The Diagnosis of Small Fiber Neuropathy Should Be Expanded and Standardized.

ABSTRACTPurpose/aim of the study: To date, there are no validated screening scales for small fibre neuropathy. This study investigated the small-fibre neuropathy and the symptom inventory questionnaire as well as the small fibre neuropathy screening list for small fibre neuropathy diagnosis.Methods: Fifty-five patients were divided into small fibre neuropathy and mixed fibre damage groups. Relevant scales, nerve conduction studies and skin biopsies were performed. Relationships between the intraepidermal nerve fibre density and different scales as well as the diagnostic and cut-off values (score at which Youden's index is largest) were determined.Results: Compared with healthy Chinese participants, 20 patients were diagnosed with small fibre neuropathy. Intraepidermal nerve fibre density was moderately and highly correlated with the small fibre neuropathy–symptom inventory questionnaire and small fibre neuropathy screening list, respectively. The diagnostic values were moderate and high for the small fibre neuropathy–symptom inventory questionnaire (cut-off value = 5, sensitivity = 80%, specificity = 81.8%) and small fibre neuropathy screening list (cut-off value = 8, sensitivity = 94.1%, specificity = 90.9%), respectively. There were no significant differences in the visual analogue scale between the small fibre neuropathy group, mixed small and large fibre neuropathy group, pure large fibre neuropathy group and the normal group.Conclusion: Small fibre neuropathy–symptom inventory questionnaire and small fibre neuropathy screening list represent potential small fibre neuropathy screening tools.AbbreviationsEMGelectromyographyENAanti-extractable nuclear antigensESRerythrocyte sedimentation rateIENFDintraepidermal nerve fibre densityIGTimpaired glucose toleranceNCSnerve conduction studiesNDSneuropathy disability scoreOGTToral glucose tolerance testPGPprotein gene productPNperipheral neuropathyROCreceiver operating characteristic curveROC-AUCarea under the ROC curveSFNsmall fibre neuropathySFN–SIQsmall-fibre neuropathy and symptom inventory questionnaireSFNSLsmall fibre neuropathy screening listVASvisual analogue scaleWHOWorld Health Organization

Differences in clinical features between small fiber and sensitive large fiber neuropathies in Sjögren's syndrome

see article on pages 440‐443 in this issue

Small fiber neuropathy (SFN) has been suggested as a trigger of restless legs syndrome (RLS). An increased prevalence of peripheral neuropathy has been demonstrated in Parkinson’s disease (PD). We aimed to investigate, in a cross-sectional manner, whether SFN is overrepresented in PD patients with concurrent RLS relative to PD patients without RLS, using in vivo corneal confocal microscopy (IVCCM) and quantitative sensory testing (QST) as part of small fiber assessment. Study participants comprised of age- and sex-matched PD patients with (n = 21) and without RLS (n = 21), and controls (n = 13). Diagnosis of RLS was consolidated with the sensory suggested immobilization test. Assessments included nerve conduction studies (NCS), Utah Early Neuropathy Scale (UENS), QST, and IVCCM, with automated determination of corneal nerve fiber length (CNFL) and branch density (CNBD) from wide-area mosaics of the subbasal nerve plexus. Plasma neurofilament light (p-NfL) was determined as a measure of axonal degeneration. No significant differences were found between groups when comparing CNFL (p = 0.81), CNBD (p = 0.92), NCS (p = 0.82), and QST (minimum p = 0.54). UENS scores, however, differed significantly (p = 0.001), with post-hoc pairwise testing revealing higher scores in both PD groups relative to controls (p = 0.018 and p = 0.001). Analysis of all PD patients (n = 42) revealed a correlation between the duration of l-dopa therapy and CNBD (ρ = −0.36, p = 0.022), and p-NfL correlated with UENS (ρ = 0.35, p = 0.026) and NCS (ρ = −0.51, p = 0.001). Small and large fiber neuropathy do not appear to be associated with RLS in PD. Whether peripheral small and/or large fiber pathology associates with central neurodegeneration in PD merits further longitudinal studies.

