Hydroxyurea and pyridostigmine repurposed for treating Covid-19 multi-systems dysfunctions

Early in the COVID-19 pandemic, medical care providers at an acute illness hospital received increasing numbers of post-acute advanced COVID-19 patients from referring hospitals where they were showing no signs of improvement after receiving treatments from standard Emergency Use Authorization (EUA)-type protocols. The care providers turned to repurposing medications to treat these patients and added hydroxyurea, a medication commonly used for treating sickle cell anemia, to the hospital's COVID-19 treatment protocol and began to see notable clinical improvements. As the pandemic continued and new concerns arose concerning COVID-19 complications, those same care providers again turned to repurposing drugs. Focusing on the neuromuscular effects seen in COVID-19 patients, care providers turned to medications used to treat chronic neuromuscular conditions. Post-acute advanced Covid-19 patients initially received an abbreviated course of hydroxyurea followed by titrated doses of pyridostigmine. Positive responses were noted with cognition, diminished oxygen demands, progressive decrease in ventilator support, improved swallowing, and mobility. The authors suggest repurposed drugs could have great utility for treating COVID-19. It is recommended larger, COVID-19 clinical trials be completed to include hydroxyurea and pyridostigmine for validating the outcomes and clinical observations seen in these presented cases.

One-Year Long-Term Follow up for Post-Acute Sequelae of Covid-19 Pots Patients

Background: Persistence of orthostatic tachycardia, palpitations, and fatigue beyond 4 weeks of an acute COVID-19 infection has been termed Post-Acute Sequelae of COVID-19 (PASC) POTS. We have previously reported 6-month outcomes of PASC POTS. Long-term management and outcomes of these patients is unknown. Objective(s): To examine the long-term management and outcomes of PASC POTS patients. Method(s): We conducted a retrospective study of all patients who were diagnosed with POTS at Cardiology, Neurology, and Rehabilitation Post-COVID clinic after a COVID-19 infection between March 1, 2020, and November 1, 2022, at the University of Texas Health San Antonio. We examined COVID history, POTS diagnosis, management, and one-year outcomes of post-COVID POTS patients. Result(s): In 42 patients that were diagnosed with PASC POTS, 33 had a one-year follow-up. 100% were female, 60.6% were Caucasian. Average age was 40.6 + 11 years while the average BMI was 31.9 + 10.4 kg/m2. The most common symptoms were fatigue (87.9%), palpitations (75.7%), brain fog (72.7%), orthostatic tachycardia, exercise intolerance, and dyspnea (70%). The mean heart rate change with 10-minute standing test was 42.68 + 26.73 beats per minute. At 12-months follow-up, the most common symptom was still fatigue (66.7%), palpitations (45.5%), orthostatic tachycardia, and orthostatic intolerance (42.4%). All patients were managed with increased salt and fluid intake, lower compression stockings and rehabilitation. Fifty five percent of patients were treated with Enhanced External Counter Pulsation (EECP), 42% were treated with beta blockers, 18% with fludrocortisone, 15% with midodrine, and 15% with Pyridostigmine. At 1 year follow-up, 33% of patients reported improvement in their symptoms, 33% reported worsening of symptoms, 24% reported stable symptoms, and 9% had resolution. Conclusion(s): PASC POTS patients continue to experience adverse symptoms even at one year. Physical therapy and rehabilitation and pharmacological therapy appear improve symptoms in a minority of patients.Copyright © 2023

A Case of Ocular Myasthenia Gravis Seen by Rheumatology as Suspected Mononeuritis Multiplex in an Adult Male Shortly after Pfizerbiontech Sars-Cov-2 Vaccination

