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Psychiatric comorbidity is common in patients with chronic pain. In peripheral neuropathic pain, particularly anxiety and mood disorders are frequently present and associated with a high level of catastrophizing. Small fiber neuropathy (SFN) is a peripheral neuropathy dominated by pain. This study aimed to investigate the prevalence of and factors associated with anxiety and depressive symptoms in SFN. All consecutive patients diagnosed with SFN at Maastricht University Medical Center+, between September 2016 and October 2021, were included (n = 1310). Data on demographics, medical history, diagnostic tests, and questionnaires about pain, SFN-specific symptoms, and mental health were collected once. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression and the Pain Catastrophizing Scale (PCS) to measure the degree of catastrophizing. One-third of the patients had an abnormal HADS score (>= 11) on the subscales anxiety and/or depression (26.5% anxiety and 23.0% depression) indicating clinical relevance. Regression analysis showed that higher pain intensity, catastrophizing, and more SFN-related complaints were significantly associated with an abnormal HADS-score. In conclusion, the prevalence of reported anxiety or depressive symptoms in SFN is 36.3%. A multidisciplinary approach, not only focusing on pain relief, is therefore essential for the treatment of SFN.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.Andelic et al. identify miRNA-driven epidermal regulatory mechanisms in SCN9A-related painful neuropathy not responding to currently available therapies. By revealing unique molecular signatures of neuropathic pain in deeply phenotyped patients, these findings could accelerate the development of personalized therapies.

BACKGROUND: Voltage-gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Nav 1.7, encoded by the SCN9A-gene, has been of special interest in the last decades because missense gain-of-function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN).METHODS: In this case report, we present a 61-year-old woman who was referred to our tertiary referral center in a standard day care setting with suspicion of SFN. We performed additional investigations: skin biopsy to determine the intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST), and blood examination (including DNA analysis) for possible underlying conditions.RESULTS: The patient showed a clinical picture that fulfilled the criteria of IEM, PEPD, and SFN. DNA analysis revealed the heterozygous variant c.554G > A in the SCN9A-gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions. Because its pathogenicity has never been functionally confirmed, the variant is classified as a variance of unknown significance (VUS)/risk factor. This suggests that another genetic and/or environmental substrate plays a role in the development of neuropathic conditions like described.CONCLUSION: We have described this as the SCN9A-pain triangle phenomenon. Treatment should focus on pain management, genetic counseling, and improving/maintaining quality of life by treating symptoms and, if indicated, starting a rehabilitation program.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.

Several conditions have been associated with the development of small fiber neuropathy (SFN). The list of metabolic, immune-mediated, infectious, toxic, drugs-related, and hereditary conditions is still growing and various hypotheses are made about the underlying pathophysiological mechanisms. Understanding these processes is important to provide new targets for treatment. In addition, the specific SFN phenotype can provide direction for the underlying etiology. This review discusses the latest developments concerning the expanding etiologies in SFN.In the past 18 months, special attention has been paid to immunological etiologies, partly due to the coronavirus disease 2019 pandemic, but also new auto-antibodies in SFN have been demonstrated. Identifying patients with immune-mediated SFN can be challenging, since contrary to the classical distal sensory phenotype, a nonlength-dependent pattern is more common.Besides the etiologies of classical SFN, small fiber pathology is increasingly described in diseases without the typical neuropathic pain features of SFN, sometimes called syndromic SFN. However, the clinical relevance is not yet fully understood.The expansion of the etiologies of SFN continues and brings more insight in possible targets for treatment. The clinical presentation may vary as a result of the underlying condition.

Background and purpose Anti-acetylcholine receptor (AChR) antibodies (ab) in the serum are detected in most patients with generalized myasthenia gravis (MG) and used as a diagnostic tool. The aim of this study was to analyse a possible association between anti-AChR-ab serum levels and clinical improvement of MG. Methods The Maastricht University Medical Center is a centre of expertise for the treatment of MG. Between 1997 and 2020, more than 4000 anti-AChR-ab blood samples were measured for clinical care using a quantitative radioimmunoassay technique. These results, in combination with clinical status obtained from the patients' electronic patient files, were retrospectively analysed by a single blinded clinician. Symptoms of MG were classified using the Myasthenia Gravis Foundation of America (MGFA) scale. Results In total, 90 anti-AChR-ab-positive MG patients with 837 blood samples were included. The median follow-up time was 72 months. The majority of the included patients were women (61.1%), were on immunosuppressive drug therapy (88.9%), and underwent a thymectomy (54.4%). Multilevel logistic regression analysis showed a significantly inverse association between change in anti-AChR-ab level and the odds of MGFA improvement (per 10% decrease of anti-AChR-ab level: odds ratio 1.21, 95% confidence interval 1.12-1.31; p < 0.001). Conclusions A change in anti-AChR-ab serum level is associated with clinical status in patients with MG. Analyses of anti-AChR-ab are not only useful for diagnostics but also in follow-up of adult symptomatic patients with MG. The use of repetitive anti-AChR-ab serum levels might be valuable in long-term monitoring for clinical improvement in patients with MG, however, further research is required for specific recommendations.

