MuSK Antibody–Associated Myasthenia Gravis With SARS-CoV-2 Infection: A Case Report

Abstract

Letters12 January 2021MuSK Antibody–Associated Myasthenia Gravis With SARS-CoV-2 Infection: A Case ReportFREELouwai Muhammed, BMBCh, MA, EdM, Aravindhan Baheerathan, MBChB, Michelangelo Cao, MD, Maria Isabel Leite, MD, DPhil, and Stuart Viegas, MBBS, DPhil, FRCPLouwai Muhammed, BMBCh, MA, EdMImperial College Healthcare NHS Trust, London, United KingdomSearch for more papers by this author, Aravindhan Baheerathan, MBChBImperial College Healthcare NHS Trust, London, United KingdomSearch for more papers by this author, Michelangelo Cao, MDUniversity of Oxford, Oxford, United KingdomSearch for more papers by this author, Maria Isabel Leite, MD, DPhilUniversity of Oxford, Oxford, United KingdomSearch for more papers by this author, and Stuart Viegas, MBBS, DPhil, FRCPImperial College Healthcare NHS Trust, London, United KingdomSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1298 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Reports about the neurologic consequences of coronavirus disease 2019 (COVID-19) describe more cases of central than peripheral nervous system involvement. Myasthenia gravis is an autoimmune neuromuscular disorder that affects the peripheral nervous system. Other observers recently described 3 patients who developed myasthenia gravis with antibodies against the acetylcholine receptor (AChR) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). Acetylcholine receptor antibodies are found in more than 80% of patients with generalized myasthenia gravis, whereas muscle-specific kinase (MuSK) antibodies are found in approximately 8% of cases. The pathogenic mechanisms of AChR antibody myastheniagravis (AChR-MG) are different from those of MuSK antibody myasthenia gravis (MuSK-MG). In addition, the 2 types of myasthenia gravis have important epidemiologic, clinical, therapeutic, immunologic, and pathologic features (2–4), and they should be considered distinct entities (Table).Table. Key Features Discriminating Between AChR-MG and MuSK-MGObjective: To describe what we believe is the first reported case of MuSK-MG after COVID-19.Case Report: A 24-year-old previously healthy woman of Pakistani origin presented to our emergency department in June 2020 with a flu-like illness consistent with COVID-19. She was discharged without a SARS-CoV-2 nasopharyngeal polymerase chain reaction swab test, which was in accordance with United Kingdom guidelines at the time. She self-isolated at home and recovered completely.Four weeks later, the patient developed diplopia, slurred speech, dysphagia, and global limb weakness. Examination revealed bilateral fatigable ptosis, complex ophthalmoplegia, symmetrical lower motor neuron facial weakness, and dysarthria. She had weakness (Medical Research Council [MRC] grade 3 to 4) and fatigability in all 4 limbs. Neck flexion and extension were also weak. Reflexes were brisk and symmetrical throughout. Her FVC was 0.97 L, so she was transferred to intensive care for monitoring without ventilator support.The patient had blood tests for creatinine kinase and thyroid function, which were normal. Testing for antinuclear, antineutrophil cytoplasmic, and antiganglioside antibodies yielded negative results, but SARS-CoV-2 antibodies were detected. Magnetic resonance imaging of the brain and spine and routine cerebrospinal fluid analysis were unremarkable. Results of single-fiber electromyography of the left orbicularis oculi were abnormal, and repetitive nerve stimulation of the left abductor digiti minimi muscle showed abnormal decrementing responses, consistent with myasthenia gravis. Computed tomography of the chest revealed no thymoma.Diagnostic radioimmunoprecipitation assay results were negative for AChR antibodies but positive for MuSK antibodies, confirming the diagnosis of generalized MuSK-MG. Two serum samples, collected 4 weeks apart, were tested for MuSK antibodies with a cell-based assay. Both samples had a higher level of IgG4 than IgG1–3 antibodies, with