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Those Causal and Chance Associations Between COVID-19 Vaccinations and Neurologic Events
What's the Difference?

Article In Brief

Researchers discuss the complexities involved with deciphering causal relationships and coincidental associations between neurologic events and COVID-19 vaccines.

What should neurologists and their patients make of this April 5 headline from a Houston news outlet? “Local teen diagnosed with Guillain-Barre syndrome (GBS) questions COVID-19 vaccine after receiving the first dose.”

Alarming though it may sound, no one quoted in the article said that the vaccine caused GBS. Then again, they didn't firmly reject the possibility of a causal relationship either.

Charles Sims, MD, an infectious disease specialist with St. Luke's Health in The Woodlands, TX, is quoted in the article as saying the association “could be a coincidence.” Even the teen's father said they weren't trying to deter anyone from the vaccine but added, “Do your research. It's a personal choice.”

Since December, when the Pfizer and Moderna vaccines received emergency approval by the US Food and Drug Administration (FDA), neurologists and their patients have been struggling to make sense of the many reports, both journalistic and peer-reviewed, that have been published.

It hasn't been easy. Even the FDA and Centers for Disease Control and Prevention (CDC) have come under fire by some in mid-April for pausing distribution of the one-shot Johnson & Johnson vaccine. At the time, the agencies said they needed to study initial reports of six cases of cerebral venous sinus thrombosis. By comparison, on the same day that they announced the pause, 988 Americans died of COVID-19.

Ten days later, the agencies reported that, in fact, a total of 15 women had developed the rare clotting disorder, three of whom had died. But most had low levels of blood platelets, and so the usual treatment—the blood-thinning drug heparin—only made matters worse. Knowing that other treatments are available to treat the clots more safely and given that nearly eight million people had already received the J&J vaccine before the pause, the CDC announced that it was allowing J&J vaccinations to resume.

In the name of transparency and caution, did the agencies simply end up scaring off people from getting vaccinated, thereby ultimately causing more deaths?

Report in Neurology

Similar questions have been raised about a paper published in the journal Neurology online on April 6 describing two cases of GBS following participation in the clinical trial for the J&J vaccine: One in the active arm and one in the placebo. The very title of the paper suggests just how carefully the authors sought to thread the needle. Rather than tease readers with an implication of causality, as the Houston news headline did, the study title explicitly warns against such a conclusion: “Guillain-Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial: Temporal Associations Do Not Imply Causality.”

“I thought it was important to be balanced and to not say the case in the active arm was caused by the vaccine,” said Anthony A. Amato, MD, FAAN, professor of neurology at Harvard Medical School and chief of the neuromuscular division at Brigham and Women's Hospital.

Dr. Amato acknowledged that some neurologists fear that any case report of GBS following vaccination against COVID-19, no matter how carefully framed, will unduly frighten some patients.

“I myself struggled with whether we should write this, whether it would scare people,” he said. “But I did it because it would be naive to think that nobody is going to publish case reports. I wanted to be sure that the first one published in a peer-reviewed journal would be responsible.”

Dr. Amato's case study makes for a case study itself of how neurologists can best understand and communicate the distinctions between association and causation when judging the risks and benefits of an intervention, including vaccines for COVID-19.

Resisting the Allure of the Anecdote

The Houston case of the teenager who developed GBS, and Dr. Amato's case report of a person who developed it during the J&J trial, have something in common: They are both anecdotes.

“My mentor once told me an anecdote is always positive,” said Michael Lunn, FRCP, PhD, professor of clinical neurology and consultant neurologist at the National Hospital for Neurology and Neurosurgery in London. “Somebody somewhere had a medical problem that they've associated with the vaccine. I'm sure they also went shopping for groceries in the week before they developed GBS, but they didn't associate shopping with their reaction. Nobody should take notice of an anecdote about something that happens routinely, as GBS does.”

Dr. Lunn pointed to the Hill Criteria for Causality, a method developed in 1965 for assessing the likelihood that two events are causally related.

One of the criteria, he noted, is plausibility. “We know it is biologically plausible that a vaccine can cause an immune attack on a bit of nerve through molecular mimicry,” Dr. Lunn said. “But we've looked at those structures in the vaccines, and there is, in fact, no obvious similarity. Then you have to look at the statistical likelihood—we know that GBS occurs at two per 100,000 people per year. To have two cases of GBS occur during the clinical trials, including one in the placebo arm, is not exceptional.”

Two editorials published last year—one in Lancet Neurology and another in the Journal of Neurology, Neurosurgery and Psychiatry—sought to address the need for defining causality in COVID-19 and neurologic disorders.

“It is crucial that neurologists and neuropsychiatrists apply a systematic strategy to determine whether there is evidence that SARS-CoV2 is causing these manifestations, whether they are a consequence of severe systemic disease alone, or simply coincidence,” stated the Journal of Neurology, Neurosurgery and Psychiatry paper.

To get to the bottom of any possible causality, the authors of the Lancet Neurology paper wrote, “Careful clinical, diagnostic and epidemiological studies are needed.”

