The symptoms of the adverse event that led to the pause in Astra Zeneca's COVID-19 vaccine trial are reportedly consistent with transverse myelitis. although the diagnosis has not been confirmed.
It is still unclear whether the adverse event that caused AstraZeneca to pause enrollment in its COVID-19 vaccine trial was transverse myelitis or not.
The New York Times is reporting this morning that in a statement to reporters yesterday an AstraZeneca spokesperson said the individual did not have a confirmed [emphasis added] case of transverse myelitis. The newspaper reported two days ago that an anonymous source said a woman in the United Kingdom who had the possible adverse reaction to the vaccine had received a diagnosis of transverse myelitis.
Stat, which broke the story that the trial had been put on hold, reported yesterday that company’s CEO, Pascal Soriot, told investors in a conference call today that the symptoms of the woman whose illness led the company to pause of the trial are consistent with transverse myelitis, although in the same story the biotech news site reported that diagnosis had not been confirmed.
The Wall Street Journal reported yesterday that a form from July that was posted on an international registry of clinical trials said a study volunteer had developed symptoms of transverse myelitis.
Meanwhile, health officials and experts are cautioning that it is common for vaccine trials to be put on hold as researchers investigate whether illnesses that occur in study volunteers are, in fact, related to the vaccine. “It’s quite common for serious adverse events to occur, most not relevant to the vaccine,” Peter Hotez, dean of the National School of Tropical Medicine at Baylor told the Journal.
Whether or not the adverse event is confirmed as a case of transverse myelitis or not, the news over the last few days has asking a lot of questions about transverse myelitis.
Here is some information for people who are unfamiliar with it:
In simple terms, it is inflammation of the spinal cord. Wolters Kluwer UpToDate, the database of reviews of medical topics, describes transverse myelitis as a “mixed inflammatory disorder that affects neurons, axons, and oligodendrocytes [the cells that produce myelin] and myelin.” A 2010 “clinical practice” article in the New England Journal of Medicine described the “pathological hallmark” of the condition as being the “focal collection of lymphocytes and monocytes with varying degrees of demyelination, axonal injury and astroglial and microglial activation within the spinal cord.”
Myelitis is the medical term for inflammation of the spinal cord. In some accounts, the modifier transverse is explained as referring to the pattern of symptoms that go across the body. But the better explanation is that transverse refers to the transverse, or horizontal, plane of the spinal cord and the fact that the inflammation is usually limited to a relatively small area of the spinal cord, not its whole length. Transverse also refers to the fact that both the ascending (that carry sensory messages to the brain) and descending (which direct voluntary movement) tracts of the spinal cord are affected.
A large proportion — how large varies with the study — of cases are associated with central nervous system autoimmune disorders, such as multiple sclerosis and neuromyelitis optica spectrum disorder, and other autoimmune disorders, such as sarcoidosis and Sjögren syndrome. In fact, transverse myelitis can be the first demyelinating event that precedes full-blown multiple sclerosis.
Another large fraction of cases — as large as two thirds in some studies — of transverse myelitis cases are labeled idiopathic, meaning that the cause is uncertain. But that is a bit of a misnomer because a large proportion of those idiopathic cases occur after an illness or infection of some kind has occurred. “Nevertheless, these are considered idiopathic because the causative nature of the infection is seldom proven,” says the Wolters Kluwer UpToDate article on transverse myelitis. The thinking is that an infection can trigger an aberrant, unregulated immune response that turns on the body — and, in this case, the spinal cord — instead of taking on the invasive organism.
Some of the infectious agents that have been linked to the development of transverse myelitis include the enteroviruses, the West Nile virus, and the Zika virus. Transverse myelitis can also be a complication of Lyme disease, which is typically caused by bacterium Borrelia burgdorfer
There have been several case reports suggesting that COVID-19 itself could trigger transverse myelitis. For example, in a letter published in May in the Journal of Neurology, German clinicians described the case of a 60-year-old man who recovered quickly from COVID-19 pneumonia but then developed symptoms suggestive of transverse myelitis three days after he was discharged.
There are reports of instances when getting a vaccine appeared to lead to transverse myelitis. But Roger Baxter of the Northern California Kaiser Permanente Vaccine Study Center in Oakland, California, and his colleagues used the Vaccine Safety Database to look at the question more systematically. Among 64 million vaccine doses, they found 7 cases of transverse myelitis and no statistically valid association between those cases and prior vaccination. They reported the results of their study in the journal Clinical Infectious Diseases in 2016. in the Vaccine Safety Database to look at the question more systematically.
An incidence of between one to eight cases per million people is cited often. Such a proportion would mean a range of between 330 and 2,640 new cases in the United States annually. The authors of the NEJM clinical practice piece noted that if cases associated with multiple sclerosis and other demyelinating disorders are included, the estimated incidence increases to about 25 cases per million, which would translate into roughly 8,000 cases occurring in the U.S. annually.
Transverse myelitis is divided into subtypes based on how large the area of inflammation is, whether it affects both sides of the spinal cord symmetrically, and other factors. The symptoms vary with these subtype and where on the length of the spinal cord the inflammation is present.
In a nontechnical explanation on its website, the Johns Hopkins Transverse Myelitis Center says the four “classic” symptoms are weakness in the arms and legs, sensory symptoms such as numbing and tingling, pain and discomfort, and bladder dysfunction, bowel motility problems’, or both.
Clinicians are encouraged to take a patient history and assess symptoms carefully because they can yield important diagnostic clues. After that, one of the first steps is an MRI scan of the spine, partly to rule out that the symptoms aren’t the result of a “compressive lesion” — something (herniated disc, for example) impinging on the spinal cord that might be treated with surgery. The contrast agents used in MRI scans can also yield some diagnostic information that may (or may not) lead to transverse myelitis diagnosis. The diagnosis also hinges on the analysis of the cerebrospinal fluid, which is collected via lumbar puncture. High white blood cells can be indicative of inflammation. Measurements of antibody can indicate whether multiple sclerosis is likely.
The authors of the NEJM article note that transverse myelitis syndrome has an extensive differential diagnosis, which means a number of other tests might be done to rule out other causes. For example, a brain MRI might be ordered to detect the presences of lesions that are indicative of multiple sclerosis.
Treatment with intravenous corticosteroids is the standard first-line treatment and has been for a while. Although the NEJM article was published 10 years ago, the authors identify intravenous corticosteroids as the front-line treatment. The authors of Wolters Kluwer UpToDate article say their preferred regimens are methylprednisolone or dexamethasone for three to five days. The Johns Hopkins Transverse Myelitis Center notes the lack of evidence from clinical trials but says “it is well recognized as a standard of care that patients suspected to have acute myelitis receive high-dose intravenous methyl-prednisolone for 3-5 days, unless there are compelling reasons not to.”
The standard second-line treatment if intravenous corticosteroids aren’t effective is plasma exchange, which involves filtering out a patient’s plasma and replacing it plasma from a donor or a saline solution that contains albumin. The Wolters Kluwer UpToDate authors say that for patients with significant deficits, waiting for end of the corticosteroid treatment isn’t necessary. The Johns Hopkins Transverse Myelitis Center takes a slightly different approach, saying that plasma exchange is often used for patients with moderate to aggressive forms of transverse myelitis “who don’t show much improvement after being treated with intravenous and oral steroids.”
Immunosuppressant or immunomodulatory agents may be used to treat people with recurring transverse myelitis or cases that don’t respond to intravenous corticosteroids or plasma exchange. The Wolters Kluwer UpToDate authors mention mycophenolate and intravenous rituximab. The Johns Hopkins center mentions intravenous cyclophosphamide.