Long COVID and Autonomic Nervous System Imbalance

By Joseph Colombo, Michael I. Weintraub, Ramona Munoz, Ashish Verma, Ghufran Ahmad, Karolina Kaczmarski, Luis Santos, Nicholas L. DePace

Excerpt from Long COVID and the Autonomic Nervous System article published in MDPI

Introduction

COVID-19 is documented to adversely affect the autonomic nervous system. In many patients, the lingering effect on the autonomic nervous system results in what has been termed long COVID. Long COVID is well documented to involve the autonomic nervous system.

Autonomic Dysfunction in Long COVID

Autonomic dysfunctions may be peripheral or central. In central cases, autonomic dysfunctions may be related to microglial hyperactivation inside the brainstem autonomic centers. Microglial hyperactivation is associated with PE. Autonomic dysfunctions may also be highly influenced by psychological factors.

Parasympathetic Excess and Sympathetic Withdrawal in Long COVID

In our findings, Long COVID is largely characterized by parasympathetic excess and sympathetic withdrawal, both potentially contributing to hypoperfusion of the brain and all structures above and around the heart. Pre-COVID-19 infection, patients presented to the clinics with more sympathetic withdrawal (45.7%) than parasympathetic excess (27.0%). Post-COVID-19 infection, these patients presented with that ratio reversed (36.2% and 46.7%, respectively). The etiology of this is not well known; however, parasympathetic excess may be more prominent post-COVID-19, due to an over-active immune system, which the parasympathetics help to control and coordinate and leads to parasympathetic excess.

Role of the Parasympathetic Nervous System in Immune Response

Given that the parasympathetic nervous system controls and coordinates the immune system, severe infections lead to excessive and prolonged parasympathetic activation in response to challenges or stressors (known as parasympathetic excess), which exacerbates autonomic and cardiovascular dysfunctions.

Orthostatic Dysfunction and COVID-19

A common, and perhaps first cause of autonomic dysfunction, due to mitochondrial dysfunction and associated oxidative stress, is orthostatic dysfunction, resulting in poor cardiac and cerebral perfusions (and, of course, all the structures around and above the heart). Orthostatic dysfunction is caused by poor vasoconstriction due to alpha-adrenergic (sympathetic) dysfunction, known as sympathetic withdrawal. Poor perfusion and dysfunction are exacerbated by the effect of COVID-19 on the lungs. Both parasympathetic excess and sympathetic withdrawal are separate and treatable dysfunctions.

Pharmaceutical Treatment of Autonomic Dysfunction

As in this study, parasympathetic excess was treated, pharmaceutically, with anti-cholinergics (e.g., Nortriptyline, see the Methods Section) and sympathetic withdrawal was treated, pharmaceutically, with oral vasoactives (e.g., Midodrine, see the Methods Section). Our findings demonstrate an initial worsening of autonomic dysfunction and symptoms associated with COVID-19 infection, and then, with autonomic treatment, these dysfunctions and symptoms may again be relieved.

Sympathovagal Balance and Post-COVID-19 Syndrome

Traditionally, upon COVID-19 infection, there is a marked increase in the resting sympathetic activity and a decrease in anti-inflammatory resting parasympathetic activity, causing a high (resting) sympathovagal balance in all patients. However, in post-COVID-19 syndrome patients, after 12 weeks or more, our data shows that there is a significant percentage of patients that develop a parasympathetic dominance as indicated by the low (resting) sympathovagal balance. This is also indicative of increasing and prolonged parasympathetic activity.

Protective Role and Complications of Parasympathetic Activation

Parasympathetic activation is meant to be protective; including, since the parasympathetics are anti-inflammatory. However, prolonged and increased parasympathetic activity, especially in response to stressors, seems to exaggerate sympathetic inflammatory activity. Within this cohort, and anecdotally with the vast majority of our patients, anti-cholinergic therapy relieves parasympathetic excess. Further studies are required to elaborate whether anti-cholinergic therapy may relieve post-COVID-19 symptoms.

Symptoms of Long COVID Linked to Oxidative Stress and P&S Dysfunction

All symptoms of long COVID may be explained by oxidative stress and P&S dysfunction. For example, P&S dysfunction leading to orthostatic dysfunction underlies poor cerebral (including all structures above the heart) perfusion, which causes fatigue, brain-fog, cognitive and memory difficulties, sleep difficulties, and other depression-like symptoms, including “coat-hanger” pain, headaches and migraines; cranial nerve dysfunctions, including visual and auditory effects (including tinnitus), taste and smell deficits, and facial sensations due to trigeminal nerve dysfunction.

Blood Pressure and Cerebral Perfusion Compensatory Mechanisms

P&S dysfunction may also increase BP (and may eventually lead to hypertension) as a compensatory mechanism to promote cerebral perfusion. Further decreases in cerebral perfusion may lead to “adrenaline storms”, which cycle anxiety-like symptoms, including shortness of breath and palpitations which may cause chest pressure or chest pain. The effects of sympathetic withdrawal and orthostatic dysfunction are exacerbated by parasympathetic excess, which may limit or decrease the heart rate and blood pressure, reducing cerebral perfusion. The decrease in BP is also associated with excessive vasodilation from parasympathetic excess.

Prolonged Parasympathetic Excess in Long COVID

If the parasympathetics increase in response to a stress (known as parasympathetic excess), the result is a secondary sympathetic excess. Our findings of prolonged parasympathetic excess in long-COVID patients appears to prolong sympathetic excess responses causing more and chronic symptoms, suggesting that this may be a mechanism contributing to long-COVID syndrome.

