COVID-19 Linked to Development of Myasthenia Gravis

Megan Brooks

August 19, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Myasthenia gravis should be added to the growing list of potential neurological sequelae associated with COVID-19, new research suggests.

Clinicians from Italy have described what they believe are the first three reported cases of acetylcholine receptor (AChR) antibody-positive myasthenia gravis after COVID-19 infection.

"I think it is possible that there could be many more cases," lead author Domenico Restivo, MD, Garibaldi Hospital, Catania, Italy, told Medscape Medical News.

"In fact, myasthenia gravis could be underestimated especially in the course of COVID-19 infection in which a specific muscular weakness is frequently present. For this reason, this association is easy to miss if not top of mind," Restivo said.

None of the three patients had previous neurologic or autoimmune disorders. In all three cases, symptoms of myasthenia gravis appeared within 5 to 7 days after onset of fever due to SARS-CoV-2 infection.

The time from presumed SARS-CoV-2 infection to myasthenia gravis symptoms "is consistent with the time from infection to symptoms in other neurologic disorders triggered by infections," the investigators report.

The findings were published online August 10 in the Annals of Internal Medicine.

First Patients

The first patient described in the report was a 64-year-old man who had a fever as high as 39° C (102.2° F) for 4 days. Five days after fever onset, he developed diplopia and muscle fatigue. The patient's neurologic examination was "unremarkable." Computed tomography (CT) of the thorax excluded thymoma and chest radiograph was normal.

He tested positive for SARS-CoV-2 on nasopharyngeal swab and real-time reverse transcriptase polymerase chain reaction (RT-PCR).

The patient's symptoms led the investigators to suspect myasthenia gravis. Repetitive stimulation of the patient's facial nerve showed a 57% decrement, confirming involvement of the postsynaptic neuromuscular junction. The concentration of AChR antibodies in serum was also elevated (22.8 pmol/L; normal value, < 0.4 pmol/L).

The patient was treated with pyridostigmine bromide and prednisone and had a response "typical for someone with myasthenia gravis," the researchers write.

The second patient was a 68-year-old man who had a fever as high as 38.8° C (101.8° F) for 7 days. On day 7, he developed muscle fatigue, diplopia, and dysphagia. A chest CT and neurologic exam were normal. Nasopharyngeal swab and RT-PCR testing for COVID-19 was positive.

As with the first patient, myasthenia gravis was suspected because of the patient's symptoms. Repetitive nerve stimulation revealed 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).

The patient improved after one cycle of intravenous immunoglobulin treatment.

Possible Mechanisms

The third patient was a 71-year-old woman with cough and a fever up to 38.6° C (101.5° F) for 6 days. She was initially negative for SARS-CoV-2 on nasopharyngeal swab and RT-PCR.

Five days after her symptoms began, she developed bilateral ocular ptosis, diplopia, and hypophonia. CT of the thorax excluded thymoma but showed bilateral interstitial pneumonia. On day 6, she developed dysphagia and respiratory failure, and was transferred to the intensive care unit where she received mechanical ventilation.

Repetitive nerve stimulation revealed 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, a second nasopharyngeal swab test for SARS-CoV-2 was positive.

The patient improved following plasmapheresis treatment and was successfully extubated.

The investigators note that this patient received hydroxychloroquine the day after the onset of neurologic symptoms, but the drug was withdrawn a day later; so they do not believe that it caused the symptoms of myasthenia gravis.

The observations in these three patients 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," the researchers write.

They offer several possible explanations for the link between COVID-19 and myasthenia gravis.

"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," the investigators write.

"The main message for clinicians is that myasthenia gravis, as well as other neurological disorders associated with autoimmunity, could occur in the course of SARS-CoV-2 infection," Restivo said.

Promptly recognizing the disease "could lead to a drug treatment that limits its evolution as quickly as possible," he added.

An "Unmasking"

Commenting on the findings for Medscape Medical News, Anthony Geraci, MD, director of neuromuscular medicine, Northwell Health, Great Neck, New York, said these case reports of myasthenia gravis after SARS-CoV-2 infection are "not unique or novel as there has been a long understanding that seropositive (AChR antibody-positive) myasthenia gravis can and is frequently 'unmasked' in the setting" of several viral and bacterial infections.

"Antibodies in myasthenia gravis are of a type that take several weeks to develop to measurable levels as in the reported cases by Restivo, giving strong support to the notion that subclinical myasthenia gravis can be immunologically upregulated in the setting of viral infection and this is a far more likely explanation of the observed association reported," added Geraci, who was not involved with the research.

He noted that at his institution, "we have also observed ocular myasthenia gravis emerge in patients with SARS-CoV-2 infection, with similar double vision and lid droop, as we have seen similarly in patients with Zika, West Nile, and other viral infections, as well as a multiplicity of bacterial infections."

"Most of our observed patients have responded to treatment much the same as reported by the three cases from Restivo and colleagues," Geraci reported.

Restivo and Geraci have disclosed no relevant financial relationships.

Ann Intern Med. Published online August 10, 2020. Abstract

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