Background/Aims Myasthenia gravis (MG) is an antibody-mediated autoimmune disease targeting proteins at the postsynaptic membrane of the neuromuscular junction. MG is thought to occur in genetically susceptible individuals following an environmental trigger. SARS-CoV-2 infection has been associated with new-onset autoimmune disease, new-onset MG, and exacerbations of pre-existing MG, with molecular mimicry between SARS-CoV-2 epitopes and autoantigen-induced autoreactivity thought to be part of the underlying mechanism. We report a case of newonset ocular MG following first dose Pfizer-BioNTech BNT162b2 SARS-COV2 vaccination which was referred to rheumatology as suspected mononeuritis multiplex. Methods A 53-year-old man of East Asian ethnicity presented to the emergency department (ED) with sudden onset diplopia and left lateral gaze restriction 7 days after receiving his first dose of the Pfizer-BioNTech BNT162b2 SARS-COV2 vaccination. He had longstanding myopia and dry eyes but no other medical history, no regular medications or significant family history. He was a current smoker, with a 50-pack year history. He did not drink alcohol or use any recreational drugs. He was found to have an isolated left VI cranial nerve (CN) palsy with an otherwise normal ocular and physical examination. Blood tests were unremarkable apart from raised cholesterol, and he was discharged with a suspected self-limiting microvascular CN lesion. Three weeks later he presented to ED with worsening diplopia, increasingly restricted eye movements, headache, nausea, vomiting and blurred vision. Ophthalmology assessment noted new right sided CN III and VI palsy, persistent left CN VI palsy, and vertical diplopia in all fields of gaze. Neurological and physical examination were normal. Bloods including an autoimmune screen were unremarkable. SARS-CoV-2 Spike antibodies were positive consistent with SARS-CoV-2 vaccination but not infection. Intracranial and thoracic imaging were unremarkable. He was referred to and seen by both rheumatology and neurology as a case of suspected mononeuritis multiplex. Results A diagnosis of ocular MG was confirmed with positive serum acetylcholine receptor antibodies, and he was started on prednisolone, and pyridostigmine to good effect. Daily forced vital capacity (FVC) showed no respiratory muscle involvement, and nerve conduction studies and electromyography were normal, excluding secondary generalisation. Conclusion A review of the literature found 14 reported cases of new-onset MG all within 4 weeks following SARS-CoV-2 vaccine. Whilst these cases provide interesting insights into the pathogenesis of autoimmune conditions such as MG, they are not epidemiological studies to inform vaccine safety. Ultimately, current evidence suggests that the risks of SARS-COV-2 infection outweigh the risk of vaccine-related adverse events, therefore we suggest clinicians should be aware of potential new-onset autoimmune conditions, but support the safety of SARSCOV2 vaccination. Further, research into possible immunological mechanisms behind this phenomenon, including identifying potential epitopes inducing molecular mimicry, could help establish the likelihood of a causative link.

The CRISIS Approach When Autonomy and Beneficence Are in Conflict (CS358)

Outcomes: 1. Utilizing CRISIS approach, participants can employ a unique strategy to holistically support patients with poor coping in an acute life-threatening situation. 2. Utilizing the CRISIS approach, participants will apply an ethical tool to mitigate the incongruence that sometimes happens between two ethical principles-autonomy versus beneficence. Autonomy is not always in harmony with beneficence. We present a patient with decisional capacity hospitalized with acute reversible neuromuscular paralysis who refused treatment despite expected recovery. Her decision created moral distress for the clinicians. An improvised palliative strategy resolved the above dilemma. Case presentation: 68-year-old female admitted with new-onset unsteady gait, diplopia, and speech impairment on waking up. She was healthy until 3 weeks before admission, when she developed upper extremity numbness progressing to both legs after a COVID-19 infection. She had bulbar and axial muscle weakness and right oculomotor nerve palsy with ptosis. Positive ice pack and pyridostigmine test indicated myasthenia gravis (MG). During hospitalization, she required mechanical ventilation secondary to acute respiratory failure from progressive paralysis. Serum-negative MG diagnosed, given the response to IVIG and pyridostigmine. The patient, amid acute crisis, refused therapies and wanted to transition to DNR-comfort care despite understanding the reversibility of her illness. Her family members supported comfort care option. Neurology was conflicted with the patient's choice because MG was treatable. Palliative care, ethics, and neuropsychology consulted to establish decision-making capacity, goals-of-care, and holistic support. Intervention(s): Palliative team utilized the CRISIS approach to address the impasse between the patient and the clinicians: 1. Continue care, collaborate with the teams 2. Respond empathetically 3. Integrate patient's autonomy 4. Support holistically 5. Improvise a care plan 6. Sustain quality of life We validated patient's autonomy. We recommended allowing time for the patient/family to process her illness. We continued holistic support and symptom management and created an improvised multidisciplinary plan to help her cope with the acute illness. The above approach enabled her to opt for therapies instead of comfort care only, and she gradually recovered. Respecting patients' autonomy and incorporating beneficence via our intervention led to positive outcomes. The CRISIS approach could help other clinicians in the situation when conflict arises between autonomy and beneficence.Copyright © 2023

