Myasthenia Gravis Associated With SARS-CoV-2 Infection

Letters10 August 2020Myasthenia Gravis Associated With SARS-CoV-2 InfectionFREEDomenico A. Restivo, MD, PhD, Diego Centonze, MD, Alessandro Alesina, MD, and Rosario Marchese-Ragona, MDDomenico A. Restivo, MD, PhDDepartment of Medicine, Neurological Unit, “Garibaldi” Hospital, Catania, Italy (D.A.R.)Search for more papers by this author, Diego Centonze, MDDepartment of Systems Medicine, Tor Vergata University, Rome, Italy, Unit of Neurology, IRCCS Neuromed Pozzilli, Italy (D.C.)Search for more papers by this author, Alessandro Alesina, MDUniversity of Catania, Catania, Italy (A.A.)Search for more papers by this author, and Rosario Marchese-Ragona, MDENT Unit, University of Padua, Padova, Italy (R.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-0845 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have neurologic symptoms (1–3). Some observers propose that these symptoms are caused by viral infection of nerve cells (4), but the possibility exists that these symptoms might be produced by autoimmune mechanisms (1–4). Myasthenia gravis is an autoimmune disease in which antibodies bind to acetylcholine receptors (AChRs) or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction (5).Objective: To describe 3 patients without previous neurologic or autoimmune disorders who were diagnosed with myasthenia gravis after the onset of coronavirus disease 2019 (COVID-19).Case Report: Patient 1 was a 64-year-old man who had fever as high as 39 °C for 4 days. Five days after fever onset, he developed diplopia and muscular fatigability. Although his chest radiograph was normal, nasopharyngeal swab and real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing for COVID-19 showed a positive result. We suspected myasthenia gravis because of his symptoms. His neurologic examination was unremarkable. Computed tomography (CT) of the thorax excluded thymoma. Repetitive stimulation of the facial nerve showed a 57% decrement, confirming involvement of the postsynaptic neuromuscular junction, and the concentration of AChR antibodies in his serum was elevated (22.8 pmol/L; normal value, <0.4 pmol/L). We administered pyridostigmine bromide and prednisone, and the patient had a response typical for someone with myasthenia gravis.Patient 2 was a 68-year-old man who had fever as high as 38.8 °C for 7 days. On day 7, he developed general muscular fatigability, diplopia, and dysphagia. Although his chest CT scan was normal, nasopharyngeal swab and RT-PCR testing for COVID-19 yielded positive results. We suspected myasthenia gravis because of his symptoms. His neurologic examination was normal, and his chest CT scan excluded thymoma. Repetitive nerve stimulation showed a postsynaptic deficit of neuromuscular transmission of the facial (52%) and ulnar (21%) nerves. His serum AChR antibody level was elevated (27.6 pmol/L). He improved after 1 cycle of intravenous immunoglobulin treatment.Patient 3 was a 71-year-old woman who had a cough and fever to 38.6 °C for 6 days. Nasopharyngeal swab and RT-PCR testing for COVID-19 showed a negative result. Five days after her symptoms began, she developed bilateral ocular ptosis, diplopia, and hypophonia. Thorax CT revealed bilateral interstitial pneumonia and excluded thymoma. One day later, she developed dysphagia and respiratory failure and was transferred to the intensive care unit, where she received mechanical ventilation through a tracheostomy. Repetitive nerve stimulation showed a postsynaptic deficit of neuromuscular transmission of the ulnar nerve (56%), and her serum AChR antibody level was elevated (35.6 pmol/L). Five days later, she had a second nasopharyngeal swab test for COVID-19, and the result was positive. Plasmapheresis was started; she improved and was extubated. This patient received hydroxychloroquine the day after the onset of her first neurologic symptoms (withdrawn a day later), so we do not believe that it caused her symptoms of myasthenia gravis.Additional information about these patients is provided in the Table.Table. Clinical and Demographic Data of 3 Patients With Myasthenia Gravis Associated With COVID-19 InfectionDiscussion: We describe what we believe are the first 3 reported cases of AChR antibody–positive myasthenia gravis after COVID-19. These observations are consistent with reports of other infections that induce autoimmune disorders, as well as with the growing evidence of other neurologic disorders with presumed autoimmune mechanisms after COVID-19 onset (1–3). We note that symptoms of myasthenia gravis appeared within 5 to 7 days after fever onset in all 3 patients, and the time from presumed infection with SARS-CoV-2 to the beginning of myasthenia gravis symptoms is consistent with the time from infection to symptoms in other neurologic disorders triggered by infections (2, 3). Several possible explanations exist. For example, antibodies that are directed against SARS-CoV-2 proteins may cross-react with AChR subunits, because the virus has epitopes that are similar to components of the neuromuscular junction; this is known to occur in other neurologic autoimmune disorders after infection. Alternatively, COVID-19 infection may break immunologic self-tolerance.References1. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection [Letter]. N Engl J Med. 2020;382:2268-2270. [PMID: 32294339] doi:10.1056/NEJMc2008597 CrossrefMedlineGoogle Scholar2. Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? [Letter]. Lancet Neurol. 2020;19:383-384. [PMID: 32246917] doi:10.1016/S1474-4422(20)30109-5 CrossrefMedlineGoogle Scholar3. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barré syndrome associated with SARS-CoV-2 [Letter]. N Engl J Med. 2020;382:2574-2576. [PMID: 32302082] doi:10.1056/NEJMc2009191 CrossrefMedlineGoogle Scholar4. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92:552-555. [PMID: 32104915] doi:10.1002/jmv.25728 CrossrefMedlineGoogle Scholar5. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375:2570-2581. [PMID: 28029925] doi:10.1056/NEJMra1602678 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Vinu ArumughamIndependent12 August 2020 Myasthenia Gravis is vaccine-induced and aggravated by SARS-CoV-2 infection "Rapid onset of specific neutralizing antibody responses beginning less than seven days after exposure to SARS-CoV–2 implies a recall rather than primary B cell response, and therefore the response is being driven by a pre-existing memory cell population." COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms https://www.researchsquare.com/article/rs-30934/v2 So the symptoms of myasthenia gravis that appeared within 5 to 7 days after fever onset in all 3 patients, is a recall response of previous vaccine-induced (subclinical) autoimmunity. Vaccination with bovine, chick, yeast antigens synthesizes cross-reactive antibodies targeting human acetylcholine receptor and MuSK protein to cause Myasthenia Gravis: Confirmed by natural experiment (VAERS data), bioinformatics, case reports, animal experiments and titer study https://doi.org/10.5281/zenodo.3421558 Disclosure of Any Conflicts of Interest (required):None. Arvind Joshi MBBS, MD; FCGP, FAMS, FICPConvener- Our Own Discussion Group13 August 2020 - I welcome the article. I have seen people with myasthenia gravis like features with AntiCholinesterase Receptor Antibodies and seropositive for Mumps or measles. I have also seen people with Tuberculosis or Leprosy with myopathy and neuropathy. People with various Infections do present with autoimmune Disorders affecting myocardium, vascular endothelium, brain, liver, gut, Kidneys, joints and connective tissues, heart and hemopoietic system, reticuloendothelial system. In fact name an organ or an organ system and there will be their autoimmune manifestations triggered by some infections. There are many people who report muscular weakness for a long time after virologic tests becoming negative for SARS-CoV-2. Not many of them are tested electrophysiologically and far less by muscle biopsy for myopathies. Proven development of Myasthenia Gravis in association with or following CoVID-19 may number far too less. This article brings out this Sequelae succinctly. It remains to be seen weather and how many people recover from CoVID-19 associated Myasthenia Gravis, and how long they take for the recovery. I laud the authors for their study. Disclosures: None Domenico A. Restivo, MD, PhD, Diego Centonze, MD, Alessandro Alesina, MD, Rosario Marchese-Ragona, MDGaribaldi Hospital; Tor Vergata University; University of Catania; University of Padua20 August 2020 Reply to Dr. Joshi We are grateful to Dr. Joshi for his comment to the article. We agree with him that many patients report muscular weakness for a long time after virologic testing has become negative for SARS-CoV-2, but only few of them are tested electrophysiologically. For this reason, proven development of myasthenia gravis associated with or following COVID-19 infection may number far too less. Moreover, further studies are necessary to understand weather and how, a recovery from myasthenia gravis may occur. We think that the knowledge of such a possible association may lead to an earlier diagnosis of myasthenia gravis in patients with COVID-19 infection. This could be particularly useful in those patients whose muscular weakness is present long after the virological test or SARS-CoV-2has turned negative. Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0845. Domenico A. Restivo, MD, PhD, Diego Centonze, MD, Alessandro Alesina, MD, Rosario Marchese-Ragona, MDGaribaldi Hospital; Tor Vergata University; University of Catania; University of Padua14 August 2020 Reply to Dr. Arumugham We thank Dr. Arumugham for his comment. We agree that rapid onset of specific pathogenic antibody responses beginning less than seven days after exposure to SARS-CoV–2 may imply a pre-existing memory cell population. So, we cannot rule out at all the hypothesis of a pre-existing subclinical myasthenia gravis. However, at least 2 out 3 patients, who had the first nasopharyngeal swab positive to COVID-19 may have been exposed to SARS-CoV-2 infection before the fever onset. Although mediated by distinct pathogenic mechanisms, the time from presumed infection with SARS-CoV-2 to the beginning of myasthenia gravis symptoms in our series is consistent with the time from infection to symptoms in other immune-mediated neurologic disorders triggered by SARS-CoV-2 (1,2). However, ours is a very limited case series and definitive conclusions can not be drawn. Further studies are necessary to better define the role of the immune response triggered by SARS-CoV–2 in patients developing neurological disorders, including myasthenia gravis. References Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? [Letter]. Lancet Neurol. 2020;19:383-384. [PMID: 32246917] doi:10.1016/S1474-4422(20)30109-5 Toscano G, Palmerini F, Ravaglia S, et al. Guillain-barré syndrome associated with SARS-CoV-2 [Letter]. N Engl J Med. 2020;382:2574-2576. [PMID: 32302082] doi:10.1056/NEJMc2009191 Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0845. Hai-Feng Li, MD, PhD (1), Yu Hong, MD, PhD (2)(1) Xuanwu Hospital, Capital Medical University, Beijing, China, (2) University of Bergen, Norway18 August 2020 - We appreciate Restivo and colleagues for reporting myasthenia gravis (MG) symptoms appeared in three acetylcholine receptor (AChR) antibody positive patients within a short period after SARS-CoV-2 infection (1). However, we do not believe that MG debut is directly associated with SARS-CoV-2 infection in these cases. Several mechanisms have been proposed for pathogen-triggered autoimmunity, including molecular mimicry, cryptic antigens exposure after infectious damage, epitope spreading, bystander activation and polyclonal activation. However, the pathogenic antibodies of MG are all specific antibodies of IgG types, which precludes their development in a short time. In MG without thymoma, autoimmune process is presumed to initiate in thymus following an unknown ‘‘trigger’’, and the resulting AChR-antibody-producing B cells become self-perpetuating in peripheral lymphatic tissue on the background of functionally defective regulatory T cells. In thymoma-associated MG, promiscuous expression of autoantigens including AChR in thymus due defective expression of the autoimmune regulator leads to breakdown of self-tolerance. Defective generation of regulatory T cells both in thymus and peripheral lymphatic tissues contribute to the maintenance of multiple tissue-specific autoimmune responses (2). Both pathogenic processes need enough time to develop. AChR antibody positive MG cases after infections of Zika virus (ZIKV) or West Nile virus (WNV) were previously reported. Two patients developed MG symptoms two months after ZIKV infections (3). Presence of thymoma in both patients suggests that there were longstanding host predisposition to MG and already pathologic event. Six patients developed MG symptoms 3~7 months after WNV infection when they were in stable recovery from acute WNV neuroinvasive disease (4). There is no evidence that this neurotropic virus causes damage to AChR. Till now, there is not yet evidence that ZIKV, WNV and SARS-CoV-2 are cross-reactive with AChR molecules. In clinically diagnosed MG patients, with time-series analysis, variation of AChR antibody titer was found with significant positive correlation with incidence of influenza virus infection, with a lag of two months (5). This suggests that influenza virus infection might affect immunological activity in MG patients with MG. However, this effect was seen after a delay of two months. Hence, the AChR antibody cannot be produced so quickly after infection. However, it is commonly seen that MG worsen rapidly after common infections due to dysfunction of immune balance without increased AChR antibody levels. Therefore, we believe all reported cases were previously established MG patients and symptoms were uncovered by the SARS-CoV-2 infection. References: Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 Infection. [published online ahead of print, 2020 Aug 10]. Ann Intern Med. 2020;10.7326/L20-0845. Melzer N, Ruck T, Fuhr P, et al. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. J Neurol. 2016;263:1473-1494. Molko N, Simon O, Guyon D, Biron A, Dupont-Rouzeyrol M, Gourinat AC. Zika virus infection and myasthenia gravis: report of 2 cases. Neurology. 2017;88:1097-1098. Leis AA, Szatmary G, Ross MA, Stokic DS. West nile virus infection and myasthenia gravis. Muscle Nerve. 