ContextMultiple factors contribute to sexual dysfunction in men with obesity. Sex hormone levels are commonly abnormal in men with obesity and this abnormality is often the focus of management in clinical practice. The role of small fibre neuropathy in obesity-related sexual dysfunction is not well established.ObjectiveWe aimed to investigate the relationship between sexual function, sex hormone levels and small nerve fibre morphology in men with severe obesity.Materials and methodsA prospective study of 29 men with severe obesity was undertaken. Sexual function was assessed using the European Male Ageing Study Sexual Function Questionnaire. Small nerve fibre morphology was quantified using corneal confocal microscopy. Sex hormone levels were measured by mass spectrophotometry.ResultsErectile dysfunction was present in 72% of the cohort with a higher prevalence of diabetes among the symptomatic group (88% vs 38%, p = 0.006). Corneal nerve fibre length (CNFL) and corneal nerve fibre density (CNFD) were both significantly lower in participants with erectile dysfunction compared to those without (p = 0.039 and p = 0.048 respectively). The erectile function score correlated with CNFL (r = -0.418, p = 0.034) and CNFD (r = -0.411, p = 0.037). Total testosterone and calculated free testosterone levels did not differ significantly between men with or without erectile dysfunction (median 8.8 nmol/L vs 9.0 nmol/L, p = 0.914; and median 176 pmol/L vs 179 pmol/L, p = 0.351 respectively), infrequent sexual thoughts (median 8.1 nmol/L vs 9.2 nmol/L, p = 0.650; and median 184 pmol/L, vs 176 pmol/L, p = 0.619 respectively) and decreased morning erections (median 9.0 nmol/L vs 8.8 nmol/L, p = 0.655; and median 170 pmol/L vs 193 pmol/L, p = 0.278 respectively).ConclusionSexual dysfunction is highly prevalent in men with severe obesity. We found an association between small fibre neuropathy with erectile dysfunction with presence of diabetes a likely a significant contributing factor. We found no associations between testosterone levels with sexual symptoms (including frequency of sexual thoughts). The influence of small nerve fibre neuropathy on response to therapeutic interventions and whether interventions that improve small fibre neuropathy can improve erectile function in this population merits further study.

To explore the relationship between clinical features, electrophysiology and intraepidermal nerve fiber density (IENFD) in peripheral neuropathy with small fibers involvement and determine the diagnostic value of 13-item small-fiber neuropathy and symptoms inventory questionnaire (SFN-SIQ) and neuropathy symptom score [lower limb] (NSS [LL]) in small fiber neuropathy (SFN). A total of 34 consecutive patients with peripheral neuropathy with symptoms of small fibers were enrolled and divided into two groups of small fiber injury and small and large fiber injury.SFN-SIQ, NSS [LL] and neuropathy disability score [lower limb] (NDS [LL]) were administered.Nerve conduction studies and skin biopsy were conducted in unilateral lower limb. The relationship between IENFD and these scales was assessed by partial correlation.Receiver operating characteristic analysis was applied for evaluating the diagnostic value of SFN-SIQ and NSS [LL] in small fiber injury. Independent sample t test was used to compare various parameters of two groups. And similar statistical method was used for IENFD abnormal and normal groups to detect the clinicoelectrophysiological differences. According to the international normative reference of IENFD, 13 patients could be diagnosed with peripheral neuropathy with small fibers involvement. IENFD was moderately correlated with SFN-SIQ (r = 0.437, P = 0.012) and marginally correlated with NSS [LL] (r = 0.334, P = 0.062). The diagnostic value of SFN-SIQ and NSS [LL] was moderate for small fiber injury (Az = 0.753, P = 0.012 for SFN-SIQ, Az = 0.712, P = 0.040 for NSS [LL]) and the best diagnostic indicator of each scale was 6. The value of NDS [LL] was apparently elevated in small and large fiber injury group versus small fiber injury group (t = -5.605, P < 0.001). The IENFD abnormal group had a higher NSS [LL] value than that of the IENFD normal group (t = -2.047, P = 0.049). No differences of electrophysiological parameters existed between IENFD abnormal and normal groups. Chinese normative reference of IENFD should be formulated for the diagnosis of small fiber neuropathy. SFN-SIQ and NSS [LL] may screen for small fiber neuropathy and both are convenient during patient follow-ups.Large sample studies are warranted to further evaluate the clinical values of SFN-SIQ and NSS [LL].