A new case of myasthenia gravis following COVID-19 Vaccination

Background: Myasthenia gravis (MG) is an autoimmune disease of unknown etiology. Infections are known as a major cause of MG exacerbations. A few studies have shown an association between new onset MG and SARS-CoV-2 infection. Case presentation: We have reported a case of new onset myasthenia gravis in a 68-year-old man presented with bulbar symptoms a few days after receiving COVID-19 vaccine (Sinopharm vaccine). The disease was confirmed by high titer of antibody against acetylcholine receptor and electrophysiological examinations. Conclusion(s): Among the adverse effects reported with the COVID-19 vaccine, new onset myasthenia gravis is very rare. The underlying mechanism is unknown but the immune response after vaccination and molecular mimicry theory has been proposed.Copyright © 2022

Long COVID: Rapid Evidence Review

Postacute sequelae of COVID-19, also known as long COVID, affects approximately 10% to 30% of the hundreds of millions of people who have had acute COVID-19. The Centers for Disease Control and Prevention defines long COVID as the presence of new, returning, or ongoing symptoms associated with acute COVID-19 that persist beyond 28 days. The diagnosis of long COVID can be based on a previous clinical diagnosis of COVID-19 and does not require a prior positive polymerase chain reaction or antigen test result to confirm infection. Patients with long COVID report a broad range of symptoms, including abdominal pain, anosmia, chest pain, cognitive impairment (brain fog), dizziness, dyspnea, fatigue, headache, insomnia, mood changes, palpitations, paresthesias, and postexertional malaise. The presentation is variable, and symptoms can fluctuate or persist and relapse and remit. The diagnostic approach is to differentiate long COVID from acute sequelae of COVID-19, previous comorbidities, unmasking of preexisting health conditions, reinfections, new acute concerns, and complications of prolonged illness, hospitalization, or isolation. Many presenting symptoms of long COVID are commonly seen in a primary care practice, and management can be improved by using established treatment paradigms and supportive care. Although several medications have been suggested for the treatment of fatigue related to long COVID, the evidence for their use is currently lacking. Holistic treatment strategies for long COVID include discussion of pacing and energy conservation;individualized, symptom-guided, phased return to activity programs;maintaining adequate hydration and a healthy diet;and treatment of underlying medical conditions.Copyright © 2022 American Academy of Family Physicians.

Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

COVID-19 and myasthenia gravis: A review of neurological implications of the SARS-COV-2.

INTRODUCTION: This review highlights the potential mechanisms of neuromuscular manifestation of COVID-19, especially myasthenia gravis (MG). METHODS: An extensive literature search was conducted by two independent investigators using PubMed/MEDLINE and Google Scholar from its inception to December 2020. RESULTS: Exacerbations of clinical symptoms in patients of MG who were treated with some commonly used COVID-19 drugs has been reported, with updated recommendations of management of symptoms of neuromuscular disorders. Severe acute respiratory syndrome coronavirus 2 can induce the immune response to trigger autoimmune neurological disorders. CONCLUSIONS: Further clinical studies are warranted to indicate and rather confirm if MG in the setting of COVID-19 can pre-existent subclinically or develop as a new-onset disease.

