Introduction: Myasthenia gravis (MG) is a rare autoimmune disorder of the neuromuscular junction associated with post-synaptic skeletal muscle membrane protein autoantibodies against the nicotinic acetylcholine receptors (ACh-R), muscle-specific kinase (MuSK) or agrin and lipoprotein receptor-related protein 4 (LRP4). The disease pathomechanism is complex, with predisposing human leukocyte antigen genes, pro-inflammatory cytokine profile, sex hormones, pharmacological agents, and environmental triggers. Several case reports suggest SARS-CoV-2 infection and Covid-19 vaccines as a possible trigger of MG.

Case Report: We present a 69-year-old previously healthy man developing ocular and facial muscle weakness three days following the second dose of BNT162B2 vaccine. The clinical signs, decremental response on repetitive nerve stimulation (RNS) and positive anti-acetylcholine receptor antibodies (antiAChR atb) were consistent with a diagnosis of acetylcholine receptor antibody-associated late onset MG. Pyridostigmine, intravenous immunoglobulin, oral steroid, and mycophenolate administration achieved pharmacological remission.

Conclusion: A literature review revealed four similar cases suggesting a possible association between late-onset MG and mRNA-BNT161B2 and mRNA-1273 vaccines. Although this clinical association does not impact the vaccine-related decision making, clinicians should be aware of the possibility of new onset MG following COVID-19 mRNA vaccination in the elderly population.

Keywords: COVID-19; Vaccination; Myasthenia gravis; Autoimmunity; Neuromuscular disease.

Copy right Statement: Content published in the journal follows Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). © Bulus E (2023)

Journal: Open Journal of Clinical and Medical Case Reports is an international, open access, peer reviewed Journal mainly focused exclusively on the medical and clinical case reports.

Citation: Bulus E, Ucem S, Yunisova G, Oflazer P. New late-onset myasthenia gravis following mRNA COVID-19 vaccination: Case report and literature review. Open J Clin Med Case Rep. 2023; 2108.

Myasthenia gravis (MG) is a rare autoimmune disorder of the neuromuscular junction associated with post-synaptic skeletal muscle membrane protein autoantibodies, most commonly (80%) against the nicotinic acetylcholine receptors (ACh-R) [1]. Other antibodies against muscle-specific kinase (MuSK) or other neuromuscular junction proteins such as agrin and lipoprotein receptor-related protein 4 (LRP4) can be detected [2,3]. The clinical features include muscle fatigue in ocular, facial, bulbar, respiratory, limb, and truncal muscles. MG can be classified based on the age of onset, involved muscles, and laboratory findings [4]. Late-onset myasthenia gravis (LOMG) is defined when the symptoms appear at ≥50 years of age and is more common in males. [5]

Table 1: Characteristics of the reported myasthenia gravis cases following COVID-19 vaccination (N/S: not specified).

The disease pathomechanism is complex, with predisposing human leukocyte antigen genes, pro-inflammatory cytokine profile, sex hormones, pharmacological agents, and environmental triggers [1]. Identified viral triggers include, but are not limited to, Epstein-Barr virus, measles, herpesviruses, hepatitis B virus, and Zika virus. Several case reports also suggest SARS-CoV-2 infection as a possible trigger of MG [6]. An etiological association can be explained by a dysregulated toll-like receptor response to virus-associated molecular patterns in the thymus followed by overexpression of ACh-R and autosensitization, although overt manifestation of a subclinical disease due to infection is equally plausible [7]. Furthermore, trivalent influenza, hepatitis B, nine-valent human papillomavirus, BCG, and Covid-19 vaccines have been associated with new-onset MG [8-10]. Herein, we report a case of new-onset MG following mRNA BNT162B2 vaccination and outline reported cases of COVID-19 vaccine-associated new-onset MG in the literature.

A 69-year-old male developed left eyelid droop and an inability to close his mouth three days following the second dose mRNA BNT162B2 vaccination. Five days later, he presented to the emergency department with difficulty rising from the chair, climbing stairs, lifting his arms, left eyelid droop and inability to close his mouth. He had a history of benign prostatic hyperplasia and contrast agent allergy. His vital signs were normal. On neurological examination left ptosis with bilateral mild weakness of eye closure was evident. Masseter muscles were weak bilaterally, causing an open-mouth appearance. Tongue muscle strength was prominently diminished, visualized by an inability to pass beyond the commissures. Muscle strength was 3/5 at neck flexors, 4-/5 at bilateral deltoideus, 4/5 at bilateral iliopsoas and extensor hallucis longus. Deep tendon reflexes were globally normoactive and pathological reflexes were absent. Cerebellar examination was normal. Speech was slightly nasal. He was admitted for inpatient investigations and management for myasthenia gravis.

