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No Excess Risk for Neurologic Events Observed to Date from COVID-19 Vaccines

Anthony Fauci, MD, called Neurology Today in mid-January to set the record straight on a question regarding the vaccines for SARS-CoV-2. The director of the National Institute of Allergy and Infectious Diseases said that he had misspoken in an early December newscast when he said that people who have had Guillain-Barré syndrome (GBS) should avoid the SARS-CoV-2 vaccines because they might trigger a recurrence of the disease.

Dr. Fauci's earlier statement prompted the publication on December 21 of an open letter coauthored by 13 leading experts in GBS and related disorders. The letter noted that no instances of GBS were seen during clinical trials of the two vaccines, that no published studies suggest any cause for concern, and that neither the Centers for Disease Control and Prevention (CDC) nor the Food and Drug Administration (FDA) recommends against the vaccine due to GBS.

Dr. Fauci, who had not previously responded to the letter, told Neurology Today: “That [interview] was conducted at a time before the CDC came out with their clear recommendations. As soon as the CDC recommendations came out, I began advising people according to the recommendations. I do stand corrected."         

Several neurologists, including three of the coauthors of the open letter to Dr. Fauci, told Neurology Today that misunderstandings about the potential for neurological risks associated with the vaccines are common. As a result, they said, many of their patients have expressed fears about taking the vaccines. “I'm hearing from my patients who are worried about it," said Richard A. Lewis, MD, FAAN, professor of neurology and director of the Electromyography Laboratory at Cedars Sinai Medical Center. As a signatory to the letter to Dr. Fauci, he said, “I personally have been very concerned about the large number of people who are not taking the vaccine when they could. My belief and that of the others who signed the letter is that it's in everyone's best interest to get one of the vaccines."

He and other neurologists emphasized that too little time has passed since vaccine rollouts to know if a miniscule increased risk of a neurological side effect might emerge with careful statistical analysis. Even if one does, however, Dr. Lewis said: “Certainly for people with chronic inflammatory demyelinating polyneuropathy [CIDP], GBS, and other neurological diseases, the risk of getting a problem from the vaccine is far outweighed by the risks of getting a serious illness from the virus itself."

The Evidence

Concerns about the risk of GBS in response to vaccines date back to 1976, when “there was a small increased risk of GBS after swine flu vaccination," the CDC has noted. Analysis by the National Academy of Medicine found that the risk from that vaccine was approximately one additional case of GBS for every 100,000 people who receive the swine flu vaccine.

Since then, according to a recent review in the Journal of Infection Diseases, the risk associated with seasonal influenza vaccine has consistently been in the range of one to two additional GBS cases per million flu vaccine doses administered. As the CDC stated on its page on vaccine safety, “Studies suggested that it is more likely that a person will get GBS after getting the flu than after vaccination."

On June 25, 2020, the New England Journal of Medicine published a letter from Italian physicians reporting five cases of GBS after the onset of COVID-19, all at three hospitals in northern Italy during a three-week period between February 28 and March 21. During that same period, an estimated 1,000 to 1,200 patients with COVID-19 were hospitalized there. 

On December 14, however, the journal Brain published an epidemiological and cohort study that found that the incidence of GBS in the United Kingdom actually fell during the first wave of COVID-19 there, dropping by up to 50 percent between March and May of 2020, compared to the same period during the four years prior.

The senior author of that study, who also coauthored the letter to Dr. Fauci, noted that GBS has an established annual incidence rate of two per 100,000 people. “During October, November and December 2020, we've been having in the UK up to 60,000 cases a day of COVID-19," Michael Lunn, FRCP, PhD, professor of clinical neurology and consultant neurologist at the National Hospital for Neurology and Neurosurgery in London, told Neurology Today.

“The data for GBS, however, for the last six months of 2020 remained entirely flat. If there was a link of COVID-19 to GBS, you would expect the number of cases of GBS to increase. There's not even a bump."

The same paper also presented an analysis of the genetic and protein structure of SARS-CoV-2 to check whether the virus had any obvious propensity to trigger an immune response causing GBS.

“Our analysis shows SARS-CoV-2 contains no additional immunogenic material known or proven to drive GBS," stated the first author of the paper, Stephen Keddie, MD, a neurologist in the department of neuromuscular diseases at University College London. “Concerns that COVID vaccination might cause GBS in any significant numbers are therefore almost certainly unfounded."

Dr. Lunn added: “When you immunize billions of the world's population, you are going to get thousands and thousands of cases of GBS associated with the vaccine by chance alone."

In its recommendations regarding the SARS-CoV-2 vaccines for people with underlying conditions, which includes those with multiple sclerosis (MS), the CDC states that people with autoimmune conditions may receive an mRNA COVID-19 vaccine. However, they should be aware that no data are currently available on the safety of mRNA COVID-19 vaccines for them.

Regarding the risk of Bell's palsy, the FDA noted in its December 10 briefing document for the meeting on the Pfizer-BioNTech vaccine, four cases were documented in the vaccine group, compared with zero cases in the placebo group. “The observed frequency of reported Bell's palsy in the vaccine group is consistent with the expected background rate in the general population," the paper noted, “and there is no clear basis upon which to conclude a causal relationship at this time, but the FDA will recommend surveillance for cases of Bell's palsy with deployment of the vaccine into larger populations."