COVID-19 PNEUMONIA COMPLICATED BY EXACERBATION OF NEW DIAGNOSIS OF MYASTHENIA GRAVIS

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: COVID-19 infection with concurrent myasthenia gravis (MG) presents a unique diagnostic challenge for the clinician. We report the case of a patient presenting with respiratory failure secondary to COVID-19 Pneumonia and being diagnosed with MG. CASE PRESENTATION: Patient is a 72-year-old male without any significant medical history presented with progressively worsening shortness of breath, associated dysphagia and fatigue for 1-week duration. Laboratory data and imaging findings were suggestive of COVID-19 pneumonia. Patient's respiratory status deteriorated requiring mechanical ventilation. His oxygenation improved with steroid and anti-viral therapy. However, he was unable to be liberated from the ventilator secondary to neuromuscular weakness. Further work up confirmed MG. Patient was treated with high-dose steroids, pyridostigmine and intravenous immunoglobulin therapy. Patient was unable to be extubated and required a tracheostomy placement. DISCUSSION: Observational studies have suggested the rate of MG exacerbation to be 10-15% in COVID-19 infection. Mortality was found to be significantly higher in these patients compared to patients without MG. Several case reports have also shown exacerbation of previously asymptomatic MG with COVID-19 infection. Studies have indicated underlying MG to be an independent prognostic risk factor in COVID-19 infection. Treatment involves achieving symptomatic improvement with use of pyridostigmine, corticosteroids and long-term steroid sparing agents, in addition to administering usual treatment for COVID-19 infection. CONCLUSIONS: Our patient presents as a case of COVID 19 infection complicated with a possibly induced or previously undiagnosed case of MG complicating the clinical course. During evaluation of patients with respiratory failure secondary to COVID-19 infection, history focused on symptoms that may indicate underlying neuromuscular diseases should be obtained for early diagnosis and proper management. Given the high co-existence, it is important for clinicians to be aware of the association and treatment strategies in such patients. Reference #1: Galassi G, Marchioni A. Myasthenia gravis at the crossroad of COVID-19: focus on immunological and respiratory interplay. Acta Neurol Belg. 2021;121(3):633-642. doi:10.1007/s13760-021-01612-6 Reference #2: Sriwastava S, Tandon M, Kataria S, Daimee M, Sultan S. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. J Neurol. 2021;268(8):2690-2696. doi:10.1007/s00415-020-10263-1 Reference #3: Rodrigues CL, de Freitas HC, Lima PRO, et al. Myasthenia gravis exacerbation and myasthenic crisis associated with COVID-19: case series and literature review. Neurol Sci. 2022;43(4):2271-2276. doi:10.1007/s10072-021-05823-w DISCLOSURES: No relevant relationships by Asad Chohan No relevant relationships by Saiara Choudhury No relevant relationships by Rahul Dadhwal No relevant relationships by Rene Franco No relevant relationships by Ahsan Syed No relevant relationships by Pahnwat Taweesedt No relevant relationships by Abhay Vakil

