Long COVID as an Autonomic Disorder: Neuromodulation might hold the key to Long-Covid and Chronic Fatigue Syndrome (ME/CFS)
Author
Dr Elisabetta Burchi, MD, MBA
Clinical Psychiatrist
Translational Research Lead at Parasym
Editor: Dr. Greta Dalle Luche, PhD, Head of R&D
Long COVID as an autonomic disorder: Neuromodulation might hold the key to Long-Covid and Chronic Fatigue Syndrome (ME/CFS)
In the wake of the COVID-19 pandemic, the emergence of the long COVID syndrome has triggered considerable scientific interest. Long COVID is a complex and persistent condition characterized by debilitating symptoms such as pain, extreme fatigue, and brain fog triggered by COVID infection, but independent of it. A recent meta-analysis concluded that 43% of people infected with the virus would continue to experience COVID symptoms after having cleared the initial infection.
Previously, the majority of long COVID cases that received immediate attention were those who presented with obvious organ damage with lasting symptoms or those with severe respiratory problems and needed extended therapy. People with neurological symptoms were often overlooked or even dismissed as merely psychological trauma due to the hospitalization. But as more evidence has surfaced, we have begun to understand more about the conditions and the associated neuropsychiatric symptoms.
Long COVID is a manifestation of an autonomic dysfunction
Dr. Liesbeth Denef from OVIVE Medical Centre recounted her harrowing experience with a COVID-19 infection and the subsequent unfolding of long COVID syndrome. “It was the most horrible experience you can ever imagine for me. I got all the symptoms and I wasn’t feeling well. Then suddenly, I got something that felt like a panic attack, like a surge coming out, I couldn’t see anymore. I was getting dizzy, I fell on the floor. I couldn’t breathe and I was like, what is happening?”
“I had the feeling that the level of inflammation in my body was very high. [When] my baseline of inflammation was very high, every other small virus that came by, I would get back to this COVID response. You are in this vicious cycle of being in this inflammatory state, and then reacting to every virus that comes by, you just can’t put it down. And what helped a lot, [was that] I knew my vagus nerve was underactive,” she explained during an interview with Parasym.
Autonomic dysfunction has been implicated in both acute COVID-19 infection and long COVID syndrome. Several reports identified more than 200 symptoms associated with long COVID and autonomic dysfunction(?), with alterations to cardiovascular, respiratory, and neurological systems. Autonomic dysfunction could persist for years after the infection with SARS-CoV-2. In addition, certain vulnerable patients may demonstrate a rapid and severe deterioration contributing to substantial morbidity and diminished quality of life.
The vagus nerve is an essential part of the autonomic nervous system. Its primary function is to regulate critical body functions such as heart rate, digestion, and respiration. The vagus nerve is also responsible for the broader “fight or flight” response, as it is part of the parasympathetic nervous system. Symptoms of autonomic dysfunction observed in the majority of long COVID patients demonstrated a high degree of similarity to individuals with impaired vagus nerve functions. Notably, symptoms such as systemic inflammation and an overactive immune system could underpin the hypothesis that vagus nerve impairment played a significant role in long COVID.
A recent study that looked into the morphological alterations of the vagus nerve in Long COVID found that over 60% of patients e had a significantly reduced diaphragm thickness and mobility, which manifested as weakened respiratory muscle that contributed to the shortness of breath. Other striking structural abnormalities detected included a substantially smaller cross-sectional area of the vagus nerve, thus pointing to an important pathogenic role of the SARS-CoV-2 virus in eliciting vagus nerve dysfunction that ultimately presented as dysautonomia.
Vagal Neuromodulation to relieve long COVID syndrome
Neuromodulation through the vagus nerve has fascinated clinicians over the years as it has been FDA approved for epilepsy and depression, but also investigated inused for many other clinical different conditions. As scientists have begun to better understand the function of vagus nerve impairment in Long Covid, several successful attempts have been made to manage the symptoms via vagus nerve stimulation. Parasym has collaborated with several renowned institutions, including the Icahn School of Medicine at Mount Sinai5, the Human Waves Clinic and Université Libre de Bruxelles6, and Casa Colina Hospital and Centers for Healthcare7 to investigate the therapeutic effect of non-invasive vagal neuromodulation in long COVID but also in associated syndromes such as chronic fatigue syndrome (or myelitis encephalopathy).
