By Erin Manning, MD
Synopsis: This study examines small fiber neuropathy (SFN) in post-COVID patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). While ME/CFS patients reported more SFN symptoms, objective testing showed limited diagnostic value beyond heat/cold detection differences.
Source: Azcue N, Teijeira-Portas S, Tijero-Merino B, et al. Small fiber neuropathy in the post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome: Clinical significance and diagnostic challenges. Eur J Neurol. 2025;32(2):e70016.
This study investigated small fiber neuropathy in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) after COVID infection. The researchers recruited 30 patients at a single site in Spain with post-COVID condition (PCC), 30 patients with ME/CFS after COVID, and 30 control patients, age- and sex-matched. Patients had to be 18-85 years of age and meet specific criteria for the diagnosis of ME/CFS who tested positive for SARS-CoV-2 and had symptoms persisting at least 12 weeks after infection. Patients with severe COVID that required hospitalization or had persistent respiratory symptoms were excluded. Patients with known conditions that can cause small fiber neuropathy or peripheral neuropathy were excluded.
Small fiber neuropathy was assessed by a device that measures electrostatic skin conductance (ESC) in the palms and soles, heat and cold evoked potentials, quantitative sensory testing (QST), and in vivo corneal confocal microscopy. Autonomic nervous system dysfunction was evaluated by pupillary response and a tilt table test and through measuring blood pressure and heart rate variability on deep breathing and Valsalva maneuver. Autonomic neuropathy and small fiber neuropathy systems were assessed via standardized patient-reported symptoms scores.
The ME/CFS patients had the most frequent small fiber neuropathy symptoms, followed by the PCC patients. Both groups had statistically significantly more symptoms than the control group. The PCC group had impaired heat detection thresholds compared to controls, and the ME/CFS group had reduced heat and cold evoked potentials compared to controls. The only difference between patients and controls on corneal confocal microscopy was in the tortuosity of the blood vessels. No statistically significant differences were found between the groups in autonomic testing or symptoms. No statistically significant differences were seen between the groups in the pupillary testing.
Commentary
Overall, the study did not find that most of this testing is helpful in determining small fiber neuropathy or autonomic neuropathy involvement in patients with PCC and ME/CFS, other than differences in heat and cold detection, even when patients report more small fiber neuropathy symptoms. This likely is related to clinical overlap between these syndromes and the nonspecific nature of the symptoms. Also, small fiber neuropathy can be patchy, which can make it more difficult to detect.
A significant limitation of this study was not using skin biopsy for detection of small fiber neuropathy. Skin biopsy currently is considered the gold standard for the diagnosis of small fiber neuropathy and may have picked up more cases in patients who were less well studied or not diagnosed by noninvasive studies. Future investigation should include skin biopsies in at least three sites in the arm and leg to better evaluate patchy small fiber neuropathy, with larger numbers of patients, to better determine if the noninvasive techniques can be helpful in differentiating patients from controls.
Erin Manning, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medicine and the Hospital for Special Surgery.
This study examines small fiber neuropathy (SFN) in post-COVID patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). While ME/CFS patients reported more SFN symptoms, objective testing showed limited diagnostic value beyond heat/cold detection differences.
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