PROGRESSIVE ASCENDING WEAKNESS AFTER THE PFIZER/BIONTECH COVID-19 VACCINE

SESSION TITLE: Autoimmune Disorders: Both Primary and Secondary SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Myasthenia gravis (MG) occurs sporadically with no known causes. We present a rare case of new onset MG s/p COVID-19 vaccination. CASE PRESENTATION: A healthy 46-year-old female presented with progressing LE weakness for 3 months. Symptoms started 5 days after her initial Pfizer COVID-19 vaccine. Her workup showed negative neuroimaging, bland basic CSF studies from LP, with negative MS profile and AChR Ab. She presented again in 1 month with difficulty rising from a seated position, raising her arms above her head with blurry vision. Exam showed bilateral ptosis that improved with an ice pack test, weakness is worst in proximal muscles, but normal reflexes. Workup was again negative. Pyridostigmine was added after discharge (DC). 2 months after, she was admitted to the ICU for acute progressive fatiguability and dyspnea. EMG/NCS of the ulnar nerve showed 60-70% electrical decrement. She underwent therapeutic PLEX. Prednisone was added at DC followed by mycophenolate. 2 weeks later, she was again admitted with myasthenic crisis. She again underwent PLEX with improvement and intubation was avoided. Biweekly PLEX was started at DC. Testing for AChR, MuSK, and LRP4 Abs were initially negative, but AChR Abs were present 6 months later. She then underwent thymectomy showing hyperplasia. DISCUSSION: MG exacerbations have been attributable to infections (50%) and medications (30%). This has worsened during the COVID-19 pandemic especially when medications such as azithromycin were used to treat acute infections. While vaccine-induced flares or onset of autoimmune diseases have been described in literatures, new onset MG following vaccines is rare, limited to 1 to 3 case reports. No case, to our knowledge, correlated to the 1st dose like our patient. The temporal relationship between the COVID-19 vaccination and onset of MG symptoms in our patient could represent a correlation, but does not prove causality. Perhaps a more plausible theory is that the vaccine may have unmasked a previously unrecognized disease in high-risk patient. We ask if the COVID vaccine induces a similar cytokine storm, which hyperstimulates the immune system to a point that breaks immunologic self-tolerance. Interestingly, our patient was initially seronegative, but the presence of AChR Ab was confirmed after sensitive cell-based assays testing. Our patient may have had pre-existing self-antigens to the AChR that were released after receiving the Pfizer COVID-19 vaccine. CONCLUSIONS: The rate of COVID-19 vaccinations will soon surpass that of infections placing vulnerable individuals at risk for MG onset. Recognizing this risk will open discussions about vaccine safety. In doing so, we can begin to formulate new parameters for post-vaccination monitoring. The risks of and complications from acute COVID-19 still outweigh the rare adverse events from vaccines;thus, eligible patients should be offered the COVID-19 vaccine. Reference #1: Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology. 2020 Jun 2;94(22):959-969. doi: 10.1212/WNL.0000000000009566. Epub 2020 Apr 13. PMID: 32284362. Reference #2: Tagliaferri AR, Narvaneni S, Azzam MH, Grist W. A Case of COVID-19 Vaccine Causing a Myasthenia Gravis Crisis. Cureus. 2021;13(6):e15581. Published 2021 Jun 10. doi:10.7759/cureus.15581 Reference #3: Chavez A, Pougnier C. A Case of COVID-19 Vaccine Associated New Diagnosis Myasthenia Gravis. Journal of Primary Care & Community Health. January 2021. doi:10.1177/21501327211051933 DISCLOSURES: No relevant relationships by andrew bui No relevant relationships by Sharonya Shrivastava

MYASTHENIA GRAVIS PRECIPITATED BY ASYMPTOMATIC COVID-19 INFECTION, VACCINE, OR BOTH? HOW GENETIC PREDISPOSITION AND IMMUNE RESPONSES PLAY A ROLE IN THE NEUROMUSCULAR JUNCTION