The peripheral nervous system (PNS) is commonly affected in immunoglobulin light chain amyloid protein (AL) amyloidosis. PNS involvement and particularly small fiber neuropathy (SFN) is often clinically underestimated, requiring a standardized approach for comprehensive assessment. We prospectively evaluated the prevalence and clinical significance of SFN in 81 patients with newly diagnosed AL amyloidosis using clinical examination, nerve conduction studies (NCSs), quantitative sensory testing (QST) examination and distal-leg skin biopsy. Neuropathy was detected in 89% of patients and SFN in 65%. Combined small and large fiber neuropathy was seen in 48.1%, pure large fiber neuropathy in 20% and pure SNF in 10%. Older age was a significant risk factor for SFN (OR 1.06, 95% CI 1.01-1.12, p=.014); patients with SFN were also more likely to have soft tissue involvement (OR 7.1, 95% CI 1.5-33.4, p=.013). After a median follow-up of 37.5months, SFN was associated with poorer overall survival (OS) and it emerged as an independent prognostic factor for early mortality (<12months) in multivariate analysis (HR 4.3 95% CI 1.23-15.04, p=.023). Our study demonstrates the high prevalence and clinical significance of SFN as an adverse factor for survival and indicates the need for multiparametric neurological evaluation in patients with AL amyloidosis at diagnosis.

Background/Objectives: Fibromyalgia syndrome is commonly associated with reduced intraepidermal nerve fiber density (IENFD), as assessed by skin biopsy, a finding referred to as small fiber pathology (SFP-FMG). The clinical significance of this abnormality, and how it relates to symptoms in fibromyalgia, remains uncertain. Reduced IENFD also represents the defining feature of small fiber neuropathy (SFN). While previous observations suggest that IENFD reduction is generally less severe in SFP-FMG than in SFN, no study has directly confirmed this finding in a large cohort. This retrospective study aimed to compare the severity of IENFD reduction in patients with SFP-FMG and those with SFN. Methods: To account for age and sex differences, we used the age-and sex-adjusted axonal loss density (ALD), defined as the percentage reduction from normative IENFD values. We retrospectively analyzed skin biopsy data from 73 patients with SFP-FMG and 134 patients diagnosed with SFN. Results: We found that the reduction in IENFD was significantly milder in patients with SFP-FMG than in those with SFN both at distal and proximal sites. Receiver operating characteristic analysis indicated that an ALD threshold of 37.6% provided good specificity for distinguishing SFN from SFP-FMG. Conclusions: These findings indicate that small fiber damage in fibromyalgia syndrome is quantitatively mild compared to patients with SFN. This may explain the absence of detectable sensory deficits on clinical examination and suggests a limited contribution of peripheral nerve damage to the pathophysiology of fibromyalgia syndrome.

Mixed small- and- large fiber diabetic neuropathy affects microcirculatory response to exercise. Pilot study

Spread of complex regional pain syndrome (CRPS) outside the affected limb is a well-recognized phenomenon; nevertheless, the actual evolution from CRPS to fibromyalgia is poorly documented. Similar mechanisms have been recently put forward to explain the development of CRPS and fibromyalgia including dorsal root ganglia (DRG) hyperexcitability and small fiber neuropathy. The aims of this study were to describe 3 cases with typical CRPS evolving to full-blown fibromyalgia and to discuss the potential pathogenetic mechanisms linking these debilitating illnesses. This was a review of medical records and PubMed search on the relationship between CRPS-fibromyalgia with DRG and small nerve fiber neuropathy. Our 3 cases displayed over time orderly evolution from CRPS to fibromyalgia. Dorsal root ganglion hyperexcitability and small fiber neuropathy have been recently demonstrated in CRPS and in fibromyalgia. Dorsal root ganglia contain the small nerve fiber cell bodies surrounded by glial cells. After trauma, DRG perineuronal glial cells produce diverse proinflammatory mediators. Macrophages, lymphocytes, and satellite glial cells may drive the immune response to more rostrally and caudally located DRG and other spinal cord sites. Dorsal root ganglion metabolic changes may lead to small nerve fiber degeneration. This mechanism may explain the development of widespread pain and autonomic dysfunction. Clinicians should be aware that CRPS can evolve to full-blown fibromyalgia. Spreading of neuroinflammation through DRG glial cell activation could theoretically explain the transformation from regional to generalized complex pain syndrome.

