Bandinelli 2025 — Post-COVID SFN systematic review: corneal in vivo microscopy + optic nerve tomography among diagnostics

One-paragraph summary

Systematic review of post-COVID-19 small fiber neuropathy (PASC-SFN) as an emerging quality-of-life-threatening disease, consolidating clinical features, diagnostic modalities, and partial-response treatments across the published literature. Key finding for the FM project: among the diagnostic modalities surveyed, the review highlights corneal in vivo microscopy (corneal confocal microscopy, CCM) and optic nerve tomography (OCT) as complementary modalities to skin biopsy (the gold standard) for SFN diagnosis — explicitly identifying these as relevant when "ocular discomfort is present." The PASC-SFN clinical presentation overlaps substantially with the FM phenotype: distal-limb burning pain and numbness with dysautonomia, cognitive, visual, and osteoarticular dimensions involving multiple organ systems. Treatments surveyed include steroids, pregabalin, gabapentin, duloxetine, vitamins, homotaurine + phosphatidylserine, alpha lipoic acid, immunosuppressants, and IVIG — with partial responses across all, motivating multidisciplinary individualized management. For the FM project, this review independently anchors corneal CFM and OCT as established SFN diagnostic modalities for a post-infectious condition mechanistically adjacent to FM (Mignolet 2026 LC-IgG mechanism; Morcos & Theoharides 2026 LC mast-cell axis). The retinal-biomarker-diagnostic-priority panel's CCM and OCT modules gain external validation from this systematic review, and the post-COVID-FM cohort the project plans to stratify gains cross-condition methodology continuity.

Claims as triples

• post_covid_syndrome — causes → small_fiber_neuropathy [evidence: systematic review consensus; confidence: emerging]
• corneal_nerve_fiber_density — predicts → small_fiber_neuropathy [evidence: CCM as established SFN diagnostic modality cited across review papers; confidence: established]
• OCT_RNFL_thickness — predicts → small_fiber_neuropathy [optic nerve tomography mentioned as adjunct diagnostic; confidence: emerging]
• pregabalin — modulates → small_fiber_neuropathy [partial response across studies; confidence: emerging]
• duloxetine — modulates → small_fiber_neuropathy [partial response; confidence: emerging]
• gabapentin — modulates → small_fiber_neuropathy [partial response; confidence: emerging]
• ivig — modulates → small_fiber_neuropathy [partial response; confidence: emerging]
• photophobia — present_in → post_covid_syndrome [visual disorders cited; confidence: emerging]

Methods note

PRISMA-screened systematic review of post-COVID-19 SFN literature. No new primary data. Reviews clinical and diagnostic features, accompanying disorders, disease evolution, and treatment evidence across published cohorts. Covers nerve quantitative sensory testing, EMG, optic nerve tomography, skin biopsy, and corneal in vivo microscopy.

Limitations

• Review-tier; no new primary FM-direct data.
• PASC-SFN is the primary focus, not FM — relevance to FM is via the mechanistic-adjacency framework (Mignolet 2026, Morcos & Theoharides 2026) and the shared diagnostic modality framework.
• Treatment-response data across the surveyed studies is heterogeneous; effect sizes are partial across all modalities (no curative intervention identified).
• The corneal CFM and OCT modalities are surveyed as adjuncts to skin biopsy, not standalone diagnostics — limits the immediate translation to non-invasive-only diagnostic panels.

Open questions raised

• Do post-COVID FM patients show distinguishable retinal signatures (RNFL, choroidal, OCTA, CCM) from idiopathic FM patients? (Q-Re-12 in project open questions.)
• Does the post-COVID-SFN cohort respond to MRGPRX2 antagonists, FcRn blockade, or other H1-cure-path arm interventions at comparable rates to FM-autoimmune-positive idiopathic FM?
• Is corneal CFM CNFD reduction in post-COVID-SFN equivalent to that in FM-SFN, or are there discriminating features?

Triangulation notes

• External validation of the retinal-biomarker-diagnostic-priority CCM + OCT panel components in a methodologically adjacent post-infectious nociplastic condition.
• Strengthens bridge B1 (Long COVID ↔ FM via autoantibody-mediated SFN): the diagnostic-modality continuity (corneal CFM + OCT + skin biopsy used across both conditions) parallels the mechanistic continuity (IgG passive transfer evidence across both — Goebel 2021 in FM, Mignolet 2026 in LC).
• Connects to Morcos & Theoharides 2026 (long COVID mast-cell axis, already in project): the PASC-SFN clinical phenotype overlaps with MC-driven sensory/autonomic symptoms.
• Connects to project's treatment ontology: pregabalin, gabapentin, duloxetine, IVIG all already in project — Bandinelli 2025 supplies cross-condition partial-response evidence in PASC-SFN that supplements the FM-direct evidence base.
• Photophobia + visual disorders cited as PASC-SFN feature: cross-condition support for the project's photophobia symptom entity in the unified post-infectious nociplastic syndrome cluster.

Bridges

• Reinforces B1 (Long COVID ↔ FM via autoantibody-mediated SFN): adds cross-condition diagnostic-modality continuity at the corneal CFM + OCT layer.
• B-Re-7 (Post-COVID SFN ↔ FM SFN diagnostic-modality concordance, NEW 2026-05-23). One endpoint at PASC-SFN (this paper); other at FM-SFN (project's existing fm_peripheral_sfn subtype). Confidence: emerging. Closing: head-to-head corneal CFM + OCT comparison between PASC-SFN and FM-SFN cohorts — would establish whether the diagnostic modalities transfer across conditions or require condition-specific normative ranges.

Cure-path implications

The review's partial-response observation for all surveyed treatments (steroids, pregabalin, gabapentin, duloxetine, IVIG, immunosuppressants) reinforces the project's subtype-stratification framework: unstratified treatment in heterogeneous PASC-SFN populations achieves only partial response — exactly as the project's chain framework predicts for unstratified treatment in heterogeneous FM populations. Subtype stratification (anti-SGC IgG, MRGPRX2-MC, β2-AR Aab, HERV-W ENV) should produce better-targeted response in both conditions.