SESSION TITLE: Autoimmune Disorders: Both Primary and Secondary SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: SARS-CoV-2 has demonstrated an impact on the lungs, leads to hypercoagulable states, and has caused immune-mediated reactions. Myasthenia Gravis (MG) represents a neuromuscular junction autoimmune disorder, with only a few case reports associated with new-onset MG following COVID-19 vaccination. Very rarely, MG has been reported in coexistence with Primary Sjogren's Syndrome (PSS). Here we present a case of new-onset MG in a patient with a positive COVID-19 a nasopharyngeal RT-PCR swab test, who received 3 doses of the Moderna COVID-19 vaccine with the latest dose 2 weeks prior to presentation and demonstrated positive PSS antibodies (Abs). CASE PRESENTATION: A 67-year-old male with no known past medical history presented with complaints of progressive weakness for 2 weeks, which began as diffuse malaise, and progressed to upper and lower extremity weakness with associated neck weakness, and dysphagia. Physical exam was remarkable for bilateral ptosis and difficulty ambulating. The patient was admitted to the ICU for suspected new-onset neuromuscular junction disorder and for close monitoring of his respiratory function. COVID-19 PCR was positive. MG and autoimmune disease workup was sent along with COVID-19 antibody testing. Chest X-Ray, CT head, and CT thorax were unremarkable. The patient was started on Pyridostigmine and IVIG, with low dose prednisone initiated on day 3 of admission. On the fifth day, symptoms improved significantly. Antibodies (Ab) against Acetylcholine (Ach) receptors were elevated and the diagnosis of MG was made. PSS Abs were also detected. Lyme, HIV, RPR, thyroid, and B12 levels were within the normal range which may mimic NMJ dysfunction. DISCUSSION: MG represents an autoimmune disorder due to autoantibodies against nicotinic AChR at the neuromuscular junction;however, these Abs can also target non-AChR muscle-specific receptor tyrosine kinase (MUSK). The exact mechanism of the autoimmune response with MG is not fully understood;however, there have been associations found with thymus gland hyperplasia and neoplasm when anti-AChR Abs are involved. Genetic predisposition is also likely to play a role. Viral and bacterial infections are established triggers for a myasthenic crisis in patients with pre-existing MG;however, there is yet to be a clear consensus regarding infections causing MG in otherwise healthy patients. As our pt did receive the COVID-19 vaccine, we have to consider an autoimmune reaction secondary to his administration. CONCLUSIONS: COVID-19 vaccines have demonstrated autoimmune responses such as myocarditis and myasthenic crisis in individuals. There have also been documented cases of MG in symptomatic COVID-19 infections. Given these findings, this patient may have experienced an environmental insult on top of a genetic predisposition and may warrant further investigation in patients with similar presentations. Reference #1: Sriwastava S, Tandon M, Kataria S, Daimee M, Sultan S. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. J Neurol. 2021 Aug;268(8):2690-2696. doi: 10.1007/s00415-020-10263-1. Epub 2020 Oct 12. PMID: 33047223;PMCID: PMC7549728. Reference #2: Chavez A, Pougnier C. A Case of COVID-19 Vaccine Associated New Diagnosis Myasthenia Gravis. J Prim Care Community Health. 2021 Jan-Dec;12:21501327211051933. doi: 10.1177/21501327211051933. PMID: 34709075;PMCID: PMC8559213. Reference #3: Witberg G, Barda N, Hoss S, Richter I, Wiessman M, Aviv Y, Grinberg T, Auster O, Dagan N, Balicer RD, Kornowski R. Myocarditis after Covid-19 Vaccination in a Large Health Care Organization. N Engl J Med. 2021 Dec 2;385(23):2132-2139. doi: 10.1056/NEJMoa2110737. Epub 2021 Oct 6. PMID: 34614329;PMCID: PMC8531986. DISCLOSURES: No relevant relationships by Brooke Kania No relevant relationships by Anas Mahmoud No relevant relationships by Ahmed Salem No relevant elationships by Jessimar Sanchez No relevant relationships by Shivanck Upadhyay No relevant relationships by Deniz Yucel

New Diagnosis of Myasthenia Gravis in the Setting of COVID-19 Infection

Objective: To report a patient presenting with bulbar symptoms in the setting of COVID-19 infection leading to a new diagnosis of Myasthenia Gravis. Background: There have been many reports of neurological complications in patients with COVID-19 infection including Guillain Barre syndrome, Bell's palsy and transverse myelitis. There are limited case series describing the effects of COVID-19 in patients with known Myasthenia Gravis, but there have only been rare reports of new onset Myasthenia Gravis in the setting of COVID-19 infection. Design/Methods: Electronic medical records of the patient were reviewed. Results: 78 year old man presented to the hospital with new onset of dysphagia, dysarthria, bilateral ptosis and left facial droop. The patient was given intravenous alteplase for possible stroke. On admission the patient also tested positive for COVID-19. His symptoms persisted post-alteplase. On exam he was noted to have fatigable ptosis, weakness of brow elevation, eye closure, horizontal movements of the tongue and intermittent dysarthria, raising the concern for myasthenia gravis. A trial of Mestinon led to improved symptoms. Serum acetylcholine receptor antibodies were positive, confirming the Myasthenia Gravis diagnosis. He received 5 sessions of intravenous immunoglobulin (IVIG) due to persistent bulbar symptoms. He initially responded well to treatment but later decompensated with respiratory failure requiring intubation. He was then treated with plasmapheresis for 5 days with symptom improvement and was successfully extubated. Conclusions: Our patient with a new diagnosis of myasthenia gravis with simultaneous COVID-19 infection eventually progressed into myasthenic crisis. This case raises the possibility of myasthenia and/or myasthenic crisis being a neurological complication of COVID-19 infection. Mechanisms behind this have been postulated to include molecular mimicry, the inflammatory cascade of COVID-19 leading to immune dysregulation, or viral illness triggering previously asymptomatic patients. Awareness of new onset myasthenia associated with COVID-19 infection can lead to earlier diagnosis and treatment.