a proportional reduction in the second sample across all IgG subclasses. No IgM MuSK antibodies were detected in either sample (Figure).Figure. Relevant clinical and laboratory findings, including the MuSK ab titers in serum samples tested by RIPA and by CBA.One pair of symbols shows the MuSK ab of IgG4, and the other shows the MuSK ab of IgG1–3. ab = antibody; CBA = cell-based assay; IVIG = intravenous immunoglobulin; MG = myasthenia gravis, MuSK = muscle-specific kinase; RIPA = radioimmunoprecipitation assay; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Download figure Download PowerPoint We administered intravenous immunoglobulin, pyridostigmine, and prednisolone to the patient, and her symptoms improved. However, the effect of intravenous immunoglobulin was relatively short-lived. The patient developed side effects with higher doses of pyridostigmine, so we reduced the dose and added salbutamol. She currently is 20 weeks from symptom onset, is receiving 50 mg of prednisolone every other day, and has mild to moderate dysarthria and mild limb weakness (MRC grade 4+). If her condition relapses as the steroid dosage is reduced, we will consider treatment with rituximab.Discussion: Other authors have reported that MuSK-MG may develop after viral infection (5), and we note that our patient's clinical syndrome combined with subsequent positive results on SARS-CoV-2 antibody testing means that she probably was infected with SARS-CoV-2 at least 4 weeks before she developed MuSK-MG. Although our findings demonstrate a temporal association between COVID-19 infection and MuSK-MG, we recognize that we cannot definitively conclude causality. Nevertheless, we believe that this report of MuSK-MG associated with COVID-19, along with reports of AChR-MG associated with COVID-19 (1), provide clues to possible mechanisms for the association. For example, cross-reactivation of SARS-CoV-2 antibodies with both AChR and MuSK proteins is highly unlikely given their molecular differences; therefore, the development of myasthenia gravis after COVID-19 more likely represents a breakdown in self-tolerance mechanisms than cross-reactivation. In addition, it is too soon after the diagnosis to determine whether this case of MuSK-MG is an acute, monophasic, postinfectious phenomenon or a chronic autoimmune disorder requiring long-term immunosuppressive treatment, which can be determined only by long-term follow-up of our patient as well as any future patients.References1. Restivo DA, Centonze D, Alesina A, et al. Myasthenia gravis associated with SARS-CoV-2 infection [Letter]. Ann Intern Med. 2020;173:1027-8. doi:10.7326/L20-0845 LinkGoogle Scholar2. Koneczny I, Cossins J, Vincent A. The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014;224:29-35. [PMID: 23458718] doi:10.1111/joa.12034 CrossrefMedlineGoogle Scholar3. Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain. 2008;131:1940-52. [PMID: 18515870] doi:10.1093/brain/awn092 CrossrefMedlineGoogle Scholar4. Evoli A, Tonali PA, Padua L, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003;126:2304-11. [PMID: 12821509] CrossrefMedlineGoogle Scholar5. Belbezier A, Deroux A, Sarrot-Reynauld F, et al. Myasthenia gravis associated with acute hepatitis E infection in immunocompetent woman [Letter]. Emerg Infect Dis. 2014;20:908-10. [PMID: 24751295] doi:10.3201/eid2005.131551 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Finsterer J, MD, PhD , Fulvio A. Scorza, MDKlinik Landstrasse, Messerli Institute, Universidade Federal de São Paulo5 February 2021 Whether SARS-CoV-2 triggers MUSK-positive myasthenia remains speculative With interest we read the article by Muhammed et al. about a 24yo female who developed anti-muscle-specific tyrosine kinase(MUSK) positive myasthenia gravis 4w after onset of an infection with SARS-CoV-2 [1]. The patient profited from steroids, pyridostigmin, immunoglobulins, and salbutamol, resulting in partial recovery of ptosis, ophthalmoparesis, bulbar signs, and quadruparesis [1]. The study raises the following comments and