Damage to thinly myelinated and unmyelinated nerve fibers causes small fiber pathology, which is increasingly found in pain syndromes such as small fiber neuropathy (SFN) and fibromyalgia syndrome (FMS). The peripheral nerve endings of the small nerve fibers terminate within the epidermis, where they are surrounded by keratinocytes that may act as primary nociceptive transducers. We performed RNA sequencing of keratinocytes obtained from patients with SFN, FMS, and healthy controls. We found 141 deregulated protein coding genes between SFN patients and healthy controls and no differentially expressed genes between patients with FMS and healthy controls. When comparing patients with SFN with patients with FMS, we detected 167 differentially expressed protein coding genes (129 upregulated and 38 downregulated). Further analysis revealed enriched inflammatory pathways. Validation of selected candidates in an independent cohort confirmed higher expression of the proinflammatory mediators interleukin-8, C-X-C motif chemokine 3, endothelin receptor type A, and the voltage-gated sodium channel 1.7 in SFN compared with patients with FMS. We provide a diverse keratinocyte transcriptome signature between patients with SFN and patients with FMS, which may hint toward distinct pathomechanisms of small fiber sensitization in both entities and lay the basis for advanced diagnostics.

Small fiber neuropathy (SFN) is an underdiagnosed condition characterized by sensory and autonomic dysfunction due to impairment of small nerve fibers in skin, blood vessels, and internal organs. Various underlying disorders are associated with SFN, and the pathophysiology of nerve fiber damage and functional impairment is the subject of extensive research. Diagnosis of SFN is challenging as standard electrodiagnostic techniques assess large fiber function and therefore are normal in SFN patients. The current gold standard for SFN diagnosis in humans is a skin biopsy, commonly obtained from the distal leg, hairy skin region, with evaluation of intraepidermal nerve fiber density (IENFD) using protein gene product 9.5 (PGP9.5) immunolabeling. While well-established in clinical practice, equivalent standardized, reproducible methods for assessing IENFD in experimental mouse models are lacking, which limits translational research in this field. Previous work in mice has relied on diverse antibodies, variable tissue sampling, and the use of confocal microscopy to trace nerve fibers. Other approaches have used chromogenic precipitate-based staining, which limits the ability to co-label multiple proteins. Here, we present a detailed, simple, and reproducible protocol for IENFD quantification of small nerves in the distal glabrous skin of the mouse hind paw. This protocol uses the two distal footpads, ensuring consistent sampling across animals. Prior to sectioning, the tissue is fixed and cryoprotected. Serial 20-μm sections are mounted on glass slides, dried, permeabilized, blocked, and immunostained with an anti-PGP9.5 monoclonal antibody, and then detected by binding secondary fluorescent-labeled antibodies. Although murine hairy skin analysis may apparently show a higher translational value, as it better reflects human biopsy sites, it is compromised by dense hair shafts and follicles, which interrupt epidermis continuity and thus interfere with sampling consistency. Polyneuropathy sensory symptoms, in fact, begin at the most distal sensory site, which is the glabrous skin of the toes. Thus, evaluation of this anatomical location best represents the clinical realm and may have the best sensitivity for identifying early axonal changes. In this protocol, we focused on IENFD quantification as done in human samples. Mechanoreceptors such as Meissner corpuscles are detectable and quantifiable by this method, and represent additional value since pressure-evoked pain, transmitted by these, is often reported by affected individuals. This immunolabeling protocol can be completed within one day [involving a small number of animals, where all three stages can be performed during a long working day (approximately 12 h)], while the entire workflow, including fixation and cryoprotection, is completed in up to 72 h. Importantly, the dermal and epidermal small fibers can be visualized using a standard fluorescence microscope, thereby avoiding the need for confocal imaging while maintaining high reproducibility. Preliminary validation in several animal models of inflammatory neuropathy and pain demonstrated a reproducible approximately 50% reduction in IENFD compared to controls, reaching statistical significance with n = 4 per group. This method supports SFN research and preclinical evaluation of novel therapeutics.Key features• Immunostaining protocol for visualizing small epidermal nerve fibers in mouse hind paw footpads.• Use of PGP9.5 labeling, with a monoclonal antibody that is used for human diagnostics, enabling translational comparability between mouse models and clinical studies.• Fluorescence microscopy analysis, without dependence on confocal imaging.• A rapid (12–72 h) and reproducible workflow for skin processing and intraepidermal nerve fiber quantification.

