Patients With Prolonged Long COVID Will Likely Suffer From Nerve Damage And Peripheral Neuropathy


A new study by researchers from Harvard Medical School and Massachusetts General Hospital-USA shows that those with prolonged Long COVID will likely suffer from nerve damage and peripheral neuropathy.

The study finings were published in the peer reviewed journal: Neurology: Neuroimmunology & Neuroinflammation.

Neuromuscular evaluations proved useful in most of these patients with long COVID. However some symptoms, exam changes and test results may have been false-negative, given that assessments were not often optimally timed (e.g., #6) and many patients reported care delays.

This reported case of multifocal motor neuropathy (Figure 1) increases the spectrum of COVID-associated dysimmune neuropathies. Critical illness neuropathy – reported in approximately 10% of intubated patients with COVID – is attributed to various prolonged insults including intense inflammation and nerve compressions.6 Inherent study limitations include bias toward referrals for sensory neuropathy and underpowering.

The initial evaluations reported occurred at varying times during the illness and treatment, whereas longitudinal assessments at standardized intervals are ideal for diagnostic and treatment decisions. Timing also complicates analysis of blood testing for immune markers (not shown).

We screened patients with newly diagnosed neuropathy for all common established causes of distal sensory neuropathy, including routinely measuring ANA, ESR, IgG anti–SS-A/SS-B antibodies, and complement components C3 and C4, the most productive markers of dysimmunity in initially idiopathic SFN.7 We did not detect evidence of Sjögren syndrome, and other inflammatory markers were only occasionally elevated.

Interpretation is complex as early elevations could be nonspecifically associated with acute COVID, and many months later, inflammation and markers might have subsided leaving residual axonopathy as the proximate cause of current symptoms. Regeneration can take up to 2 years or be incomplete.

These results identify small-fiber neuropathy as most prevalent in this small group of patients with long COVID, also known as post-acute sequelae of SARS CoV-2 infection.2

In SFN, the small-diameter unmyelinated and/or thinly myelinated sensory and autonomic fibers are predominantly affected, although most patients with severe or advanced polyneuropathy, e.g., case 9, develop large- and small-fiber damage.

The small fibers are disproportionately vulnerable, with their lack of myelin exposing them to environmental stressors including immunity, while inability to use saltatory conduction increases metabolic demand, and cytoplasmic paucity limits axonal regeneration.

However, small-fiber axons grow throughout life to reinnervate continuously dividing tissues such as the skin and to help repair injuries. If toxic conditions improve, axon elongation and sprouting accelerate to increase the probability of reinnervating enough target cells to resolve symptoms.

Here, most patients treated with sustained IVIg, the primary treatment for inflammatory neuropathy, with preliminary evidence of effectiveness for dysimmune SFN,8 perceived improvement (e.g., Figure 1, eFigure 1,

Some treated only with corticosteroids did as well; participant 3 reported that prednisone helped her toward 90% improvement and was discontinued only because of adverse effects. Others improved substantially without immunotherapy (e.g., case 17), documenting spontaneous recovery and need to individualize treatment decisions.

The hypothesis that some long COVID symptoms reflect underlying small-fiber pathology is supported by research observation of small-fiber loss applying in vivo corneal confocal microscopy to patients with long COVID.9

As with other post-COVID neurologic illnesses, susceptibility to inflammatory mediators appears essential.

Autopsy study of post-COVID patients identified neuritis with perivascular macrophage infiltrates but no viral antigens, implicating inflammatory immune responses rather than direct infection. In addition, 1/4th of human DRG neurons express mRNA for SARS-CoV-2–associated receptors and deploy ACE2 protein.

Thus, virus or spike protein fragments may attach to them, promoting formation of antibodies that can also target adjacent neural epitopes. Here, the slightly delayed onsets, prolonged postinfectious courses, and apparent responses to continued immunotherapy suggested dysimmune mechanisms.

This report strengthens evidence linking several idiopathic multisymptom conditions – including SFN and fibromyalgia – with dysimmunity, sometimes incident to infections or vaccinations.2

As with COVID-incident Guillain-Barré syndrome and all referral-based case series, the current cases neither confirm causality nor the clinical significance or magnitude of any association.

However, identifying small-fiber neuropathy and multifocal motor neuropathy in 1 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.


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