concerns. The main shortcoming is that the patient was never tested positive for SARS-CoV-2 with a PCR-test. The clinical impression of “a flu-like illness consistent with COVID-19” is not sufficient to diagnose COVID-19. Diagnosing a flu-like episode upon antibodies against SARS-CoV-2 as COVID-19 four weeks later is not acceptable either. The patient could have had contact with the virus without ever developing symptoms before or after the flu-like episode. Thus, establishing a causal relation between SARS-CoV-2 and MUSK-myasthenia is not justified. The flu-like episode could have been indeed a simple flu and could have triggered myasthenia. Furthermore, we do not agree with the statement that involvement of the central nervous system(CNS) in COVID-19 is more frequent than involvement of the peripheral nervous system(PNS) [1]. Given the fact the ageusia/hypogeusia, anosmia/hyposmia, and myalgia are one of the most frequent manifestations of a SARS-CoV-2 infection at onset worldwide [2], and that these symptoms can be attributed to PNS-involvement (cranial nerve neuropathy) [3], PNS-involvement in COVID-19 is in fact by far more prevalent than CNS-involvement. Though it is well established that salbutamol has a beneficial effect in some of the congenital myasthenic syndromes(CMSs), particularly those due to variants in SLC5A7, COLQ, COL13A1, CHRNE, DOK7, MUSK, and GMPPB, there is currently no evidence that the compound is effective for MUSK-myasthenia. Thus, we should know the rationale for application of salbutamol in the index patient. Not only 3 patients have been reported in whom SARS-CoV-2 triggered the developed of newly diagnosed myasthenia but at least two more patients [4]. Missing are nerve conduction studies to rule out Guillain-Barre syndrome, increasingly recognised as a PNS complication of COVID-19 and developing up to 33d after onset of a SARS-CoV-2 infection [5]. Though cerebro-spinal fluid(CSF) investigations have been reported as normal, we should know if there was a dissociation cyto-albuminique(DCA) or not. Overall, the study did not convincingly establish a causal relation between SARS-CoV-2 and MUSK-myasthenia why attributing the development of MUSK-myasthenia to SARS-CoV-2 relies on a speculation. PNS-involvement in COVID-19 is definitively more frequent than CNS-involvement. References 1 Muhammed L, Baheerathan A, Cao M, Leite MI, Viegas S. MuSK Antibody-Associated Myasthenia Gravis With SARS-CoV-2 Infection: A Case Report. Ann Intern Med. 2021 Jan 12:L20-1298. doi: 10.7326/L20-1298. 2 Ninchritz-Becerra E, Soriano-Reixach MM, Mayo-Yánez M, Calvo-Henríquez C, Martínez-Ruiz de Apodaca P, Saga-Gutiérrez C, Parente-Arias P, Villareal IM, Viera-Artiles J, Poletti-Serafini D, Alobid I, Ayad T, Saussez S, Lechien JR, Chiesa-Estomba CM. Subjective evaluation of smell and taste dysfunction in patients with mild COVID-19 in Spain. Med Clin (Engl Ed). 2021 Jan 22;156(2):61-64. doi: 10.1016/j.medcle.2020.08.004. 3 Gogia B, Gil Guevara A, Rai PK, Fang X. A case of COVID-19 with multiple cranial neuropathies. Int J Neurosci. 2020 Dec 30:1-3. doi: 10.1080/00207454.2020.1869001. 4 Finsterer J, Scorza FA. Perspectives of neuro-COVID: myasthenia. Front Neurol 2020 (in press) 5 Finsterer J, Scorza FA, Fiorini AC. SARS-CoV-2-associated Guillain-Barre syndrome in 62 patients. Eur J Neurol. 2021 Jan;28(1):e10-e12. doi: 10.1111/ene.14544. Disclosures: Nothing to declare Louwai Muhammed, BMBCh, MA, EdM, Aravindhan Baheerathan, MBChB, Michelangelo Cao, MD, Maria Isabel Leite, MD, DPhil, Stuart Viegas, MBBS, DPhilDepartment of Neurology, Imperial College Healthcare NHS Trust, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom7 February 2021 Authors response to commentary on our manuscript posted by Finsterer et al. on 5 February 2021 We thank Dr Finsterer and colleagues for their comment. In response: The nature of the flu-like illness has no bearing on the temporal association between SARS-CoV-2 infection and the development of MuSK-MG. The first confirmed UK infection was on 29 January 20201. As