2014;49:26-29. Iwasa K, Yoshikawa H, Hamaguchi T, et al. Time-series analysis: variation of anti-acetylcholine receptor antibody titer in myasthenia gravis is related to incidence of Mycoplasma pneumoniae and influenza virus infections. Neurol Res. 2018;40:102-109. Disclosures: None Domenico A. Restivo, MD, PhD, Diego Centonze, MD, Alessandro Alesina, MD, Rosario Marchese-Ragona, MDGaribaldi Hospital; Tor Vergata University; University of Catania; University of Padua20 August 2020 Response to Li We thank Dr Li and collegues for their comments to our article (1). As reported in a previous similar comment by Dr Arumugham, We agree that rapid onset of specific pathogenic antibody responses beginning less than seven days after exposure to SARS-CoV–2 may imply a pre-existing memory cell population. So we cannot rule out at all the hypothesis of a pre-existing subclinical myasthenia gravis. However, at least two out of three patients, nasopharyngeal swab positive to COVID-19 may have been exposed to SARS-CoV-2 infection before the fever onset. We do not know how long time before, they had been exposed to the viral infection, Although mediated by distinct pathogenic mechanisms, the time from presumed infection with SARS-CoV-2 to the beginning of myasthenia gravis symptoms in our series is consistent with the time from infection to symptoms in other immune-mediated neurologic disorders triggered by SARS-CoV-2 (2, 3). However, our case series is very limited and definitive conclusions cannot be drawn. Further studies are necessary to better define the role of the immune response triggered by SARS-CoV–2 in patients developing neurological disorders, including myasthenia gravis. References: Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 Infection. [published online ahead of print, 2020 Aug 10]. Ann Intern Med. 2020;10.7326/L20-0845. Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? [Letter]. Lancet Neurol. 2020;19:383-384. [PMID: 32246917] doi:10.1016/S1474-4422(20)30109-5 Toscano G, Palmerini F, Ravaglia S, et al. Guillain-barré syndrome associated with SARS-CoV-2 [Letter]. N Engl J Med. 2020;382:2574-2576. [PMID: 32302082] doi:10.1056/NEJMc2009191 Disclosures: None Giuliana Galassi, MD , Alessandro Marchioni , MDUniversity of Modena25 August 2020 Comment on myasthenia gravis associated with SARS –CoV-2 infection Restivo et al (1) report 3 patients without a pre-existing diagnosis of myasthenia gravis (MG) who developed acutely ocular and bulbar signs during SARS–CoV-2 infection. Remarkably none of the patients exhibited limb weakness and neurological examination was defined normal inspite of ocular signs and dysphonia antedating respiratory failure in case 3 where the condition should be defined a myasthenic crisis (2) . The description of these cases is of high clinical interest but there are comments to be made. First, we cannot exclude a pre-existing MG exacerbated by the SARS-CoV-2 pneumonia. Neurological symptoms started within 5 to 7 days after fever onset with a parainfectious more than a post-infectious profile. Hence it is reasonable to conclude that SARS-CoV-2 played a coincidental rather than a causal role. Second, It is well known that infections may interfere with the neuromuscular transmission through several mechanisms, either by affecting pre- or postsynaptic ion channels or by affecting acetylcholinesterase (2). Infections are major external causal factor for nearly all autoimmune disorders,. through augmentation of T cell signaling causing a pro-inflammatory environment due to a hyper-reactive antiviral immune respons, epitope spreading (2). On the other hand impair immunity in MG results in an increased risk of infections inducing a polyclonal activation of immunoactive cells including autoreactive B- and T-lymphocytes Third the electrophysiological study confirmed early involvement of neuromuscular junction in facial muscle in case 1 and 2 who exhibited clinically only ocular signs. This feature would suggest a generalized MG. Fourth, acetylcholine receptors (AChRs) antibodies in all cases were found with an unusually short delay and with high titer suggesting an hyperactivation of the immune system or a pre-existing memory cell population. This finding should be tentatively explained . In MG patients, regulatory T cells (Tregs), that play a key role in maintaining self-tolerance, show impaired function (3). Moreover, in a subset of early onset MG, a plasma increases of Th17 cytokines, which are commonly involved in autoimmunity and inflammation, has been demonstrated, suggesting a role of IL-17A in the disease (4). Interestingly severe CoVID-19 pneumonia causes a reduction of level of peripheral Tregs and an increased level of IL-17 .Thus, theTh17 /Tregs imbalance due to SARS-CoV-2 could be the pathophysiological background underlying development of the autoantibodies (3,4). Another explanation might be through a molecular mimicry mechanism, involving similarities between foreign and self-peptides with cross-reaction of antibodies directed against viral antigens with AChR subunits. Lucchese et al (5) recently showed the SARS-CoV-2 shares sequences of proven immunologic potential with the human heat shock proteins involved in a number of immune-mediated clinical conditions.