Preprint: Neuropathic symptoms with SARS-CoV-2 vaccination, 2022, Safavi, Walitt, Oaklander, Nath et al

[Andy]

Abstract
Background and Objectives Various peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown.

Results In an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities (≤5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks.

Conclusions This observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.

Open access, https://www.medrxiv.org/content/10.1101/2022.05.16.22274439v1

 

[Andy]

Twitter thread from Brian Vastag about this

 

[Hutan]

An obvious question is 'did the patients have the symptoms before the vaccination?' - the researchers do seem to have tried to exclude that possibility:

We excluded patients whose complaints were non-neurologic or limited to worsening or recrudescence of prior neurological symptoms and those with underlying conditions or risk factors for neuropathy and dysautonomia. All patients were extensively investigated for other causes of SFN. Two had organ-specific autoimmune disorders (one with Crohn’s disease, one with Hashimoto thyroiditis) in clinical remission at the time of vaccination.

Another is 'is the timing of symptoms appearing within a month of vaccination a coincidence'? Could the symptoms actually be related to a Covid-19 infection, or just chance? The median time for the appearance of symptoms was 4 days after vaccination.

Comparing cutaneous deposition of CD31, IgG, IgM, C1q, and C4d between 5 patients and 9 age/sex matched healthy controls revealed more C4d deposition on endothelial cells in all patients

The circumstantial evidence here suggests that in some individuals SARS-CoV-2 vaccination neuropathy may be dysimmune. The fact that participants were screened, and common causes of neuropathy eliminated, the presence of oligoclonal bands in the CSF of two of five participants, deposition of immune complexes on skin biopsy and apparent response to immunotherapy supports possible immune involvement. Plus, almost all patients here were female. Females comprised 69% in one case series of neuropathy incident to COVID-19,9 they comprise the large majority of SFN patients,19 and of patients with most systemic and organ-specific immune syndromes. Similarly, POTS and multiple types of peripheral neuropathy are well-described after other vaccinations20 or illnesses, including brachial plexitis.21

The current series extends the hypothesis that COVID-incident neuropathies are dysimmune rather than directly infectious. Postmortem peripheral nerve pathology after fatal COVID-19 infections identified inflammatory perivascular infiltrates of predominantly macrophages without viral antigen in nerves. Detection of interferon stimulated gene MxA in endothelial cells suggested type 1 interferon response.22 It is currently unknown if similar mechanisms might contribute to potential vaccine-induced neuropathies.

It's an interesting study, not least because of the people involved, and the acceptance the study seems to indicate for infectious (and now potentially non-infectious) immune challenges resulting in dysautonomia and small fibre neuropathy.

 

[Hutan]

On potential complement involvement:

Currently, there is insufficient immunological detail. Here, we did not detect the few characterized autoantibodies associated with dysautonomia or neuropathy, but most are not yet characterized. The increased deposition of C4d complement on cutaneous endothelial cells seen here is consistent with immune-mediated activation of the classical complement pathway.

C3d and C4d regulatory molecules covalently bind to tissues to formation a cytolytic complex. Endothelial C3d and C4d deposition is reported in SLE and small vessel vasculitis and low blood levels have been reported in some surveys of small-fiber neuropathy.33, 34 Cases of seronegative immune-mediated sensory/autonomic neuropathy post-viral infection and post-vaccination implicate memory T-cell responses rather than autoantibodies, as do patients that respond dramatically to high dose corticosteroids but not to plasma-exchange.7 And genetic susceptibility to various immune conditions including sensory neuropathy and autonomic dysfunction is documented37 Autoantibody generation driven by molecular mimicry and independent immuno- dysregulation may both contribute.7