ObjectiveThis is the first double-blind randomized controlled trial evaluating the efficacy and safety of IV immunoglobulin (IVIG) vs placebo in patients with idiopathic small fiber neuropathy (I-SFN).MethodsBetween July 2016 and November 2018, 60 Dutch patients with skin biopsy–proven I-SFN randomly received a starting dose of IVIG (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIG (1 g/kg) or placebo were administered at 3-week intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale score at 12 weeks compared to baseline.ResultsThirty patients received IVIG, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIG, the mean average pain was decreased by at least 1 point compared to 30% of the patients receiving placebo (p = 0.588, odds ratio 1.56, 95% confidence interval 0.53–4.53). No significant differences were found on any of the other prespecified outcomes, including general well-being, autonomic symptoms, and overall functioning and disability.ConclusionsThis randomized controlled trial showed that IVIG treatment had no significant effect on pain in patients with painful I-SFN.Trial Registration InformationClinicalTrials.gov Identifier: NCT02637700, EudraCT 2015-002624-31.Classification of EvidenceThis study provides Class I evidence that for patients with painful I-SFN, IVIG did not significantly reduce pain compared to placebo.

Background and study aims Percutaneous endoscopic gastrostomy (PEG) and percutaneous radiologic gastrostomy (PRG) are techniques used for long-term enteral feeding. Our primary aim was to analyze procedure-related and 30-day mortality and complications between PEG and PRG in relation to indications. Patients and methods A single-center retrospective analysis was performed thath included all adult patients receiving initial PEG (January 2008 until April 2016) and PRG (January 2010 until April 2016). Outcomes were mortality (procedure-related, 30-day), complications (early (≤ 30 days) and late) and success rates. Results A total of 760 procedures (469 PRG and 291 PEG) were analyzed. Most common indications were head and neck cancer (HNC), cerebrovascular accident (CVA) and amyotrophic lateral sclerosis (ALS). Success rates for placement were 91.2 % for PEG and 97.1 % for PRG (P = 0.001). Procedure-related mortality was 1.7 % in PEG and 0.4 % in PRG (P = 0.113). The 30-day mortality was 10.7 % in PEG and 5.1 % in PRG (P = 0.481 after multivariate logistic regression) CVA was associated with higher 30-day mortality, whereas ALS, higher body weight, and prophylactic placements in HNC were associated with lower rates.Tube-related complications were less frequent in PEG, both early (2.7 % vs. 26.4 %, P ≤ 0.001) and late (8.6 % vs. 31.5 %, P ≤ 0.001). The percentage of major complications and infections did not differ. Conclusions With respect to procedure-related and 30-day mortality, PEG and PRG compare equally. PRG had a higher procedural success rate. Tube-related complications and pain are less frequent after PEG compared to PRG. The choice for either PEG or PRG therefore should primarily be based on local facilities and expertise.

