Microneurography Reveals Unmyelinated Small Nerve Fiber Dysfunction in Long COVID.

Objective: To review the microneurography findings of long coronavirus disease 2019 (COVID) patients who presented to the clinic with multisystem involvement affecting neurological, cardiovascular, gastrointestinal, genitourinary, pulmonary, and immunological domains.

Methods: We analyzed 36 consecutive long COVID patients using microneurography. We evaluated abnormalities in C nociceptors, including spontaneous activity, peripheral sensitization, multiple spikes, conduction failure, and alterations in activity-dependent slowing of conduction velocity. Sympathetic nerve fiber function was assessed using the recovery cycle of excitability. Results were compared with a large normative database.

Results: The mean age was 40.9 ± 9.2 years (range 17-60 years), with a female predominance (30/36, 83.3%). Patients were seen from 15 to 61 months after onset of symptoms (35.7 ± 11.3 months). All patients presented with neuropathic symptoms, mainly pain and orthostatic intolerance. A total of 32 patients (88.9%) had objective electrophysiological abnormalities in peripheral C fibers, including spontaneous nociceptor activity (61.1%), peripheral sensitization (27.8%), and multiple spikes (11.1%). Long COVID patients also showed a significant shift in C nociceptor populations, with a higher prevalence of type 1B mechano-insensitive C nociceptors compared with healthy controls. Changes in activity-dependent slowing of conduction velocity differed in opposite directions between mechano-sensitive and mechano-insensitive C nociceptors. Postganglionic sympathetic fibers also showed abnormal recovery cycles with a lack of supernormality, suggesting impaired neuronal homeostasis.

Interpretation: This study provides novel electrophysiological evidence linking small nerve fiber dysfunction to long COVID. These findings align with previous histological evidence of small nerve fiber loss, reinforcing the hypothesis that peripheral nerve dysfunction contributes to the multisystem symptoms of long COVID. ANN NEUROL 2025.