As to the risk of GBS, Katherine Grusich, a CDC public affairs specialist, told Neurology Today: “As of Janury 8, no cases of GBS were reported in the clinical trial data submitted to FDA for vaccine authorization. There has been one case of GBS reported to the Vaccine Adverse Event Reporting System [VAERS] following COVID-19 vaccination. As of December 31, no cases of Bell's palsy had been reported to VAERS. The CDC and FDA are rigorously evaluating data from our surveillance systems, and reviewing all serious adverse event reports with clinicians to determine any association with vaccination."

She added: “The continued safety of these vaccinations as they are delivered to the public is the utmost importance to the federal government, so if a link is found between a serious neurological side effect and a COVID-19 vaccine, public health officials will take swift and appropriate action to determine if recommendations for using the vaccine should change."

Indeed, single cases of transverse myelitis resulted in temporary pauses in two of the vaccine trials. The Lancet published a paper on January 9 on the Oxford-AstraZeneca vaccine, noting that one such case occurred 14 days after the booster shot, as well as two additional cases “considered unlikely to be related to the intervention."

One of those cases was attributed to pre-existing MS, and the other occurred in the control group. In any case, “all participants have recovered or are recovering," the paper noted.

Another case of transverse myelitis occurred in Peru in a patient participating in the trial of a vaccine from the Chinese company Sinopharm. That resulted in a temporary halt of the trial on December 14, but the suspension was lifted just two days later. ​

Too Soon to Know?

Peter D. Donofrio, MD, FAAN, professor of neurology and division chief of neuromuscular disorders at Vanderbilt University School of Medicine, emphasized that despite the reassuring data so far, too little time has passed since the vaccines were approved to know with certainty what their side effect profile will prove to be.

“It's only been a matter of weeks since distribution began," said Dr. Donofrio, chair of the medical advisory board of the GBS/CIDP Foundation and coauthor of the letter to Dr. Fauci. “We really cannot yet know about the risks of neurological complications."

Even so, he added, “I have a sense that people who develop any neurological complications will want to attribute it to the vaccines rather than to serendipity. People have very strong feelings about vaccines."

Although the risk of complications from the vaccines appears low for now, Dr. Lewis noted that patients receiving immune-suppressing drugs for the treatment of CIDP, MS, or myasthenia gravis might see a blunted response to the vaccines.

“It doesn't mean they shouldn't get the vaccine," Dr. Lewis said. “But they may not get the full protection of the vaccine, because they're on immunosuppressives."

Although no signal of increased risk of Bell's palsy was seen in the clinical trials for the COVID-19 vaccines, an abstract presented at the AAN annual meeting in 2018 suggested that there might nevertheless be a slight risk associated with some other vaccines.

Based on an analysis of national data from the VAERS, the study found that 24 percent of the 445 reported cases of facial nerve palsy following vaccination between 1990 and 2010 occurred during the 2009-2010 season. That was the same season when concerns about the H1N1 swine flu led to an increase in vaccinations. The paper also found that over the entire 10-year span of the study, most cases of Bell's palsy associated with vaccination were reported in October (34 percent), the month when many vaccines against the flu are given.

The senior author of that abstract, Erin M. Feinstein, DO, assistant professor of neurology and program director of residency for adult neurology at Rutgers Health NJ Medical School, said that she was unable at the time of the study to find the precise underlying numbers of vaccinations given in the United States.

“We saw an increase of facial nerve palsy at the same time as a huge spike of vaccinations for H1N1," she said. “Does that mean there's something about the vaccines that caused it? It's impossible to know."

Despite the lack of data specific to the vaccines for SARS-CoV-2, Dr. Feinstein said, “We know there are clear neurological complications in people who develop COVID-19. We've seen an increased risk of stroke, an increased risk of memory changes. So by getting the vaccine, any potential risks are weighed by the known neurologic risks of COVID-19."

Even for patients with a history of Bell's palsy associated with HSV-1 or the varicella zoster virus, Maria A. Nagel, MD, professor in neurology and ophthalmology at the University of Colorado School of Medicine, said she recommends that they take the vaccine against SARS-CoV-2 when it's offered. 

"No statistically signficant incease in Bell's palsy due to the current COVID-19 vaccines has yet to be shown," she said. "If Bell's palsy does develop incidentally, it should be treated immediately."

However, Dr. Nagel added, "I do have a special subset of patients with recurrent Bell's palsy due to underlying medical conditions and/or immune dysfunction. For them I would still encourage vaccination because they are already on valacyclovir for prophylactic antiviral therapy. So even if, five years from now, it turns out that Bell's palsy is indeed a side effect of the vaccines, these special patients will have been covered with antivirals at the time of vaccinatiion."

That said, she added, "The doctor has to discuss the risks and benefits of the vaccine, what we know and what we don't know, and then it's ultimately the patient's decision."

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