There is currently no approved treatment specifically for long COVID. Early results are currently available to showcase the true potential of vagal neuromodulation in treating long COVID syndrome. In the pilot study conducted by the Human Waves Clinic and Université Libre de Bruxelles, 20 patients who underwent vagal neuromodulation therapy for only 10 days demonstrated substantial improvement over multiple clinical outcomes. The study authors stated that a mere 10 sessions with the Parasym device could lead to “very significant improvement” for patients, and such an effect persisted over one week after the treatment had ended.
Figure 1: Improvement in the outcome measures of long COVID syndrome after vagal neuromodulation therapy in (A) Intensity of symptoms, (B) fatigue score, and (C) Depression score
Dr Denef, who is not involved in the study but runs her own clinic and long COVID webinars, said “I’ve been feeling much better so I feel like ready to help other people,” said Dr Denef after her successful therapy with the Parasym device. “I put everybody on the Parasym device, and I’m seeing amazing results,” she added.
The intimate link with chronic fatigue syndrome
One of the most commonly reported long COVID symptoms is post-viral fatigue, which is also frequently reported in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Long COVID and ME/CFS share manysymptoms beyond fatigue, such as problems with attention and concentration, muscle aches and pain, and post-exertional malaise where any exertion would severely exacerbate all other symptoms.
“ [Long Covid] runs very similar to chronic fatigue syndrome, or myalgic encephalomyelitis. It doesn’t appear to be related to the severity of the original COVID infection, it could be people who’ve got a very mild original infection, but then over the coming weeks and months, they start noticing this post-exertional malaise. So they will do any sort of activity, but they just feel disproportionately tired afterwards,” explained Dr David Strain, a Senior Clinical Lecturer at the University of Exeter Medical School who is also a member of the NHS Long-COVID Taskforce.
In a recently completed collaborative study between Parasym and the Icahn School of Medicine at Mount Sinai, it was shown that close to 60% of all patients who suffered from long COVID syndrome demonstrated significant improvement with the use of Parasym in at least one of the predetermined criteria, ranging from fatigue to quality of life.
“Vagal nerve stimulation actually makes a lot of sense biologically and seems plausible.” said Dr. Strain. “It is something that would fit with the observations. We have seen in ME that there is actually a hyperadrenergic status for those who are having their [exacerbations], therefore, a vagal stimulator would seem to be a sensible choice in those patients,” he added.
“Vagus nerve stimulation would actually make a very attractive treatment for patients who were most severely affected,” Dr. Strain concluded in his interview with Parasym.
Patient selection criteria and stimulation protocol
As the more severe manifestations of long COVID seems to be induced by a state of hyperinflammation, patients with elevated inflammatory markers might benefit most from vagal neuromodulation therapy. In the Human Waves Clinic’s study, patients with long COVID syndrome and high level of inflammatory markers showed substantial benefits with the therapy. Nonetheless, we postulated that any patients who report long COVID syndrome post-infection may benefit from the treatment.
Parasym protocol of use is designed to be very practical and accessible to everyone everywhere. The results reported were obtained with as short as 30 min of daily stimulation at home.
Parasym is currently offering opportunities for research collaboration, focusing on the role of neuromodulation in long COVID and/or CFS. We hope the program will spark a wider interest among healthcare professionals to inquire about the benefits of vagal neuromodulation as an effective therapy for long COVID and welcome any clinicians to reach out to us.
To participate in the program as a clinic, research institution or a healthcare professional, please contact us
To learn more about Nurosym device, visit our website.
References:
1. Chen, C. et al. Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review. J. Infect. Dis. 226, 1593–1607 (2022).
2. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).
3. Woo, M. S. et al. Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol. (Berl.) 146, 387–394 (2023).
4. Lladós, G. et al. Vagus Nerve Dysfunction in the Post-COVID-19 Condition. SSRN Scholarly Paper at https://doi.org/10.2139/ssrn.4479598 (2023).
5. Natelson, B. Vagus Nerve Stimulation as Treatment for Long Covid. https://clinicaltrials.gov/study/NCT05608629 (2023).
6. Long-Covid Treatment | ParasymTM. http://parasym.co/long-covid.html.
7. Zheng, A. Multimodal Investigation of Post COVID-19 in Females: A Pilot Study. https://clinicaltrials.gov/study/NCT05225220 (2023).
8. Natelson, B., Blate, M. & Soto, T. Transcutaneous Vagus Nerve Stimulation in the Treatment of Long COVID-Chronic Fatigue Syndrome. Preprint at https://doi.org/10.1101/2022.11.08.22281807.
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