Dolphin
Senior Member (Voting Rights)
LETTER TO THE EDITOR
Open Access
Uncovering Hidden Profiles: From Pain-Centric to Multi-Symptom Small Fiber Neuropathy
Svetlana Blitshteyn, Michael Stingl, Jill R. Schofield
First published: 23 December 2025
https://doi.org/10.1111/ene.70466
Dear Editor,
We read with great interest the study by Murin et al., “Uncovering Hidden Profiles: From Pain-Centric to Multi-Symptom Small Fiber Neuropathy.” The authors describe a cohort of 203 patients with small fiber neuropathy (SFN) with only 20% of the entire cohort having severe neuropathic pain, which was termed the “algesic” group. The other 80% of patients had significant fatigue, myalgia, and generalized weakness, and either no or mild neuropathic pain [1]. Importantly, most patients also experienced autonomic symptoms, with the most common being dry eyes, dry mouth, and GI dysmotility prior to undergoing a skin biopsy, compared to healthy controls [1]. Noteworthy is that patients in cluster 2 (termed “myalgic”) consisting of 60% of the cohort had especially severe fatigue compared to other symptoms—more intense than neuropathic symptoms. In this cluster, patients also experienced significantly more severe weakness and myalgias than burning pain [1]. Interestingly, autonomic symptoms were present in all three clusters [1].
It's important to note that traditionally, neuropathic pain was required for a diagnosis of SFN, and the absence of neuropathic pain as a feature often excluded neuropathy from the differential diagnoses in patients presenting with fatigue, myalgia, and generalized muscle weakness. The study by Murin et al. illustrates that neuropathic pain may be mild or absent, but SFN may still be present, as confirmed via reduced epidermal nerve fiber density [1]. We emphasize that at least 50% of patients with postural orthostatic tachycardia syndrome (POTS) and Long COVID and nearly a third of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were found to have SFN when assessed via skin biopsy, quantitative sudomotor axon reflex test, corneal microscopy or microneurography [2, 3]. However, many patients with these disorders do not experience severe—or any—neuropathic pain and, instead, typically present with fatigue, lightheadedness/dizziness, generalized weakness, and myalgia [1, 3]. Murin et al.'s study compellingly demonstrates that SFN can present predominantly with fatigue and weakness rather than pain, challenging conventional diagnostic assumptions [1]. The fact that patients with fatigue and generalized weakness may have SFN without exhibiting neuropathic pain or significant abnormalities on neurologic exam should be emphasized in neurology training, which we believe is essential to improving diagnostic accuracy and optimizing treatment outcomes.
Finally, autoimmune conditions and abnormal autoimmune markers were common in this and other cohorts of patients with SFN [1, 3-5], suggesting an autoimmune and immune-mediated etiology, which is similarly identified as a major pathophysiologic mechanism in patients with POTS, Long COVID and ME/CFS. Additionally, dysautonomia more broadly is a common manifestation of a wide variety of systemic disorders, many of which are autoimmune, immune-mediated, inflammatory and post-acute infectious in nature [3, 4]. Currently, the mechanistic interplay between SFN and dysautonomia, and whether SFN is an underlying mechanism of dysautonomia or an associated comorbidity in the autoimmune and immune-mediated pathways that drive both conditions, is unknown. Regardless, immunotherapies for patients with SFN, POTS, ME/CFS, and Long COVID, especially when accompanied by comorbid autoimmune conditions or abnormal autoimmune or immunologic markers, may be considered, and carefully designed randomized controlled trials are needed to assess their efficacy in each disorder [5].