Stellate Ganglion Block Successfully Treats Long COVID/PASC: A Case Series

The SARS-CoV-2 pandemic has resulted in a secondary pandemic of individuals suffering from pernicious symptoms termed “Long COVID” or PASC. In spite of signicant societal impact, the condition remains mysterious and effective treatment remains elusive. Individuals experience debilitating symptoms including fatigue, “brain fog,” loss or altered smell and/or taste, anxiety and depression. Most of these symptoms are included in the “sickness behavior response” initiated from the brainstem when levels of circulating pro-inammatory cytokines are high. Ordinarily a feedback loop prevents excessive production of these cytokines, however the SARS-CoV-2 virus has demonstrated the ability to induce the sympathetic nervous system (SNS), likely due to imbalance between ACE1 and ACE2 activity. Persistent sympathetic drive causes increased cytokine release, which interferes with the feedback loop that ends “sickness behaviors.” The stellate ganglion is a paravertebral collection of sympathetic nerves located in the cervical region that provides a convenient entry point to reduce activity of the SNS using local anesthetic blockade. The stellate ganglion block (SGB) has a well-established safety and ecacy prole for a variety of conditions involving the SNS. In this case report series, we treated three consecutive “Long COVID” patients with SGB. All three patients reported signicant and durable improvement in symptoms including fatigue, “brain fog,” and smell and taste derangements. Our ndings provide evidence implicating dysautonomia as the main etiology of Long COVID/PASC symptoms and suggest that SGB is an effective intervention for this condition with the potential to change the course of the second COVID pandemic, “Long COVID”/PASC. with Long COVID/PASC. Injection of local anesthetic onto the stellate ganglion, a cervical paravertebral collection of sympathetic nerves, reduces sympathetic output of the ANS. In this case series, we successfully treated three consecutive Long-haul COVID patients using SGB, implicating dysautonomia as the main etiology of Long COVID/PASC and suggesting a novel treatment.


Introduction
The global pandemic caused by the SARS-CoV-2 virus has resulted in millions of deaths and untold suffering worldwide. A subset of individuals develops a range of symptoms that persist inde nitely after recovery from acute infection. The constellation of symptoms, which can range from mild to debilitating, is known colloquially as "Long COVID" and formally as PASC (Post-Acute COVID-19 syndrome, or Post-Acute Sequelae of SARS-CoV-2 infection). Symptoms can include fatigue, shortness of breath, "brain fog," sleep disorders, fevers, gastrointestinal symptoms, anosmia, dysgeusia, anxiety, and depression. PASC can follow severe COVID-19 or develop following asymptomatic infection. The condition continues to ba e the medical community and effective treatments remain elusive.
The stellate ganglion is a collection of sympathetic nerves located paravertebrally between C6 and C7, with projections to the arm, head, and chest. The stellate ganglion block (SGB) was rst described in the 1930s as a treatment for re ex sympathetic dystrophy of the upper limbs [1]. The stellate ganglion in uences blood ow to the upper extremities, making blockade useful in the treatment of Raynaud's phenomenon and hyperhidrosis [2]. More recently, SGB is showing promise in the treatment of PTSD [3] [4], cardiac arrhythmia [5], hot ashes associated with cancer treatment and menopause [6], as well as immunological disorders such as allergies, asthma, atopic dermatitis, and ulcerative colitis [7]. Although the functional connectivity of the stellate ganglion in humans remains only partially known, central effects of SGB are hypothesized to occur due to communication with CNS structures that in uence the sympathetic branch of the autonomic nervous system [7]. SARS-CoV2 has demonstrated the ability to cause post-acute sympathetically-mediated autonomic dysfunction affecting sleep [8], resting heart rate [9], orthostatic intolerance and dyspnea [10]. This case series provides evidence implicating dysautonomia as the main etiology of Long COVID/PASC symptoms and suggests that SGB is an effective intervention for this condition, with the potential to change the course of the second COVID pandemic, Long COVID/PASC. Case Presentation 1. A 48-year-old male who recovered from severe COVID-19 presented to our clinic 16 months after onset of initial illness. The patient sustained signi cant lung damage during acute phase of infection and had required supplemental oxygen for more than a year. Due to deconditioning, he completed six months of physical therapy in order to resume activities of daily living. While he had intermittently regained some ability to detect smell and taste, these senses were distorted and generally unpleasant. The patient reported severe mental fogginess and de cits including di culty retrieving words, recalling numbers, di culty recognizing familiar faces, and episodes of topographical disorientation in familiar places.
