Nerve damage and a buildup of immune cells in the cornea may be a sign of "long COVID," a long-term syndrome that emerges in some people after COVID-19 infection, a new study suggests.
These preliminary results will need to be verified in a larger group of people with long COVID, or COVID-19 long-haulers, as they're known, an expert told Live Science. But the findings do hint at something scientists already suspected: Some symptoms of long COVID emerge due to peripheral nerve damage, she said.
COVID-19 long-haulers experience a wide range of symptoms, and a large proportion report neurological problems, including headache, numbness in the body, loss of smell and "brain fog," or trouble thinking and concentrating, Live Science previously reported. This constellation of symptoms hints that long COVID may partly arise from damage to nerve cells in the body, said senior author Dr. Rayaz Malik, a professor of medicine and consultant physician at Weill Cornell Medicine-Qatar in Doha.
Specifically, preliminary evidence suggests that long COVID may involve damage to small nerve fibers — thin wires that branch off of specific nerve cells in the body and relay sensory information about pain, temperature and itchiness, among other sensations to the central nervous system. Small-fiber nerve cells also help control involuntary bodily functions, such as heart rate and bowel movements; therefore, damage to these cells can cause a wide array of symptoms.
Malik and his colleagues study small-fiber nerve loss in people with diabetes and neurodegenerative diseases like multiple sclerosis; they noticed that people with long COVID appear to share similar symptoms with these patients, so they decided to investigate the potential link.
Using a technique called corneal confocal microscopy (CCM), the team took snapshots of nerve cells in the cornea, the transparent layer of the eye that covers the pupil and iris. The team used the non-invasive procedure to count the total number of small-fiber nerve cells in the cornea, while also assessing the length and degree of branching of those fibers. In their work with other conditions, the team has found that, when you find damage in the small-fiber nerves of the cornea, that often indicates that there's similar damage elsewhere in the body. "This is like a very good barometer, almost, of nerve damage elsewhere," Malik explained.
According to the new study, published Monday (July 26) in the British Journal of Ophthalmology, people who develop neurological symptoms after a COVID-19 infection show significant small-fiber nerve loss in the cornea, compared with COVID-19 survivors without lingering neurological symptoms. What's more, the degree of nerve-fiber damage correlated with the participants' symptom severity, meaning greater nerve damage was linked to more pronounced symptoms.
The small study included 40 people who had recovered from COVID-19 between one and six months prior to their assessment; out of the full group, 29 people had recovered from COVID-19 at least three months prior. In addition to getting the corneal scan, each participant completed a survey that included questions about any neurological symptoms of long COVID.
They also filled out questionnaires about neuropathic pain, which can include numbing, prickling and burning sensations in the body, as well as muscle weakness, according to UC Davis Health. Another questionnaire helped the researchers to pinpoint the location and severity of the participants' muscle pain; it also helped flag additional symptoms like fatigue and bowel issues, the authors noted.
Of the 40 participants, 22 showed lingering neurological symptoms — including headache, dizziness and numbness — four weeks after recovering from their initial COVID-19 infections. And 13 out of the 29 who had been recovered for at least three months reported having neurological symptoms at week 12 post-infection. "It's very clear, if you look at the graphs ... people who've got the neurological symptoms definitely have a reduction" in small-fiber nerves, while the other participants don't, Malik said.
The study authors also assessed 30 healthy individuals with no history of COVID-19 infection for comparison. They found that, compared with these 30 control participants, all the COVID-19 survivors harbored a large number of immune cells on their corneas; more specifically, immune cells called dendritic cells that help inform the immune system of foreign invaders appeared in unusually high quantities.
The people with lingering neurological symptoms showed a roughly fivefold increase in these dendritic cells, compared with the healthy controls; those without neurological symptoms showed about a twofold increase.
"So there's clearly something, there's an immune process that is still ongoing," even after the initial COVID-19 infection clears, Malik said. "So maybe there is an immune trigger that is switched on and it takes time for it to kind of settle down," he said. And in the meantime, this runaway immune response damages nerve cells.
The new study cannot prove that an immune response caused the observed nerve damage. However, the idea does align with existing evidence that most neurological damage from COVID-19 is caused by inflammation, not by the virus infecting nerve cells directly, according to a 2020 commentary in the journal Pain.
"It's not the infection, per se, it's the immune response it provokes," said Dr. Anne Louise Oaklander, an associate professor of neurology at Harvard Medical School and assistant in pathology at the Massachusetts General Hospital, who was not involved in the new study. "Infection revs up your immune cells to start firing, to fight the enemy, and there's going to be collateral damage," she said. In this case, small-fiber nerve cells may fall victim to friendly fire.
Oaklander added that she was "excited" about the new study, as it provides evidence of small-fiber nerve damage in long COVID patients. The data are helpful to biomedical researchers, like Oaklander, who are trying to understand the causes of long COVID and how to treat the syndrome. However, for now, she said the research doesn't necessarily provide any solutions for patients.
In their paper, Malik and his colleagues suggest that corneal confocal microscopy could be used as a diagnostic tool to help identify people with long COVID — particularly those with neurological symptoms. However, currently, the technique is primarily used for research and is not widely available in clinical settings, Oaklander said.
The gold standard for assessing small-fiber nerve damage involves taking a small skin biopsy from a patient's leg and measuring the nerve endings within, she said. Doctors can screen for symptoms of nerve damage with written surveys and neurological exams, but they currently require a skin biopsy to confirm their diagnoses. For this reason, it would be helpful if future studies of long COVID patients included these skin biopsies, along with the standard questionnaires used to screen for small-fiber sensory neuropathies, Oaklander suggested. ("Neuropathy" refers to damage to the nerves that run through the body outside the brain and spinal cord.)
For now, Malik said his group plans to follow up with their initial group of 40 participants, to see how their corneal nerves and long COVID symptoms change through time. In addition, they plan to replicate their study in larger groups of patients to validate the results.
"People might say, 'Well, 40 patients isn't enough.' We agree; you need larger studies," Malik said. Assuming the results can be confirmed in larger cohorts, eventually, this line of research may provide helpful hints as to how doctors can treat long COVID, he added. Treatments for post-infectious neuropathies do exist, it's just a question of whether they'd work for long COVID patients with post-infectious small-fiber neuropathy, and if so, how they can best be applied, Oaklander said.
Originally published on Live Science.