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Prolonged, often disabling, small-fiber neuropathy in long COVID may be caused by a defective immune response, a small longitudinal study suggested.

Peripheral neuropathy was identified in 59% of 17 people with long COVID (16 of whom had mild cases of SARS-CoV-2 infection), reported Anne Louise Oaklander, MD, PhD, of Massachusetts General Hospital in Boston, and co-authors in .

This is one of the early papers looking into causes of long COVID, Oaklander noted. "Our findings suggest that some long-COVID patients had damage to their peripheral nerve fibers, and that damage to the small-fiber type of nerve cell may be prominent," she said in a statement.

"Research from our team and others is clarifying what the different types of post-COVID neuropathy are, and how best to diagnose and treat them," she added. "Most long COVID neuropathies described so far appear to reflect immune responses to the virus that went off course."

Since early in the pandemic, COVID-19 patients have described lingering symptoms after acute infection, including nerve pain, memory and concentration problems, frequent headaches, and intractable fatigue. Many people with long-COVID neurologic symptoms were healthy and active prior to SARS-CoV-2 infection; most were never hospitalized for acute COVID-19 illness.

In this study, Oaklander and colleagues analyzed data on 17 patients who met the WHO and who were referred for peripheral neuropathy evaluations. People with prior neuropathy history were excluded.

Participants were 22 to 66 years old and had a mean age of 43. Most (69%) were women, 94% were Caucasian, and 19% were Latino. Some were evaluated early in their long COVID course and others later. On average, participants were followed for 1.4 years.

Initial small-fiber neuropathy symptom scores were abnormal, averaging 41% of ideal. Initial neuromuscular examinations averaged 77% of ideal; abnormal distal pin and vibration sensations and absent Achilles reflexes were most prevalent. Pain scores averaged 4.8/10.

Of 17 participants, 59% had one or more test interpretations confirming neuropathy: 10 of 16 had lower leg skin biopsies, two of 12 had electrodiagnostic tests, and four of eight had autonomic function tests.

One patient was diagnosed with critical illness axonal neuropathy. Another developed hand weakness and atrophy 3 weeks after mild COVID and was diagnosed with multifocal demyelinating neuropathy. "This reported case of multifocal motor neuropathy increases the spectrum of COVID-associated dysimmune neuropathies," Oaklander and co-authors noted.

Most participants (65%) received immunotherapies, either corticosteroids, IV immunoglobulins (IVIg), or both. Most patients treated with sustained IVIg -- the primary treatment for inflammatory neuropathy -- perceived improvement.

Patient-reported improvement varied over time, reflecting varying illness severity, treatment status, and assessment timing. The average improvement was 52%, and no one reported complete resolution.

identified corneal small nerve fiber loss in patients with long COVID, especially those with neurologic symptoms, supporting the hypothesis that some long COVID symptoms may reflect underlying small-fiber pathology, Oaklander and colleagues noted.

"As with other post-COVID neurologic illnesses, susceptibility to inflammatory mediators appears essential," they observed. "Autopsy study of post-COVID patients identified neuritis with perivascular macrophage infiltrates but no viral antigens, implicating inflammatory immune responses rather than direct infection."

The current cases confirm neither causality nor the clinical significance or magnitude of any association, the researchers emphasized.

"However, identifying small-fiber neuropathy and multifocal motor neuropathy in one small sample of patients with WHO-defined long COVID provides rationale and preliminary data for larger investigations and may influence interim medical evaluations of similar patients," they wrote.

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