We performed right-sided SGB and observed the expected physiological responses (e.g., Horner's syndrome). Within hours, the patient reported reduction in mental fogginess and partial restoration of taste. The following day, left-sided stellate ganglion block was performed. The patient reported additional improvement in his mental clarity and sense of taste. On follow-up at 11 days after his second SGB, the patient noted "incredible" durable improvement in his mental clarity and concentration, speci cally citing restoration of numerical recall ability, word-nding capacity, and facial recognition. He had experienced no episodes of disorientation since treatment, and reported normal ability to smell and taste.

2.
A 42-year-old female who recovered from a mild course of COVID mainly presenting as low oxygen saturation, fatigue, anosmia and dysgeusia, presented to our clinic eight months after onset of initial illness. Since recovering from acute illness, she continued to experience debilitating fatigue, mental fogginess, di culty concentrating, elevated resting heart rate, sleep disturbance, lack of appetite and food aversion due to diminished and altered sense of taste and smell. Due to decrement in performance, she had been let go from her job and was teaching 4-hour CPR courses with di culty, relying on her teaching manual to recall facts and procedures previously well known to her. The unpalatability of any food had led to a 30-pound weight loss that was continuing to progress. Patient charts indicated a resting HR in the 60s prior to COVID-19; at presentation she reports that it had not been less than mid-80s since recovering from acute COVID-19.
We performed right-sided SGB. The patient noted immediate improvement in her dysgeusia and marked improvement in mental clarity and concentration. She later recalled being able to drive home without conscious effort to recall the route, demonstrating noticeable improvement in procedural memory. Two days later we performed left-sided SGB. On follow-up at 22 days after her second SGB, the patient reported that her sleep had returned to normal and she felt rested upon awakening. Her resting HR was measured at 69, and she reported restoration of taste and smell. Since her treatment, she was able to teach a 9-hour course for CPR instructors without the need to reference the teacher's manual or written notes, demonstrating a drastic improvement in declarative memory. These improvements in symptoms were durable at 30-day follow-up. 3. A 44-year-old female contracted COVID-19 approximately eight months prior to her presentation for treatment of PASC. Her initial COVID-19 symptoms were loss of smell and taste, mental fogginess, headache, and dyspnea. Approximately one week after onset of symptoms her headache worsened, prompting evaluation in the ER but not hospitalization. Her headache symptoms dissipated over the following two weeks, but she experienced declining cognitive function and developed stuttering speech, signi cant cognitive impairment, and hemi-sided paralysis, prompting hospitalization and evaluation for MCV. Her MRI demonstrated in ammation, but neither stroke nor viral encephalitis. She was discharged with a diagnosis of brain injury secondary to COVID-19 and prescribed intense occupational, physical, and speech therapy for profound de cits in procedural and declarative memory, speech impediment, impaired coordination, inability to concentrate, and debilitating fatigue. She was unable to continue her work as a special education teacher.
She presented to the clinic after approximately seven months of slow but steady improvement in her physical and mental condition with the help of intense daily physical, occupational, and speech therapy. She continued to experience debilitating fatigue and speech impediment, and had returned to limited duties and shortened hours at work. She reported that ongoing dysgeusia had led to food aversion and signi cant unintentional weight loss. She was experiencing generalized body pain (4/10) described as dull with pins and needles. When exacerbated, her pain reached 10/10 and she was unable to get out of bed. She noted that acute stress exacerbated her right-sided motor de cits. She also experienced intermittent headaches described as "crawling pain in my brain." We performed right-sided SGB followed by left-sided SGB the following day. Within hours of the rst procedure, the patient reported drastic improvement in smell and taste. At three-day follow-up she indicated that her physical and mental stamina had improved signi cantly, allowing her to perform routine household activities without debilitating lapses in procedural memory. She began a new job as a high-school teacher and was able to teach a full day of classes, which she states would have been "impossible" prior to treatment. On follow-up at 15 days, the patient reported durable resolution of stuttering and 75% improvement in all other symptoms.

