Painful Small Fiber Neuropathy Research Articles

Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases.

Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age ≤ 45 years old and a Pain Numerical Rating Score ≥ 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the "Nicotinic acetylcholine receptor signaling pathway". Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.

Fabry’s Disease and Dysferlinopathy: co-occurence of two rare genetic disorders

Fabry’s Disease (FD) is a rare X-linked inherited disorder of glycosphingolipid metabolism due to absent or deficient activity of α-galactosidase A (GLA) enzyme that can present with multisystemic involvement, including painful small fiber neuropathy. Dysferlinopathy is a heterogeneous spectrum of neuromuscular disorders inherited in an autosomal recessive manner. In this report, we present a case of co-occurrence of these two rare genetic disorders

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study.

No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study. The study was conducted at 68 sites in 13 countries (Europe and Canada) between May 17, 2018, and April 12, 2021. Following a 4-week open-label period in which 265 adults with painful SFN (a mixture of large and small fibre neuropathy was not exclusionary) received oral vixotrigine 350mg twice daily (BID), 123 participants (with a ≥30% reduction from baseline in average daily pain [ADP] score during the open-label period) were randomised 1:1:1 to receive 200mg BID, 350mg BID or placebo for a 12-week double-blind (DB) period. Primary endpoint was change from baseline in ADP at DB Week 12. Secondary endpoints included the proportion of participants with a ≥30% reduction from baseline in ADP and the proportion of Patient Global Impression of Pain (PGIC) responders at DB Week 12. Treatment-emergent adverse events (AEs) were monitored. Statistical significance was set at 0.10 (2-sided). The trial was registered on ClinicalTrials.gov (NCT03339336) and on ClinicalTrialsregister.eu (2017-000991-27). A statistically significant difference from placebo in least squares mean reduction in ADP score from baseline to DB Week 12 was observed with vixotrigine 200mg BID (-0.85; SE, 0.43; 95% CI,-1.71 to 0.00; p=0.050) but not 350mg BID (-0.17; SE, 0.43; 95% CI,-1.01 to 0.68; p=0.70). Numerically, but not statistically significantly, more participants who received vixotrigine vs placebo experienced a ≥30% ADP reduction from baseline (68.3-72.5% vs 52.5%), and only the 350mg BID group had significantly more PGIC responders vs placebo (48.8% vs 30.0%; odds ratio=2.60; 95% CI, 0.97-6.99; p=0.058) at DB Week 12. AEs were mostly mild to moderate in the vixotrigine groups. The most common AEs (≥5% of vixotrigine-treated participants) in the DB 200mg BID and 350mg BID vixotrigine groups were falls, nasopharyngitis, muscle spasm, and urinary tract infection. In our study, vixotrigine 200mg BID, but not 350mg BID, met the primary endpoint; more vixotrigine-treated participants experienced a ≥30% reduction from baseline in ADP at DB Week 12. Vixotrigine (at both dosages) was well tolerated in participants with SFN. Biogen, Inc.

Limbic Connectivity Underlies Pain Treatment Response in Small-Fiber Neuropathy.

Small-fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small-diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain-related brain changes after skin nerve degeneration. Diffusion-weighted and resting-state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain-related network was assessed using network-based statistic (NBS) analysis. Compared with age- and sex-matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti-neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition-integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition-integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655-667.

Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy.

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

Editors' Note: Part 3: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

“Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.[1][1],[2][2] Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.1,2 Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. [1]: #ref-1 [2]: #ref-2

Author Response: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

We appreciate the comments on our article by Drs. Oaklander and Dalakas.1 We agree that immune-related forms of painful small fiber neuropathy (SFN) could potentially benefit from IV immunoglobulins (IVIg), and as mentioned, there are case series that underline the positive effect of IVIg. The group of autoimmune-related SFN was not the focus of our study. Our study cohort was targeted on patients with I-SFN because no underlying condition is found in 53% of the SFN population, which is a large proportion of clinical patients and clinically relevant.2