Myasthenia Gravis Syndrome Following COVID-19 Vaccination and Subsequent Tolerance of Booster Vaccine: A Case Report

Objective: The COVID-19 pandemic has led to the rapid development of multiple safe and effective vaccines. Few neurological adverse events (AEs) associated with COVID-19 vaccines have been reported. Background: Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction, which can involve crises of muscular weakness that can be triggered by numerous stressors including medications, infections and vaccines. Little is known about the relationship between COVID-19 vaccines and MG. Here, we present a case of new-onset generalized MG following the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Design/Methods: A 46-year-old female with a past medical history of anxiety and sinus tachycardia reported drooping of her right eyelid within 48 hours of receiving her first Pfizer-BioNTech COVID-19 vaccine. Results: Over the next few weeks, she developed significant progressive fatigable extremity and bulbar muscle weakness, including ptosis, diplopia, dysarthria and fatigable mastication. Within months, she had multiple hospitalizations with unrevealing brain and spinal imaging, negative anti-AchR, anti-Musk and anti-LRP antibodies, a normal chest CT and EMG/NCS demonstrating moderate-to-severe electrical decrements in extremity and bulbar muscles. She was diagnosed with seronegative MG, and her symptoms significantly improved with Pyridostigmine treatment. She was subsequently hospitalized twice for MG crisis and received plasmapheresis, steroids and Mycophenolate with symptom stabilization. She has since tolerated a third dose of the vaccine without worsening of MG symptoms. Conclusions: Given the close temporal association, it is plausible that the vaccine unmasked subclinical MG in this patient, or less likely, induced de-novo MG. Rare COVID-19 vaccine-associated neuro-immunological cases have been observed and this case highlights the need for continued vaccine monitoring, as well as the potential to tolerate booster vaccination if the underlying neuro-immunologic condition is controlled. In addition to this case presentation and review of the relevant literature, we also present our analysis of the ongoing Vaccine AE Reporting System as it pertains to MG.

Immune Mediated Bulbar Myasthenia Gravis Incited by SARS-CoV2 mRNA Vaccination

Objective: NA Background: A 32 year-old man with no medical history and no prior documented SARS-CoV2 infection developed malaise, dyspnea, and exercise intolerance in the days following first dose SARS-CoV2 vaccine administration (Pzifer-BioNTECH mRNA). Dysarthria and dysphagia manifested within hours of the second vaccine dose administration, and progressed to severe bifacial weakness with reduced eyelid and mouth closures within one week's time. Design/Methods: NA Results: Severe dysphagia prompted hospitalization and neurology consultation. At an outside hospital, IVIG (2 gm/kg) and pyridostigmine were initiated for empiric treatment of suspected myasthenia gravis. The patient's facial strength, dysphagia and dysarthria improved. Anti-AChR and anti-MuSK serologic studies were non-reactive. A thymoma was not identified. MR brain, cerebrospinal fluid, and ganglioside antibody serologic studies were without explanatory pathological findings. A nerve conduction study, obtained in the outpatient setting, demonstrated decrement in facial nerve-nasalis CMAPs with low frequency repetitive stimulation, consistent with a post-synaptic neuromuscular disorder. Monthly IVIG infusions and pyridostigmine were prescribed. The patient's symptoms worsened and he was rehospitalized. A repeat nerve conduction study revealed post-exercise and repetitive stimulation-induced decrements in median-abductor policus brevis and spinal accessorytrapezius CMAPs, confirming a systemic post-synaptic neuromuscular disorder. AChR binding and blocking antibodies were ultimately detected through repeat serologic testing, consistent with autoimmune myasthenia gravis. Plasma exchange and prednisone therapies engendered near full symptom resolution. Conclusions: While myasthenia gravis symptom exacerbation and crisis in the setting of vaccination are well described, no cases of new-onset myasthenia gravis following vaccination are reported to date. Further, the patient's bifacial weakness with impaired eyelid closure was atypical in contrast to ptosis and diploia typically observed in oculo-bulbar forms of myasthenia gravis. The immune-mediated mechanism and clinical phenotype of SARS-CoV2 vaccinationassociated myasthenia gravis require further investigation.

The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1ß, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.

A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).