E2 ModerateModerate confidencePEM unclearCross-SectionalPeer-reviewedReviewed
Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges.
Azcue, Naiara, Teijeira-Portas, Sara, Tijero-Merino, Beatriz et al. · European journal of neurology · 2025 · DOI
Quick Summary
This study found that both long-COVID patients and people with ME/CFS show signs of damage to small nerve fibers in the eyes and altered sensation to heat, compared to healthy people. Researchers used specialized imaging and tests to measure nerve fiber structure and how well patients could detect temperature changes. The findings suggest that small fiber nerve damage may contribute to symptoms like pain and abnormal sensations in these conditions.
Why It Matters
This research provides objective, measurable evidence that ME/CFS patients have small fiber neuropathy—a finding often overlooked or dismissed—using validated diagnostic techniques. Demonstrating similar neuropathic patterns in both PCC and ME/CFS supports the biological basis of these conditions and could lead to better diagnostic tools and treatments targeting nerve fiber pathology.
Observed Findings
- Both PCC and ME/CFS patients had significantly higher autonomic symptoms, neuropathic symptoms, and fatigue scores than healthy controls (all p<0.001).
- PCC patients showed significantly impaired heat detection thresholds compared to controls (p<0.01).
- Both patient groups exhibited increased tortuosity (abnormal twisting) of small corneal nerve fibers on IVCCM imaging compared to controls (p<0.01).
- Small fiber tortuosity was the strongest discriminator between patients and controls, with AUC=0.720 (p<0.01).
Inferred Conclusions
- Both PCC and ME/CFS patients demonstrate objective evidence of sensory small fiber neuropathy, characterized by impaired heat detection and pathological corneal nerve fiber changes.
- Small fiber pathology may contribute to neuropathic and autonomic symptoms in both conditions.
- A multimodal diagnostic approach combining quantitative sensory testing and corneal confocal microscopy is valuable for detecting and characterizing small fiber neuropathy in these conditions.
Remaining Questions
- Does small fiber neuropathy cause the symptoms of ME/CFS, or is it a consequence of the underlying disease process?
- How does small fiber damage progress over time in ME/CFS, and does it correlate with symptom severity or disease progression?
What This Study Does Not Prove
This study does not establish whether small fiber damage causes ME/CFS symptoms or results from the disease process; it only shows an association. The cross-sectional design cannot determine if small fiber neuropathy develops before, during, or after symptom onset, nor can it prove that treating small fiber dysfunction will improve outcomes.
Tags
Symptom:PainFatigueSensory SensitivityTemperature Dysregulation
Biomarker:Neuroimaging
Phenotype:Infection-TriggeredLong COVID Overlap
Method Flag:Small SampleMixed CohortStrong PhenotypingWeak Case DefinitionExploratory OnlyPEM Not Defined
Metadata
- DOI
- 10.1111/ene.70016
- PMID
- 39888240
- Review status
- Editor reviewed
- Evidence level
- Single-study or moderate support from human research
- Last updated
- 12 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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