Follow-up Editors' Note: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy

“Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” by Geerts et al., compared the administration of IVIG to placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. In the October 19th Editors' Note, we summarized an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article).[1][1] Wilder-Smith and Spoendlin worried that this article may inappropriately dissuade clinicians from giving IVIG to patients with autoimmune SFN. They asked the authors to (1) provide additional data on the patients who were excluded because of autoimmune disease and (2) perform subgroup analysis based on symptom duration because patients with shorter duration of symptoms may be more likely to benefit from IVIG. Faber responded that 193 of 257 (75%) patients screened for enrollment were excluded; 41 had known autoimmune conditions. Faber agreed that a randomized study on the impact of IVIG on autoimmune SFN is needed. Because 75% of patients who were screened were excluded, Wilder-Smith and Spoendlin suggested that the study population does not reflect the population of patients with SFN routinely seen in clinical practice. They also requested additional information about the excluded patients and more clinical data for all screened patients, and further underscored the potential benefit for IVIG in patients with autoimmune SFN. In response, Faber et al. provided a table detailing the explanations for exclusion and noted that their exclusion rate is on par with the median exclusion rate for randomized-controlled trials (77%). They also reiterated that their focus was on patients with idiopathic SFN, not patients with autoimmune SFN, and that their findings indicate IVIG is not beneficial for this select patient population. However, they agreed that a future randomized-controlled trial is needed to evaluate the role of IVIG in autoimmune SFN. “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” by Geerts et al., compared the administration of IVIG to placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. In the October 19th Editors' Note, we summarized an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article).1 Wilder-Smith and Spoendlin worried that this article may inappropriately dissuade clinicians from giving IVIG to patients with autoimmune SFN. They asked the authors to (1) provide additional data on the patients who were excluded because of autoimmune disease and (2) perform subgroup analysis based on symptom duration because patients with shorter duration of symptoms may be more likely to benefit from IVIG. Faber responded that 193 of 257 (75%) patients screened for enrollment were excluded; 41 had known autoimmune conditions. Faber agreed that a randomized study on the impact of IVIG on autoimmune SFN is needed. Because 75% of patients who were screened were excluded, Wilder-Smith and Spoendlin suggested that the study population does not reflect the population of patients with SFN routinely seen in clinical practice. They also requested additional information about the excluded patients and more clinical data for all screened patients, and further underscored the potential benefit for IVIG in patients with autoimmune SFN. In response, Faber et al. provided a table detailing the explanations for exclusion and noted that their exclusion rate is on par with the median exclusion rate for randomized-controlled trials (77%). They also reiterated that their focus was on patients with idiopathic SFN, not patients with autoimmune SFN, and that their findings indicate IVIG is not beneficial for this select patient population. However, they agreed that a future randomized-controlled trial is needed to evaluate the role of IVIG in autoimmune SFN. [1]: #ref-1

The Human SCN10AG1662S Point Mutation Established in Mice Impacts on Mechanical, Heat, and Cool Sensitivity.

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.

Editors' Note: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy

In “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” Geerts et al. report no significant difference in Pain Intensity Numerical Rating Scale score for patients with idiopathic small fiber neuropathy (I-SFN) 12 weeks after randomized administration of IVIG or placebo. In “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” Geerts et al. report no significant difference in Pain Intensity Numerical Rating Scale score for patients with idiopathic small fiber neuropathy (I-SFN) 12 weeks after randomized administration of IVIG or placebo.

Reader Response: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

Geerts et al.1 showed, in a randomized controlled trial, that intravenous immunoglobulin (IVIg) has no significant effect on pain in patients with painful idiopathic small fiber neuropathy (SFN). A potential exception is represented by patients with idiopathic SFN with a nonlength-dependent (NLD) phenotype, as they were excluded by the design of the study.

Author Response: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

We would like to respond to the comments made by Pu Song and Xingshun Xu about the chosen administration of IV immunoglobulin (IVIG), which is based on a regimen for chronic inflammatory demyelinating polyneuropathy (CIPD). These authors also expressed doubts about our conclusion that IVIG was not effective in patients with painful with idiopathic small fiber neuropathy (I-SFN).

Author Response: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

We would like to respond to the comments made by Drs. Wilder-Smith and Spoendlin on our study1 related to the heterogeneous group of patients with idiopathic small fiber neuropathy (I-SFN), who might benefit from intravenous immunoglobulin (IVIg) therapy. Before study entry, all patients had a diagnostic SFN workup, which includes tests for several associated conditions, as mentioned in the inclusion criteria.1 Of 257 patients, there were 193 patients who did not meet the inclusion criteria, 41 of which (16%) were excluded because of known autoimmune conditions, which is in line with previous findings.2 Future studies are needed to definitely determine whether IVIg may have a therapeutic role in the treatment of autoimmune conditions that cause SFN. There are some open-label clinical studies suggesting a potential therapeutic role,3,4 but stronger evidence from a randomized study is needed. Our RCT showed that IVIg treatment had no significant effect on pain in patients with painful I-SFN and should therefore be discouraged.

Author Response: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

We would like to respond to the comments made by Mr. Franco Gemignani on our article1 regarding the nonlength-dependent small fiber neuropathy (NLD-SFN) phenotype as a potential condition that could benefit from intravenous immunoglobulin therapy (IVIg). We fully agree that future studies in NLD-SFN would be needed to determine whether IVIg would have a therapeutic role in these conditions. There are some open-label clinical studies suggesting a potential therapeutic role,1,2 as well as distal SFN case-studies showing a positive effect of IVIg, whereas the results of our RCT showed that IVIg treatment had no significant effect on pain in patients with painful idiopathic SFN. This underlines the pitfalls of case reports or open case studies and the importance of double-blind randomized trials.

Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype.

Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN. We created 2 independent knock-in mouse lines carrying the Nav1.7 I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multielectrode array recordings show that Nav1.7 I228M knock-in DRG neurons are hyperexcitable compared with wild-type littermate-control neurons, but despite this, Nav1.7 I228M mice do not display mechanical or thermal hyperalgesia or intraepidermal nerve fiber loss in vivo. Therefore, although these 2 Nav1.7 I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of-function mutations in Nav1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyperexcitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice.

Current Diagnosis and Treatment of Painful Small Fiber Neuropathy.

Small fiber neuropathy (SFN) could cause significant morbidity due to neuropathic pain and autonomic dysfunction. SFN is underdiagnosed and the knowledge on the condition is limited among general public and health care professionals. This review is intended to enhance the understanding of SFN symptoms, causes, diagnostic tools, and therapeutic options. There is evidence of SFN in up to 40% patients with fibromyalgia. The causes of SFN are glucose metabolism defect, dysimmune, gluten sensitivity and celiac disease, monoclonal gammopathy, vitamin deficiencies, toxic agents, cancer, and unknown etiology. Auto-antibodies targeting neuronal antigens trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor 3 (FGFR3) are found in up to 20% of patients with SFN. Treatment of SFN includes treating the etiology and managing symptoms. SFN should be considered in patients with wide-spread body pain. The search for known causes of SFN is a crucial step in disease management.

Corneal Epithelial Dendritic Cell Response as a Putative Marker of Neuro-inflammation in Small Fiber Neuropathy

ABSTRACT We report a case of a 41-year old female with systemic lupus erythematosus and Sjögren’s syndrome, who developed symptoms of painful small fiber neuropathy (SFN). Examination using in vivo confocal microscopy (IVCM) revealed dense accumulations of putative dendritic cells in the central cornea that was postulated to represent a peripheral neuro-inflammatory response. Interventions with higher dose prednisolone, and then intravenous immunoglobulin resulted in substantial, progressive improvements in her symptoms, which were paralleled by cumulative reductions in corneal dendritic cell density (DCD). This case identifies corneal DCD as a potential non-invasive marker of symptomatic SFN due to inflammatory causes.

Biopsy-Proven Small-Fiber Neuropathy in Primary Sjögren's Syndrome: Neuropathic Pain Characteristics, Autoantibody Findings, and Histopathologic Features.

Painful small-fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large-fiber involvement. SFN can be diagnosed by punch skin biopsy results that identify decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves. We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh). There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti-Ro 52 (P = 0.01) and anti-Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking-and-glove pain, and 12 patients had nonstocking-and-glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients). SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking-and-glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies.

(170) Diagnostic Criteria for Idiopathic Small Fiber Neuropathy – A Systematic Literature Review

Small fiber neuropathy (SFN) is increasingly recognized as an important cause of distal symmetric pain and sensory symptoms, but its diagnosis remains elusive. We sought to systematically assess the published screening and diagnostic criteria for painful idiopathic small fiber neuropathy (SFN). A systematic literature review was performed using the PubMed database from inception to January 9, 2018, excluding studies where SFN was of known or well-established etiology. Study characteristics and diagnostic criteria for idiopathic SFN were extracted and analyzed. 67 clinical studies and 9 guideline/review publications met the inclusion criteria. Among the clinical studies, 13 studied patients with exclusively idiopathic SFN, and 54 studies enrolled subjects with SFN of mixed etiology. The results demonstrate that diagnostic criteria for idiopathic SFN substantially vary in regard to inclusion of pain, specific sensory and autonomic symptoms and signs, nerve conduction studies, quantification of cutaneous innervation, quantitative sensory testing, or special investigations. The most common sets of criteria included the combination of 1) SFN symptoms, 2) neurological signs or nerve conduction studies to rule out large fiber involvement, and 3) results of skin biopsy quantifying intraepidermal innervation. Given the wide variation in diagnostic approaches, there is urgent need for evidence-based guidelines for this often-underdiagnosed condition.

The Clinical Features of Painful Small-Fiber Neuropathy Suggesting an Origin Linked to Primary Sjögren's Syndrome.

We attempted to determine whether clinical features could differentiate painful small-fiber neuropathy related to primary Sj€ogren's syndrome (pSS-SFN) from idiopathic SFN (idio-SFN). Validated clinical questionnaires and neurophysiological investigations specific for pain and SFN assessment were performed in 25 patients with pSS-SFN and 25 patients with idio-SFN. Patients with idio-SFN had more frequent severe burning sensations and higher mean anxiety scores and daily pain intensity compared to patients with pSSSFN. Conversely, patients with pSS-SFN had reduced electrochemical skin conductance measured by Sudoscan_, and almost half of them had the sensation of walking on cotton wool. Our results suggest that idio-SFN more specifically involved small sensory fibers than pSS-SFN, in which subtle dysfunction of larger sensory fibers and damage of distal autonomic sudomotor innervation may occur. A practical algorithm is proposed to help to differentiate SFN associated with pSS from idio-SFN, based on information very easy to obtain by clinical interview.