our patient had SARS-CoV-2 antibodies in June 2020, and as the virus did not exist in the UK before January 2020, we can be confident she was exposed between February and May 2020. She therefore developed MuSK-MG shortly after virus exposure. We clearly state that "Although our findings demonstrate a temporal association between COVID-19 infection and MuSK-MG, we recognize that we cannot definitively conclude causality”. Nonetheless, this case will add to any future evidence suggesting a link between SARS-CoV-2 and MuSK-MG. Several studies suggest CNS complications (e.g. stroke and encephalopathy) are more common than PNS complications2. The mechanisms underlying anosmia in COVID-19 remain unclear and factors such as nasal congestion, brain infiltration, and olfactory-epithelium support-cell damage may be involved3. It is therefore speculative to conclude that these symptoms, which are manifestations of the disease rather than complications, are due to olfactory neuropathy. In any case, the olfactory neurons are anatomically part of the CNS rather than PNS4. Therefore, our assertion that the neurological complications of COVID-19 demonstrate a predilection for the central over peripheral nervous system still stands. Our use of salbutamol is based on current best evidence. B2-adrenoceptor agonists have shown benefit in MuSK-MG animal models 5. We use salbutamol in MuSK-MG patients that are intolerant of pyridostigmine, with half showing improvement (Viegas, unpublished observation). We did not state there have "only" been three previous cases of myasthenia gravis following COVID-19. The particular case-series we referenced was relevant to our discussion and there was no indication to reference every case in the literature. The history and neurological examination findings were consistent with a myasthenic disorder rather than Guillian-Barre-Syndrome. We confirm the CSF was acellular (<1WBC/cmm) and had normal protein (0.22mg/ml). This was implied by our statement that "routine cerebrospinal fluid analysis were unremarkable”. As mentioned, nerve conduction studies were normal and ganglioside antibodies were negative. Unfortunately, word count limitations precluded a detailed description of all investigations. In conclusion, this case highlights a temporal association between SARS-CoV-2 infection and the development of MuSK-MG, which was worthy of reporting. CNS sequelae of COVID-19 remain more common than PNS sequelae in our UK experience. References: Moss P, Barlow G, Easom N, Lillie P, Samson A. Lessons for managing high-consequence infections from first COVID-19 cases in the UK. The Lancet. 2020;395(10227):e46. doi:10.1016/S0140-6736(20)30463-3 Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. The Lancet Neurology. 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0 Butowt R, von Bartheld CS. Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2020:1073858420956905-1073858420956905. doi:10.1177/1073858420956905 van Riel D, Verdijk R, Kuiken T. The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. https://doi.org/10.1002/path.4461. The Journal of Pathology. 2015/01/01 2015;235(2):277-287. doi:https://doi.org/10.1002/path.4461 Ghazanfari N, Morsch M, Tse N, Reddel SW, Phillips WD. Effects of the ß2-Adrenoceptor Agonist, Albuterol, in a Mouse Model of Anti-MuSK Myasthenia Gravis. PLOS ONE. 2014;9(2):e87840. doi:10.1371/journal.pone.0087840 Author, Article, and Disclosure InformationAuthors: Louwai Muhammed, BMBCh, MA, EdM; Aravindhan Baheerathan, MBChB; Michelangelo Cao, MD; Maria Isabel Leite, MD, DPhil; Stuart Viegas, MBBS, DPhil, FRCPAffiliations: Imperial College Healthcare NHS Trust, London, United KingdomUniversity of Oxford, Oxford, United KingdomDisclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1298.Corresponding Author: Louwai Muhammed, BMBCh, MA, EdM, Department of Neurology, St Mary's Hospital, Paddington, London W2 1NY, United Kingdom; e-mail, [email protected] article was published at Annals.org on 12 January 2021. 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