In the post-acute phase of COVID-19, there is an increased risk of neurologic sequelae that affect the central nervous system (CNS), such as anosmia, dizziness, headache, stroke, cognitive and memory disorders, extrapyramidal and movement disorders, mental disorders, and encephalitis or encephalopathy, as well as the peripheral nervous system (PNS), such as sensory disorders, polyneuropathy, Guillain–Barré syndrome, orthostatic intolerance, and syncope. In this retrospective study, the authors from the United States presented patients diagnosed with a new-onset small fiber neuropathy (SFN) after COVID-19.
Patients diagnosed with SFN experience neuropathic symptoms like distal symmetric burning pain, allodynia, impaired temperature sensation, paresthesia, and numbness.
Manifestations of autonomic paralysis in SFN include anhidrosis, orthostatic hypotension, lack of tears and saliva, impaired control of heart rate, weak bowel and bladder sphincters with overflow incontinence, and weakness and dilatation of the esophagus and colon. The skin punch biopsy is a reliable diagnostic tool for SFN diagnosis. It was reported that SFN and symptoms of dysautonomia are associated with autoantibodies to trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor 3 (FGFR3).
It is assumed that immune dysregulation during SARS-CoV-2 infection may contribute to small fiber nerve damage. A recent study found decreased corneal nerve fiber density, nerve fiber length, and nerve branch density in patients with long COVID more than 20 months after acute infection. https://discovermednews.com/reduced-corneal-innervation-increased-dendritic-cell-density-long-covid-patients/
About the study
This retrospective study enrolled 16 individuals diagnosed with a new-onset SFN after documented acute COVID-19. The majority of patients had mild COVID-19, and 38% were hospitalized during the acute infection, but none needed intensive care. The median age was 47 years (ranging from 40 to 58), and 75% of the cohort were women.
The inclusion criteria were as follows: a diagnosis of post-acute/long COVID syndrome based on the World Health Organization definition, a positive punch skin biopsy, no prior neuropathy diagnosis, and negative electrodiagnostic and laboratory tests for any other cause of neuropathy. The onset of symptoms after COVID-19 vaccination and a previous diagnosis of neuropathy from any other causes were considered the exclusion criteria.
A skin punch biopsy was used to diagnose SFN.
Results
Participants with a new-onset SFN after COVID-19 reported symptoms of dysautonomia as follows: 69% of participants had orthostatic hypotension, 77% had altered sweating, and 85% had labile heart rate. 92% of patients reported post-exertional malaise, a characteristic symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The symptoms of neuropathy such as numbness, paresthesia, and allodynia occurred a median of 2.5 weeks after the onset of COVID-19.
Three of 16 individuals diagnosed with a new-onset SFN were positive for autoantibodies to TS-HDS, while three others were positive for autoantibodies to FGFR3. Nine patients were tested for autoantibodies for sensory neuropathy, and six were positive.
Six patients who experienced post-exercise malaise and dysautonomia underwent an invasive cardiopulmonary exercise testing (iCPET), which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS.
Eight patients were treated with IVIG for a median of 9.5 months (3 to 18.5 months). Most of them (63%) experienced resolution of neuropathic symptoms. In the remaining 37%, the intensity and duration of their symptoms were significantly reduced. Importantly, patients without complete resolution of neuropathic symptoms were subsequently diagnosed with diabetes or pre-diabetes.
Original illustration from the study of McAlpine LS et al , 2023
Conclusion
This study presented 16 patients diagnosed with a new-onset small fiber neuropathy after COVID-19. The authors concluded that further studies are necessary to investigate the underlying pathophysiology of small nerve fiber damage after COVID-19, and the link between SFN and ME/CFS. In addition, larger clinical trials should demonstrate the efficacy of IVIG in treating SFN that developed after the SARS-CoV-2 infection.
This study was published on a preprint server and is currently being peer-reviewed.
Journal Reference
McAlpine LS et al. Small Fiber Neuropathy after COVID-19: A Key to Long COVID. medRxiv preprint. https://doi.org/10.1101/2023.11.07.23297764
