies when we screen patients with various questionnaires and so on. I have noticed that patients mention that drinking glass of wine or beer helps with their symptoms.

And in the beginning I thought that's probably just a general effect of alcohol. Most people feel better after maybe a glass of drink. And I myself was little skeptical about this in the very beginning, and I'm talking about 15, 20 years ago. But listening more carefully to patients actually helped, more and more [00:08:00] patients started reporting when asked directly, does alcohol help your symptoms? And they could precisely describe how it helps them. So I came to thinking that maybe there is more just the general effect of alcohol in this patient. In conversations with clinicians, I also discovered that they also observed or heard from patients that their symptoms improved from alcohol.

So this gradually turned into a study that we published back in 2015, and that was the first study in patients with dystonia that looked into their alcohol responsiveness. The first study was online survey where we distributed the online questionnaires through patient support organization as well as through our extensive database, clinical [00:09:00] database.

And we received responses from over 400 patients and carefully asking them about, not directly, having questions about generally about their disorder and so on, but also incorporating questions whether alcohol helps, whether others notice difference in their voice quality and whether they would be interested in taking any drugs that have effects similar to alcohol, we discovered that close to 58% of patients report that their voice symptoms do improve after two drinks, one to two drinks. And importantly, their friends and family members have also noted that in the majority of them, there is indeed voice improvement. Which made us [00:10:00] think that this is not a only a patient's subjective experience, but maybe a real part of phenomenology and potentially even pathophysiology given that alcohol has a central effect.

Dr. Divyani Garg: Wow. It is amazing that you listen to the patient experience and took it far forward which has resulted in so much work on this aspect. And the really intriguing part of which is, and I wanted to ask you about this is, why is alcohol responsiveness observed in some dystonia? We know that alcohol responsiveness is well established in the SGCE related myoclonus dystonia syndromes, but also in essential tremor.

What is the pathophysiology to explain this alcohol responsiveness.

Prof. Kristina Simonyan: We don't quite understand the pathophysiology, a full spectrum of predispositions to alcohol responsiveness or central response in terms of being coupled [00:11:00] with symptom improvement. Neither in essential tremor which has been known for decades to be alcohol responsive, nor in dystonia or other movement disorders.

And I think this is the field that really needs a focus because this may also lead to the development of drugs or interventions that mimic the effects of alcohol. They can harness this part of pathophysiology for the development of novel therapies. Following our initial study that I just talked about which was focused on laryngeal dystonia.

Few follow up studies using data from dystonia coalition cohort across different forms of dystonia have also confirmed that patients with other forms of dystonia, as well respond to alcohol. [00:12:00] Obviously not everybody responds to alcohol, but there is a sizable population of patients to make this an interesting observation and interesting phenomenology that which led us obviously to the conduct of this standardized challenge, alcohol test study where we were able to rely not only on patient's own response, but also objectively evaluate the effects of alcohol on dystonic symptoms. And in terms of pathophysiology there are more ongoing studies that are looking into brain changes associated with alcohol intake in these patients.

So hopefully this data will be available soon and we can have a little more deeper understanding of [00:13:00] what may or may not be involved and how it may be different from patients who do not respond to alcohol.

Dr. Divyani Garg: So the study has a very interesting methodology, particularly with respect to the intervention that was used and the follow up. And so can you walk us through the standardized alcohol challenge test? What makes it rigorous compared to self reports, and also briefly through the study methodology.

Prof. Kristina Simonyan: Of course. Patients were recruited with laryngeal dystonia and also those who had accompanying voice tremor, which is part of a dystonia phenomenology. And they underwent rigorous testing at the baseline as well as after alcohol intake, which included, their vital signs, breath alcohol content levels, cognitive assessment assessment, of sleepiness following alcohol intake as well as a baseline and the assessment of [00:14:00] suicidality which was important to assess the side effects and risk effects of taking alcohol and also as potentially developing other drugs that have similar effects as alcohol. But we want to prevent serious side effects.

This was very fun study for everyone. As you can imagine, especially that patients would come on Monday morning and get two shots of alcohol as part of the study. All patients receive standard 0.8 gram over liter of non-diluted 40 proof vodka, which was calculated based on each patient's total body water content.

So that's the standard for this alcohol challenge test that has been used also in other movement disorders most recently in essential tremor. To sustain the effects of [00:15:00] alcohol we gave patients two drinks because based on our previous study from 2015, the majority of patients mentioned that they need one to two drinks with the average of two.

So we wanted to make sure we don't undertreat and we capture the full set of symptoms. They went through baseline assessments, as I already mentioned. They received the alcohol drink and then they went through the same assessments 15 minutes later and then got another drink.

And then we repeated the assessments every 15 minutes for three hours. We collected data on their own response, which is important to have patient driven outcomes. But we also collected the clinician objective measures where we recorded their voice symptoms at each time point and [00:16:00] also assess cognitive function, suicidality, sleepiness, and so on.

And we evaluated these rating scales as well as blindly counted quantified symptoms in their voice recordings before and after alcohol. So in this way, in this study, we combined both clinician the global improvement and patient global impression measures, which led us understand how the two would correspond to each other and how patient's own perspective on their voice symptoms aligns or does not align with a clinician observed improvement

Dr. Divyani Garg: That sounds wonderful, especially the Monday morning challenge would've prompted enthusiastic participation, I'm certain

Prof. Kristina Simonyan: Certainly.