Ana-Claire Meyer, MD, FAAN, a member of the AAN Science Committee with expertise in clinical trials, said that the welter of medical and news reports about the safety and effectiveness of COVID-19 vaccines has been a useful learning process for the lay public.

“The public has been watching science and medicine develop in real-time,” she said. “That can be scary for the public. They want to believe that all the risks are known. But that's not how science works. From my perspective, the transparency around the data is something to be applauded. It's critical for trust.”

Dr. Meyer added: “However, this is complicated information. It's really important and incumbent on us as a medical community to find ways of communicating the difference between an association and a true causal relationship to our patients. If a case of GBS happens in someone who received the vaccine but also in someone who did not receive the vaccine, does that mean the vaccine actually caused the case of GBS or was the GBS caused by something else and happened just after the vaccine by chance? It is also really important for us to clearly communicate the risk vs. benefit of vaccination. For each patient, you have to weigh their individual risk of vaccine side effects against the risk of ending up in the hospital or dying from COVID-19. What is their age, gender, their comorbidities? I talk it through with my patients to help them think about what getting the vaccine means to them as an individual.”

Sherry H-Y. Chou, MD, MSc, FNCS, FCCM, associate professor of critical care medicine, neurology, and neurosurgery at the University of Pittsburgh, said that in some ways, doctors and patients are caught in a Catch-22.

“We need this information now on the possible neurologic effects of COVID-19, but the data is coming in piecemeal,” Dr. Chou said. “Case reports and surveillance systems are the first and only way to begin getting the information. Eventually, the case reports will evolve into case series, then cohort studies, then into systematic reviews or meta-analyses. Dr. Amato's publication in a peer-reviewed journal can be the building block of understanding whether or not the association is causal.”

The challenge, she said, is that reports of neurologic syndromes associated with COVID-19 or with the vaccines designed to prevent it are inevitable.

“Neurologic syndromes occur regardless of whether someone gets a vaccine or not,” Dr. Chou said. “That's why this is hard. We need high-quality data to really tell us: Does the vaccine increase your risk for neurologic events or not?”

While she said she understands why some neurology patients might be afraid of anything they think could worsen their symptoms, Dr. Chou emphasized: “Of all the scientific data we have on COVID-19 to date, the vaccine data is strongest. It's the only area where we have randomized, controlled trials, more so than with the drugs we're giving to people to treat the disease. There is no evidence of increased neurological complications in phase 3 studies of the FDA-approved vaccines.”

Phantom Harms, Ghostly Benefits

While neurologists struggle to find the right way to address patients' fears and concerns, an organization in the United Kingdom was established in 2016 to help doctors and others do exactly that.

“Our mantra is to inform but not persuade,” said Alexandra Freeman, DPhil, executive director of the Winton Centre for Risk and Evidence Communication, based at Cambridge University. Staffed by psychologists, statisticians, communications specialists, and programmers, the center has most recently been tasked by the UK's medicines regulator to develop a graphic showing the potential risks and benefits, stratified by age, of the AstraZeneca COVID-19 vaccine.

“The biggest problem that doctors and patients have about interpreting these risk statistics,” Dr. Freeman said, “is when one potential harm or benefit is less obvious than the other. In the case of vaccines, you might get a sore arm and a headache, but the benefit is hidden because you never see the cases of COVID-19 that were prevented. These are the most difficult concepts because the benefits are ghostly. That's why you really do need to look at the numbers.”

Even when statistics are presented clearly, Dr. Freeman said, doctors and patients must trust the source of those numbers.

“We have found that people often judge the trustworthiness of a source based on how they perceive that source's motivations,” Dr. Freeman said. Unfortunately for vaccine manufacturers, she said, people believe that “anyone who's selling a drug has conflicts of interest. Those conflicts are things people are sensitive to. Academics and the media often complain, ‘Why do people trust their friends and family and their anecdotes more than they trust the data?’ The answer is obvious: because your friends and family aren't trying to sell you something.”

Even when a doctor or group has no perceived profit motive, she added, “There can still be mistrust from individuals and communities who perceive doctors as being part of the establishment who have power over others, particularly marginalized communities.”

The best a doctor can do when speaking to patients about the vaccines for COVID-19, Dr. Freeman said, is to provide clear and balanced information on risks and benefits and let them make their own decision. “Trust is easily lost and hard to gain,” she said. “You have to be upfront about what you know and what you don't know. And you have to be quick to correct yourself when more information comes in.”

Link Up for More Information

• Marquez Loza AM, Holroyd KB, Johnson SA, et al. Guillain-Barré syndrome in the placebo and active arms of a COVID-19 vaccine clinical trial: Temporal associations do not imply causality Neurology 2021: Epub 2021 Apr 6.
    • Ellul MA, Varatharaj, Nicholson TR, et al. Defining causality in COVID-19 and neurological disorders J Neurol Neurosurg Psychiatry 2020;91(8):811–812.
    • Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19 Lancet Neurol 2020;19 (9):767–783.