Discussion
A number of groups have noted the association between autonomic nervous system dysfunction and the symptoms of PASC [10] as well as the comorbidities associated with increased morbidity/mortality in COVID-19 [11]. The autonomic nervous system and immune system are inherently linked through the cholinergic anti-in ammatory pathway (CAP), a component of the parasympathetic nervous system in which the afferent vagus nerve senses pro-in ammatory cytokines and the efferent vagus nerve releases acetylcholine that binds the α7 subunit of the acetylcholine receptor (AChR) in macrophages, thereby inhibiting cytokine release [12]. This feedback loop prevents cytokine-associated tissue damage. In addition to its role in CAP, the afferent vagus nerve monitors cytokines and catecholamines in the periphery and reports levels to the brainstem where the information is integrated into complex behaviors. When circulating levels of pro-in ammatory cytokines and catecholamines are su cient, the brain initiates "sickness behavior"-a constellation of autonomic responses including behavioral inhibition, fatigue, malaise, depressed mood, reduced social exploration, hyperalgesia, anhedonia, anxiety, and neurocognitive issues [13].
The targeting of the ACE2 receptor by SARS-CoV-2 has been speculated to cause an ACE1:ACE2 imbalance that leads to an excess of angiotensin II [14,15], which activates sympathetic out ow to peripheral target organs including the heart and kidneys, an effect that is consistently seen in chronic heart failure (CHF) [16]. Circulating levels of norepinephrine (NE) in cardiac sympathoexcitation are increased due to spillover of 10-20% of synaptic NE into circulation [16]. While NE is largely associated with anti-in ammatory activity due to post-ganglionic activation of β2-adrenergic receptors in lymphoid tissues [17], circulating NE is also sensed by myeloid cells via α1 adrenoreceptors, leading to increased myeloid expression of cytokines and activating sickness behavior. In some cases, spillover NE may be su cient to disrupt the CAP's anti-in ammatory signal to macrophages and complete the feedforward loop seen in cytokine release syndrome [18], a condition that resembles the respiratory distress and multiorgan failure seen in severe COVID-19. We hypothesize that the chronic autonomic dysregulation known to follow SARS-CoV-2 infection [8-10] perpetuates sickness behavior after resolution of infection, leading to the symptoms seen in Long COVID/PASC. Reduction of sympathetic activation would be expected to break this vicious cycle of autonomic dysregulation.
Our patients uniformly reported signi cant improvement in fatigue, mental fogginess, and memory issues after SGB, con rming a sympathetically mediated process involved in the maintenance of PASC symptoms. Given the involvement of the sympathetic nervous system in the initiation and maintenance of sickness behavior, we believe that SGB produces these bene cial effects by attenuating chronically aberrant sympathetic dominance. This supports the theory that dysautonomia is the main etiology of Long COVID/PASC. The olfactory and gustatory improvement immediately following SGB is as inexplicable as the deterioration of these senses with SARS-CoV-2 infection, but presumably involves a sympathetically mediated process. Numerous drugs from multiple classes are associated with changes in smell and taste, including the ACE2 inhibitor losartan [19] and the sympathomimetic midodrine [20]. Improvement in anosmia after SGB has been reported previously, although the mechanism for the effect is unknown [21][22][23].
The stellate ganglion block has been used for nearly a century to treat a variety of sympathetically mediated medical conditions and its safety pro le has been well established. Its application in treating Long COVID/PASC is novel. The lack of effective treatments for Long COVID/PASC makes the stellate ganglion block an attractive therapeutic modality that deserves further investigation.