Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a systemic multiple-organ disease characterized by a broad spectrum of clinical manifestations. The infection with SARS-CoV-2 can lead to a new disease called long-COVID or post-acute COVID-19 syndrome (PACS). The most frequent, persistent, and disabling symptoms of long COVID are neurological. Patients diagnosed with long COVID or PASC frequently have symptoms of dysautonomia and neuropathy. It is assumed that immune dysregulation during viral infection may contribute to small fiber nerve damage and the occurrence of small fiber neuropathy (SFN). In this retrospective study, the authors from the United States presented a case series of a new-onset SFN that developed after COVID-19.
Neuropathic symptoms in patients diagnosed with SFN include distal symmetric burning pain, allodynia, impaired temperature sensation, paresthesia, and numbness. Anhidrosis and orthostatic hypotension, which are the two most frequent manifestations of autonomic paralysis, occur frequently in SFN. Other autonomic manifestations include a 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 diagnosing of SFN. Previous investigations have found an association between autoantibodies to trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor 3 (FGFR3) and the SFN and symptoms of dysautonomia.
Interestingly, a recent study performed with confocal microscopy, used to identify small-fiber neuropathy in immune-mediated small-fiber neuropathies and peripheral neuropathies, has shown a 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 was conducted on individuals who developed new-onset SFN after being diagnosed with COVID-19. A skin punch biopsy was used to diagnose SFN.
The inclusion criteria were: a diagnosis of 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 exclusion criteria were: the onset of symptoms after COVID-19 vaccination and a previous diagnosis of neuropathy from any other causes.
Results
This retrospective study included 16 patients who developed new-onset SFN after a documented COVID-19. The median age was 47 years (ranging from 40 to 58), and 75% of the cohort were women. The majority of patients had mild COVID-19, and 38% were hospitalized during the acute infection, but none needed intensive care.
The symptoms of neuropathy such as numbness, paresthesia, and allodynia occurred a median of 2.5 weeks after the onset of COVID-19. Three patients were positive for TS-HDS, while three others were positive for FGFR3. Nine patients were tested for autoantibodies for sensory neuropathy, and six were positive.
Symptoms of dysautonomia included orthostatic hypotension in 69%, altered sweating in 77%, and labile heart rate in 85%. 92% of patients reported post-exertional malaise, a characteristic symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 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.
Original illustration from the study of McAlpine LS et al , 2023
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. The remaining 37% had significantly reduced intensity and duration of their symptoms. Notably, patients without complete resolution of neuropathic symptoms were subsequently diagnosed with diabetes or pre-diabetes.
Conclusion
According to the authors, further studies are necessary to better understand 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.
The results of the study have been published on a preprint server and are 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
