Long COVID: Nerve damage may arise from immune system dysfunction

• In a recently published study, researchers investigated the reasons behind neuropathic symptoms in long COVID.
• They found that neuropathic symptoms in long COVID may arise from immune system dysfunction.
• Larger studies can build on these findings to help scientists better understand the underlying mechanisms.

More than half of the individuals who recover from SARS-CoV-2 experience long-term disability, including mental health conditions and pulmonary and neurological disorders.

The authors of the current study note that there is an overlap between long COVID symptoms and those of small-fiber polyneuropathy (SFN), which affects the small nerve fibers in the skin.

Investigations into the relationship between long COVID and neuropathy could help clinicians better evaluate and treat patients.

Recently, researchers from Harvard Medical School examined individuals with no prior neuropathy history who developed neuropathic conditions after recovering from a SARS-CoV-2 infection.

They found that some people with long COVID have long lasting nerve damage resulting from infection-triggered immune dysfunction.

“The information helps us better understand the pathophysiology that may underlie some long COVID symptoms, which can guide treatments to bring symptomatic relief and validation to patients,” Dr. Mary Kelley, one of the authors of the study, told Medical News Today.

The authors published their study in Neurology: Neuroimmunology & Neuroinflammation.

Patient recruitment

For the study, the researchers recruited 17 people with a confirmed SARS-CoV-2 infection, no prior history of neuropathy, and a neuromuscular referral. The participants met the criteria for having long COVID, according to the World Health Organization’s (WHO’s) definition. Of the participants, 69% were female, 19% were of Latinx ethnicity, and 94% were white.

The researchers tracked standardized symptoms, clinical examinations, objective neurodiagnostic test results, and outcomes for each participant over an average of 1.4 years.

As most of the participants had received symptom-relieving medications, the researchers examined potential preventive treatments, too.

Among the 17 people in the study, 16 had mild COVID-19, while one was in intensive care with ventilatory support for a month.

Diagnostic tests for neuropathy revealed that 62.5% of lower leg skin biopsies and 50% of upper thigh biopsies and autonomic function tests confirmed SFN.

The treatments included IV immunoglobulins (IVIg) — the primary treatment for inflammatory neuropathy, with early evidence for treating SFN — and corticosteroids. Most of those who received the IVIg treatment perceived improvement in their symptoms, and the same was true for some of those on corticosteroids.

The researchers noted that some of the participants also made a spontaneous recovery. Due to this, they acknowledge in their paper the need to individualize treatment decisions for patients.

Dysfunctional immune response

To explain their findings, the researchers write that one-quarter of human dorsal root ganglia (DRG) neurons — that is, neurons that communicate between the peripheral nervous system and the spinal cord — express mRNA that is susceptible to attaching to SARS-CoV-2 spike proteins.

This may promote the formation of antibodies that target neurons as well as SARS-CoV-2.

The researchers further explain that the delayed onset of symptoms that occurs in long COVID, alongside prolonged postinfectious courses and apparent responses, suggests that mechanisms arise from a dysfunctional immune response.

“Given the nature and design of the small nerve fibers, they are particularly vulnerable to damage by things like inflammation, illness, and immunological derangements, generally speaking,” said Dr. Kelley.

Although it seems that there are underlying immune causes, what lies behind these mechanisms remains unknown.

Study limitations and future research 

Michael Lipton, Ph.D., who is a professor of radiology and of psychiatry and behavioral sciences at Albert Einstein College of Medicine and was not involved in the study, told MNT that due to the study’s small size, it is not possible to understand the underlying mechanism and causes.

“From what we have learned about COVID-19 neurological sequelae, likely mechanisms are related to inflammation and perhaps autoimmunity. These mechanisms would be consistent with the neuropathy found in this case series,” he said.

The researchers conclude that their results provide a basis for larger investigations into neuropathy in those with long COVID.

They also note some limitations to their work, including referral biases and the small sample size. They add that the initial evaluations occurred at varying times during the course of illness and treatment, whereas longitudinal assessments at standardized intervals are ideal.

Jacqueline Becker, Ph.D., a clinical neuropsychologist and assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York — who was also not involved in the study — shared her thoughts on the research with MNT.

“What is particularly surprising about the findings from this study is that the majority of patients had mild acute COVID-19, whereas this may have been less surprising in a cohort with severe acute disease.”

– Dr. Becker

“Given the small sample size and inherent bias toward referrals for neuropathy in the study, we cannot determine that the neuropathy found in these patients was directly caused by COVID-19. It does, however, suggest that there may be a link, which will hopefully prompt larger, prospective investigations,” she explained.

​​Dr. Seth Congdon, who is co-director of the COVID-19 Recovery (CORE) Clinic at Montefiore Medical Center and was not involved in the study, added that the research still leaves many unknowns that require further investigation: “[It is] unclear how best to treat small fiber neuropathy. It is important to screen for different conditions that can cause/exacerbate neuropathy, including diabetes, vitamin B12 deficiency, thyroid dysfunction, heavy alcohol use, autoimmune conditions (Sjögren’s, lupus, etc.), and treat them if found.”

“The IVIg results are intriguing, but this is a medication that poses logistical challenges. It is limited in availability, usually administered at an infusion center/clinic, [and] requires pre- and post-treatment evaluation and monitoring,” he added.

“Another thing I am unsure about is if IVIg puts patients at risk of having their humoral immunity from prior infection or immunization erased? Further research, including ideally a randomized clinical trial, is needed,” he concluded.

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