ABSTRACTBackgroundFibromyalgia (FM) is a complex chronic pain disorder characterized by widespread musculoskeletal pain and symptoms suggesting autonomic dysfunction. Small fiber neuropathy (SFN) has been described in a subgroup of patients. We aimed to explore the value of structured symptom assessment to identify patients with SFN or autonomic neuropathy.MethodsForty‐six female FM patients were assessed in a cross‐sectional study including clinical examinations, validated questionnaires (modified neuropathic pain symptom inventory (m‐NPSI), PainDETECT and the composite autonomic symptom score (COMPASS 31)) and diagnostic tests (intraepidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and quantitative sudomotor axon reflex test (QSART)). m‐NPSI > 58, PainDETECT > 18, and COMPASS 31 > 16 were defined as suggestive of neuropathic pain and dysautonomia, respectively. SFN was defined as negative findings (hypoalgesia and reduced thermal sensation) and an abnormal diagnostic test (IENFD, thermal detection thresholds or QSART). Cardiovascular autonomic neuropathy (CAN) was defined as two abnormal cardiovascular reflex tests. Symptom scores were compared with patient controls and patients with an established diagnosis of neuropathy.ResultsAmong FM patients, one had SFN, while two had definite CAN. Thirty‐two, 20, and 43 of the FM patients had NPSI, PainDETECT, and COMPASS 31 scores suggesting neuropathy/dysautonomia. NPSI was higher in FM than in neuropathy patients. Increased mechanical pain sensitivity (15/46) and paradoxical heat sensation (23/46) were frequent QST findings in the FM group.ConclusionSFN or autonomic neuropathy was infrequent in FM patients and not related to symptom scores, which were higher than those for patients with neuropathy.

Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated.

This article reviews the clinical features, pathophysiology, and treatment of small fiber sensory neuropathy. Neuropathic pain is prevalent among patients with peripheral neuropathies of diverse etiologies. For example, in one recent study using the sensitive Neuropathic Pain Symptom Inventory as a screening tool, neuropathic pain was reported in 94% of patients with different peripheral nervous system diseases. Neuropathic pain is frequently underrecognized or inadequately treated. Furthermore, the paucity of clinical signs with small fiber neuropathy may delay recognition of an organic process. Pain, or uncomfortable symptoms, typically results from damage to small unmyelinated nerve fibers (C fibers) or thinly myelinated nerve fibers (A delta fibers). Recent research has helped discover the location of the "pain generators" within the injured peripheral nerves. Small fiber neuropathies are relatively common in clinical practice, but until recently most of the available neurodiagnostic tests focused on large caliber nerve fibers. In the past two decades, the widespread use of quantitative sensory testing and punch skin biopsies to evaluate small caliber nerve fibers has substantially changed the neurologist's ability to diagnose and manage small fiber sensory neuropathy. Neuropathic pain from small fiber neuropathy is prevalent and is caused by a wide variety of disorders, many of which are treatable, especially if recognized early in the process.