Dr. Divyani Garg: So, in the study a total of 109 patients were enrolled into the study I noted, and roughly around half of the patients showed meaningful symptom improvement after alcohol intake, which was [00:17:00] interestingly independent of the patient demographics or the dystonia subtype or the severity.

What does this reveal about the neurobiology of laryngeal dystonia?

Prof. Kristina Simonyan: This is very interesting question because we just talked about botulinum toxin and how patient demographics and dystonia subtypes form different forms of dystonia may or may not affect the outcomes. It is likely that alcohol has more universal effect independent of form of dystonia because patients both with adductor and abductor with or without voice tremor responded to alcohol and there were no statistically significant differences between different forms, in terms of other response. Some explanation for this is the central [00:18:00] action of alcohol versus botulinum toxic injections.

And again, this potentially opens the avenue for the development and further use of drugs that mimic the effects of alcohol. It is also notable that we have collected blood samples from these patients as we wanted to address some aspects of pathophysiology linked to this alcohol responsiveness and as we described in the paper, we have identified five variants that were enriched within the GABAergic pathway related genes in patients who responded to alcohol versus those who did not respond. And among those five genetic variants, two specific variants were associated with the improvement of dystonic voice symptoms.

Our [00:19:00] conclusion was that together with a central effect and potentially effect on modulation of abnormal neural activity in these patients, there is also genetic predisposition for alcohol responsiveness in certain patients. And this is an important finding because future studies may consider using this information for developing prescreening tools or prescreening measures that would stratify patients for treatment with alcohol effect mimicking drugs. We obviously cannot give alcohol in the clinic and we cannot prescribe alcohol as a drug to treat symptoms. But there is a family of drugs that act similar to alcohol and they can be explored. And in fact, [00:20:00] we have already gone that direction.

And we recently published a double blind randomized controlled trial of sodium oxybate, which mimics the effects of alcohol. It is a standard treatment for sleep disorders. And repurposing it for patients with alcohol responsive dystonia, we in fact found that their symptoms significantly improve, and it has also a central effect on normalizing abnormal brain activity in these patients associated with treatment.

Dr. Divyani Garg: Fantastic. For those of our listeners who are interested in the neurobiology of laryngeal dystonia, I just want to call out to another wonderful podcast that was recorded by Professor Simonyan, which is episode 140 on a task specific brain oscillatory activity in laryngeal dystonia. Thank you for sharing about the genetic aspects because that was something very interesting and striking in the paper that you have assessed genetic variants in the genes, [00:21:00] specifically related to the GABAergic synapse.

And I understand that it was important to combine the clinical testing with this genetic analysis. One is to understand the neurobiology, and the second was as a guidance to future therapy. Now given the risks of alcohol consumption, how should clinicians interpret these findings without encouraging harmful drinking behaviors?

Do you wanna put out a word of caution?

Prof. Kristina Simonyan: Of course. Alcohol consumption should come with warning no matter if individual has dystonia or not. Especially with dystonia patients. It was sobering finding that patients with dystonia do not necessarily abuse alcohol, but they do take more alcohol, especially the ones who improve from alcohol.

They tend to drink alcohol before major events where they need their voice being better or in situations, then they [00:22:00] need to project and they know their voice improves. This was a finding from our 2015 study and that also was another motivation to continue this research because obviously alcohol consumption should come with a warning. There are many risks involved, especially drinking alcohol during day and being at work or engaging in highly important executive or cognitive functions and so on. As I said we cannot and should not prescribe alcohol as treatment for laryngeal dystonia or any other dystonia.

However we can harness this knowledge and look into interventions that mimic the effects of alcohol, but do not come with risks and side [00:23:00] effects of alcohol consumption. And those drugs are much better studied, more controlled, and so on.

Dr. Divyani Garg: That's wonderful. And you did mention that you are already looking at drugs that kind of mimic alcohol's mechanisms like sodium oxybate or octanoic acid, and I was even wondering about gabapentin as an option. Would that be in the same line?

Prof. Kristina Simonyan: Generally, in the same line however it appears, and there is more research needs to be done for this. It appears that these drugs act on a different GABAergic receptors, and that makes all the difference. Usually benzodiazepines are not as effective in laryngeal dystonia. And as opposed to that to benzodiazepines, sodium oxybate for example, or octanoic acid, they have been shown to much better [00:24:00] improve dystonic symptoms.

So again, we don't understand quite well the pathophysiology the mechanism of action specifically in dystonia patients. However knowledge from some experimental studies in animals indicate that how they act different subunits of GABAergic receptors, makes the difference for clinical outcomes.

And again, more research is needed in this space to fully understand the interaction between GABAergic drugs. The ones that show benefits and the ones that not. So the interaction between these drugs and neuro pathophysiology and genetics of dystonia that research still needs to be expanded and developed for us to fully understand how these [00:25:00] drugs and how alcohol in general works in these patients.

Dr. Divyani Garg: Wonderful. So with that, we come to the end of this podcast. Thank you Professor Sionyan for joining me today and for your wonderful insights. It has been truly a pleasure to converse with you.

Prof. Kristina Simonyan: Thank you so much. It was a pleasure talking to you.