Repetitive nerve stimulation (NCV) with 2 Hz and 3 Hz stimulation revealed significant decrement, an amplitude and area alteration at the right accessory and right facial nerves, which were consistent with a postsynaptic neuromuscular junction disorder. Initial laboratory tests revealed elevated creatinine kinase of 385 U/L (normal limit 200 U/L). Patient ptosis, deltoid, iliopsoas and masseter muscle weakness improved fully in one hour after oral 60 mg pyridostigmine bromide administration. In addition, dysarthria and neck flexor weakness showed significant improvement. Anti-Ach-R antibody titer was 309 nmol/L (normal <0.25 nmol/L), confirming the diagnosis of generalized late-onset myasthenia gravis. Thorax computed tomography ruled out a thymoma. A 5-day regimen of 0.4 gr/kg/day intravenous immunoglobulin (IVIg) together with oral 60 mg pyridostigmine bromide four times daily. Following complete symptom resolution under symptomatic treatment with IVIg, the patient was discharged with a prescription of 10 mg/ day prednisolone in addition to continuing pyridostigmine bromide treatment. On 3-week and 3-month follow-up, the patient was asymptomatic under pyridostigmine and 10 mg/day prednisolone treatment with normal neurological examination except a mild neck flexor weakness (4/5). The prednisolone dose was reduced to 5 mg/day in the 12th month of follow-up. At the 15th month follow-up, it was learned that the patient started to have difficulty while breathing, swallowing and in keeping his neck upright position for 1 week. Muscle strength in cranial area and extremities got worsened in neurological examination. Patient was hospitalized again with the diagnosis of myasthenic crisis with bulbar involvement and 0.4 g/kg/day IVIg was administered for 5 days with pyridostigmine bromide treatment. He was discharged with prednisolone 15 mg/day and pyridostigmine bromide 60 mg five times daily treatments with clinical improvement. After one month due to the presence of fluctuating bulbar findings in the examination, 0.4 g/kg/day IVIg booster was administered and mycophenolate was added to treatment. Patient is being followed up under prednisolone 15 mg/day, pyridostigmine bromide, monthly 0.4 g/kg/day IVIg booster and mycophenolate 2000 mg/day treatments.

The mRNA-BNT162b2 vaccine is a highly efficacious and safe tool to establish immunity against SARS-CoV-2 [11]. The immune-related adverse events following vaccination in patients with no previous history of autoimmune disease include myocarditis [12], pericarditis [13], acute pancreatitis [14], polymyalgia rheumatica, and multiple sclerosis [13]. In addition, five cases of new-onset myasthenia gravis have been reported following BNT162b2 [9,13]. Table 1 summarizes the current reports of COVID-19 vaccination associated MG cases in the literature. Five of these cases including our case are late-onset, male and experienced the first symptom in the first week following the second dose administration of an mRNA vaccine. Only one of them was a female patient diagnosed with early-onset MG following BNT162b2 vaccine [15].

There is a COVID-19 infection associated with a MG exacerbation in the literature [16]. In a cohort of patients with pre-existing diagnosis of MG, inactivated or recombinant subunit COVID-19 vaccination did not lead to symptom exacerbation [17], however a dysphagia episode following mRNA-1273 vaccine in an MG patient has been reported [10]. In light of these reports, new-onset MG cases can be explained by a latent MG becoming clinically apparent following mRNA vaccination. Alternative hypotheses explaining such occurrences are molecular mimicry, bystander effect, and epitope spreading [18]. Finally, the possible activation of ACh-R by SARS-CoV-2 spike protein has been suggested to have a pro-inflammatory role in COVID-19 [19]. Whether this association can be linked with ACh-R antibody formation in patients with COVID-19 infection or vaccination requires further investigation.

The occurrence of new-onset MG following COVID-19 mRNA vaccination should not impact any vaccine administration practices; however, the alterations in humoral and adaptive immune responses following mRNA vaccination, especially in elderly populations should be investigated.

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