Conclusion and Need for Further Research

Pharmaceutical therapy for P&S dysfunction (anti-cholinergics for parasympathetic excess and oral vasoactives for sympathetic withdrawal) needs to be very low to prevent additional symptoms, thereby exacerbating P&S dysfunction. From Table 3, COVID-19 significantly increases autonomic dysfunctions and the associated symptoms, and autonomic therapy significantly reduces autonomic dysfunctions and the associated symptoms. Further studies are needed, including blinded, controlled studies.

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients Joseph Colombo 1,*, Michael I. Weintraub 2,*, Ramona Munoz 1 , Ashish Verma 1 , Ghufran Ahmad 1 , Karolina Kaczmarski 1 , Luis Santos 3 and Nicholas L. DePace 1 1 Franklin Cardiovascular, Autonomic Dysfunction and POTS Center, Sicklerville, NJ 08081,USA;  rmunoz@franklincardio.com (R.M.); ashish@ashishverma.com (A.V.); ghufran.kmc@gmail.com (G.A.); kikaczmarski@gmail.com (K.K.); dovetech@erols.com (N.L.D.) 2 Department Neurology and Medicine, New York Medical College, Valhalla, NY 10595, USA 3 New Jersey Heart, Sicklerville, NJ 08081, USA; drlou214@icloud.com * Correspondence: jcolombo@physiops.com (J.C.); miwneuro@gmail.com (M.I.W.)

NeuroSci 2022, 3, 300–310. https://doi.org/10.3390/neurosci3020021

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By Joseph Colombo and Nicholas L. DePace

 Pathophysiology of Long‑COVID

The mechanism behind the causation of Long-COVID syndrome may be multifactorial.  Immune response, antibody generations, direct effects of the virus, complications of the critical illness, psychosocial factors, and post-intensive care syndrome, post-traumatic stress, and oxidative stress may be operative mechanisms. Cardiac deconditioning may also be a factor.

The mechanism of heart failure involving pro-inflammatory cytokines with interleukin 1 and interleukin 6 tumor necrosis factors may cause prolonged effects. Redox imbalance linking COVID-19 and chronic fatigue syndromes and systemic inflammation and neuroinflammation have also been postulated. Oxidative phosphorylation may be operative in a hyper inflammatory state with altered cardiorespiratory function. It is thought that viral infections cause a shift in mitochondrial energy system contribution from ATP synthesis to innate immune signaling occurring in order to eradicate pathogens, promote inflammation, and eventually restore tissue homeostasis. An increased rate of glycolysis and downregulation of oxidative phosphorylation are seen. Oxidative stress has been implicated in many acquired myocardial disorders and may lead to significant autonomic dysfunction.

This Post is an excerpt from: Current Cardiology Reports https://doi.org/10.1007/s11886-022-01786-2 HEART FAILURE (HJ EISEN, SECTION EDITOR) Long‑COVID Syndrome and the Cardiovascular System: A Review of Neuroradiologic Effects on Multiple Systems Nicholas L. DePace1,2,3 · Joe Colombo1,3,4 Accepted: 12 September 2022 © The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2022

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By Joseph Colombo, Michael I. Weintraub, Ramona Munoz, Ashish Verma, Ghufran Ahmad, Karolina Kaczmarski, Luis Santos, and Nicholas L. DePace

Long COVID and the Autonomic Nervous System

The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. SARS-CoV-2 targets diverse organs and tissues after entry into the human body. Long-COVID syndrome is defined as persistent symptoms beyond 12 weeks after acute COVID-19 infection. Viruses, by inducing an inflammatory state, can damage tissue. At a cellular level, the mitochondria are susceptible to the effects of inflammation and oxidative stress. Given that nerve cells, including brain cells, and heart muscle cells contain significantly more mitochondria than other cells in the body, it is to be expected that they will be the most affected by oxidative stress. The results of mitochondrial dysfunction includes primarily autonomic dysfunction (including both parasympathetic and sympathetic (P&S)) and cardiovascular dysfunction.

 Arguably, the first symptom of P&S dysfunction is orthostatic dysfunction. Orthostatic dysfunction is a significant contributor to poor cardiac and cerebral perfusion (and, of course, all structures around and above the heart). Autonomic dysfunction is also induced as a result of the severity of the infection. Furthermore, COVID-19 injures the lungs, reducing their ability to exchange oxygen, exacerbating the poor perfusion and resulting dysfunctions. The initial respiratory compromise, due to the COVID-19 virus, on the medullary respiratory control centers (including the pre-Bötzinger complex) may be so dramatic that P&S symptoms and signs are often overlooked or misunderstood. Respiratory pacing from the pre-Bötzinger complex involves vagus nerve afferents, among other brainstem structures;  feedback from the COVID-19-damaged lung; aortic and carotid chemo, baro, and vagal receptors; and medullary chemoreceptors. All involving P&S nerves. Brainstem cardiorespiratory centers (e.g., the Nucleus Tractus Solitarius, Dorsal Vagal Motor Nucleus, and Nucleus Ambiguus, all of which are autonomic nuclei) are also implicated in COVID-19 infection. Furthermore, sympathetic involvement in cytokine storms and the angiotensin system, and parasympathetic involvement in immune function, provides further evidence of P&S compromise in COVID-19 infections.

Any resulting damage to these nerves further implicates P&S dysfunction in long-COVID syndrome. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This study presents the data obtained from autonomic dysfunction patients who were P&S tested and treated prior to COVID-19 infection due to other causes of autonomic dysfunction. Then, they were P&S tested and treated after surviving COVID-19 infection. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This is hypothesis generating. Long COVID is characterized by parasympathetic excess and alpha-sympathetic withdrawal. Anti-cholinergic therapy may relieve post-COVID-19 symptoms associated with parasympathetic excess. This is hypothesis generating and further trials are needed.

This Post is an excerpt from NeoroSci: https://www.mdpi.com/2673-4087/3/2/21