(5)Mimicry between virus and neuronal proteins (namely DAB1, AIFM and SURF1) of respiratory pacemaker in the brainstem has been hypothesized based on SARS-CoV-2 proteome analysis. Given that no matter which mechanism the authors propose, it needs time to function. We think that up to now the role of SARS-CoV-2 in triggering MG is far to be proven. References Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated with SARS-CoV-2 Infection. [published online ahead of print, 2020 Aug 10]. Ann Intern Med. 2020;10.7326/L20-0845. Gilhus NE, Romi F, Hong Y, Skeie GO. Myasthenia gravis and infectious diseases 2018 .J Neurol. 2018; 265:1251-1258. doi: 10.1007/s00415-018-8751-9. Thiruppathi M, Rowin J, Ganesh B, et al. Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. Clin Immunol 2012;145:209-223. doi: 10.1016/j.clim.2012.09.012. Xie Y, Li HF, Jiang B, Li Y,et al. Elevated plasma interleukin-17A in a subgroup of Myasthenia Gravis patients. doi: Lucchese G, A. mimicry between SARS-CoV-2 and respiratory pacemaker 2020 doi: J, MD, PhD MD MD MD August 2020 SARS-CoV-2 With interest we the article by Restivo et al. about 3 patients with ptosis, and dysphagia with an onset after infection with SARS-CoV-2 in 2 patients and and an onset before a positive SARS-CoV-2 test in a patient We have the following comments and ptosis, and we should know the results of in all three patients, a brainstem or were excluded in all three patients to the neurological is a known of SARS-CoV-2 infection is that the receptor titer in was already 5 days and in 7 days after onset of the SARS-CoV-2 infection. it that the patient was infected already than 5 7 days days or that the viral infection was not the for the the In the SARS-CoV-2 test positive after onset of it the the symptoms were due to an infection other than with SARS-CoV-2 and that myasthenia in was not related to there a infected patients but only three patients with myasthenia reported up to now, it is rather that SARS-CoV-2 the development of in this study is a of the three patients we should know neurological after of the COVID-19 infection and It is well known that may be positive in the of infectious disease or patients the presumed between SARS-CoV-2 and myasthenia in the three reported patients remains There are several against a as and of the neurological were References 1 Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 [published online ahead of print, 2020 Aug 10]. Ann Intern Med. 2 M, COVID-19 and or 3 K, S, S, P, positive for receptor antibody in patients exposed to J Disclosures: There are no conflicts of interest Restivo DA, Centonze D, Alesina A, Marchese-Ragona August 2020 Reply to and We with interest the comment to our article (1) by et al. We agree with them that some clinical and about these patients were not reported in the In we have to be all three patients that excluded brainstem including and Moreover, all the three patients nerve of and limb as well as these tests were normal, to nerve We not in the about a diagnosis because all patients showed a clinical ptosis, diplopia, dysphagia general muscular weakness that could by associated with a very response to nerve a involvement of the neuromuscular junction as well as an of serum In two out of three patients and test that a of muscle in both patients. these lead to the diagnosis of myasthenia gravis. is not the possible diagnosis with myasthenia gravis. In a not cause bilateral 3). Moreover, in our it is that a of the brainstem so as to the as in the case in which diplopia is associated with not or involvement As reported in previous similar comments Arumugham, and Dr we agree that is that high antibody beginning few days after exposure to SARS-CoV–2 may imply a pre-existing memory cell population. So, none these three patients had had in the similar symptoms or previous autoimmune disorders, we cannot rule out at all the hypothesis of a pre-existing subclinical myasthenia gravis. However, at least two out of three patients and who had the first nasopharyngeal swab positive to COVID-19 may have been exposed to SARS-CoV-2 infection before the fever onset. We do not know how long time before, they had been exposed to the viral infection. patient in this patient the test positive after the onset of myasthenia the to not rule out that the patient had been infected by In the SARS-CoV-2 for swab is not so being (2). a number of patients may result negative. Moreover, in this the clinical and chest CT scan were of infection the of the first and for other infections were negative. The fact that the high number of infected patients, no cases of myasthenia had previously been reported is only of the fact due to the of some very common symptoms in infection, such as generalized and muscle weakness which can be the not think at first of myasthenia gravis. For this reason, we think it is of for the to be that this neurological can be associated with infection. the we are following these patients. 3 patients are to take for myasthenia gravis bromide and for patients and 2 and with antibodies were present in all 3 patients at the with a serum titer than in the first References Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated with SARS-CoV-2 Infection. [published online ahead of print, 2020 Aug 10]. Ann Intern Med. 2020;10.7326/L20-0845. H, J, Zhou M, et for COVID-19 and