BACKGROUND: A proportion of thymoma-patients without a history of myasthenia gravis (MG) before thymectomy, appears to have positive anti-AChR-antibodies in the serum. These subclinical MG-patients could be underdiagnosed because analyzation of anti-AChR-antibodies in thymomas is not always performed in patients who did not experience neurological symptoms. The prevalence and long-term outcomes of subclinical MG are never described in literature yet. METHODS: We retrospectively analyzed 398 consecutive patients who underwent a robotic-assisted thoracoscopic surgery at the Maastricht University Medical Center+ (MUMC+) between April 2004 and December 2018. In the MUMC+, a robotic approach is the standard surgical approach in patients with thymic diseases. Inclusion criteria were thymomas, thymectomy performed in the MUMC+ with a follow-up of at least one year and age above 18 years old. Exclusion criteria were patients with thymic carcinomas, refused participation, or those who were lost to follow-up. RESULTS: Of the 102 included thymoma-patients, 87 patients (85%) were tested for anti-AChR-antibodies before thymectomy, of which 57 patients were diagnosed with clinical MG and seven subclinical MG-patients were found. Of the 15 patients who were not tested for anti-AChR-antibodies, four more subclinical MG-patients were discovered in the years after thymectomy. The median follow-up time was 62 months. In total, 11 subclinical MG-patients were found, with a mean age of 54 years and predominantly females (64%). Ten subclinical MG patients (91%) developed clinical-MG, within six years after thymectomy. Immunosuppressive drugs were prescribed in five patients. Four patients were diagnosed with a recurrence of the thymoma. No surgical mortality was reported. Two patients died due to a myasthenic crisis. CONCLUSIONS: The prevalence of subclinical MG in thymomas was found to be 10.8%. One in four patients who experienced no neurological symptoms before thymectomy, appeared to have anti-AChR-antibodies and 91% of these patients developed clinical MG within 6 years after the thymectomy. Analyzing anti-AChR-antibodies in the serum is recommended in all suspected thymomas before a thymectomy is performed.

Small-fiber neuropathy (SFN) is a disorder of thinly myelinated A delta and unmyelinated C fibers. SFN is clinically dominated by neuropathic pain and autonomic complaints, leading to a significant reduction in quality of life. According to international criteria, the diagnosis is established by the assessment of intraepidermal nerve fiber density and/or quantitative sensory testing. SFN is mainly associated with autoimmune diseases, sodium channel gene variants, diabetes mellitus, and vitamin B12 deficiencies, although in more than one half of patients no etiology can be identified. Recently, gain-of-function variants in the genes encoding for the Na(v)1.7, Na(v)1.8 and Na(v)1.9 sodium channel subunits have been discovered in SFN patients, enlarging the spectrum of underlying conditions. Sodium channel gene variants associated with SFN can lead to a diversity of phenotypes, including different pain distributions and presence or absence of autonomic symptoms. This suggests that SFN is part of a clinical continuum. New assessments might contribute to a better understanding of the cellular and molecular substrates of SFN and might provide improved diagnostic methods and trial designs in the future. Identification of the underlying mechanisms may inform the development of drugs that more effectively address neuropathic pain and autonomic symptoms of SFN.

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

Background The optimal technique for long-term enteral feeding has not yet been established. Both percutaneous endoscopic gastrostomy (PEG) and percutaneous radiologic gastrostomy (PRG) are widely used. Aim was to extensively review outcomes of PEG and PRG. Materials and methods A systematic review using Medline, Embase, and Cochrane was performed, using standardized tools for assessing bias. Main outcomes were infectious and tube-related complications, procedure related and 30-day mortality. Pooled risk differences (RDs) with corresponding 95% confidence intervals (95% CIs) were calculated using random effects. Arcsine transformations were applied. Results In total, 344 studies were identified, of which 16 were included, reporting on 934 PEGs and 1093 PRGs. No differences were found for infectious complications [RD, 0.03 (-0.05 to 0.11)], procedure-related mortality [RD, 0.01 (-0.04 to 0.06)], or 30-day mortality [RD, 0.06 (-0.01 to 0.13)]. Tube-related complications were higher in PRG [RD, 0.16 (0.06-0.26)]. Subgroup analysis was performed for head and neck cancer (HNC) and motor neuron disease. In HNC, this revealed significantly lower tube-related complications and procedure-related mortality after PEG. In motor neuron disease, no differences were seen. The level of evidence appears sufficient considering the low degree of heterogeneity. Conclusions No differences were found with regard to mortality or infectious complications. PEG showed lower risk of tube-related complications. Subgroup analysis revealed PEG to be favorable in HNC based on lower rates of procedure-related mortality and tube-related complications. Local experience and availability should be taken into account in the decision process.

Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high‐throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC‐associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence., The location of causative variants leading to the filaminopathies A are mapped onto FLNA protein monomers. Variants leading to ‘loss‐of‐function’ disorders (left monomer) and ‘gain‐of‐function’ disorders (right monomer) can clearly be seen to cluster. ‘Hotspot’ regions are marked with larger symbols. PH: periventricular heterotopia, CIPX: congenital intestinal pseudo‐obstruction, IMT: isolated macrothrombocytopenia, FCMPD: familial cardiac myxomatous polyvalvular dystrophy, OPD: otopalatodigital syndrome, FMD: frontometaphyseal dysplasia, CKCO: condition comprising contractures, keloid, cardiac defects and optic anomalies, MNS: Melnick‐Needles syndrome, DCD: digitocutaneous dysplasia, ABD: actin‐binding domain, CHD: calponin homology domain, H: hinge.

Gain-of-function variants in voltage-gated sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in 5–10% of patients with idiopathic small fiber neuropathy (I-SFN). Our previous in vitro observations suggest that enhanced sodium channel activity can contribute to a decrease in length of peripheral sensory axons. We have hypothesized that sustained sodium influx due to the expression of SFN-associated sodium channel variants may trigger an energetic deficit in neurons that contributes to degeneration and loss of nerve fibers in SFN. Using an ATP FRET biosensor, we now demonstrate reduced steady-state levels of ATP and markedly faster ATP decay in response to membrane depolarization in cultured DRG neurons expressing an SFN-associated variant NaV1.7, I228M, compared with wild-type neurons. We also observed that I228M neurons show a significant reduction in mitochondrial density and size, indicating dysfunctional mitochondria and a reduced bioenergetic capacity. Finally, we report that exposure to dexpramipexole, a drug that improves mitochondrial energy metabolism, increases the neurite length of I228M-expressing neurons. Our data suggest that expression of gain-of-function variants of NaV1.7 can damage mitochondria and compromise cellular capacity for ATP production. The resulting bioenergetic crisis can consequently contribute to loss of axons in SFN. We suggest that, in addition to interventions that reduce ionic disturbance caused by mutant NaV1.7 channels, an alternative therapeutic strategy might target the bioenergetic burden and mitochondrial damage that occur in SFN associated with NaV1.7 gain-of-function mutations. NEW & NOTEWORTHY Sodium channel NaV1.7 mutations that increase dorsal root ganglion (DRG) neuron excitability have been identified in small fiber neuropathy (SFN). We demonstrate reduced steady-state ATP levels, faster depolarization-evoked ATP decay, and reduced mitochondrial density and size in cultured DRG neurons expressing SFN-associated variant NaV1.7 I228M. Dexpramipexole, which improves mitochondrial energy metabolism, has a protective effect. Because gain-of-function NaV1.7 variants can compromise bioenergetics, therapeutic strategies that target bioenergetic burden and mitochondrial damage merit study in SFN.

Small fiber neuropathy is a painful sensory nervous system disorder characterized by damage to unmyelinated C-and thinly myelinated A delta-nerve fibers, clinically manifested by burning pain in the distal extremities and dysautonomia. The clinical onset in adulthood suggests a time-dependent process. The mechanisms that underlie nerve fiber injury in small fiber neuropathy are incompletely understood, although roles for energetic stress have been suggested. In the present study, we report time-dependent degeneration of neurites from dorsal root ganglia neurons in culture expressing small fiber neuropathy-associated G856D mutant Nav1.7 channels and demonstrate a time-dependent increase in intracellular calcium levels [Ca2+](i) and reactive oxygen species, together with a decrease in ATP levels. Together with a previous clinical report of burning pain in the feet and hands associated with reduced levels of Na+/ K+-ATPase in humans with high altitude sickness, the present results link energetic stress and reactive oxygen species production with the development of a painful neuropathy that preferentially affects small-diameter axons.

Small-fiber neuropathy (SFN) patients experience a spectrum of sensory abnormalities, including attenuated responses to non-noxious temperatures in combination with a decreased density of the small-nerve fibers. Gain of-function mutations in the voltage-gated sodium channels SCN9A, SCN10A and SCN11A have been identified as an underlying genetic cause in a subpopulation of patients with SFN. Based on clinical-diagnostic tests for SFN, we have set up a panel of two read-outs reflecting SFN in zebrafish, being nerve density and behavioral responses. Nerve density was studied using a transgenic line in which the sensory neurons are GFP-labelled. For the behavioral experiments, a temperature-controlled water compartment was developed. This device allowed quantification of the behavioral response to temperature changes. By using these read-outs we demonstrated that zebrafish embryos transiently overexpressing the pathogenic human SCN9A p.(I228M) or p.(G856D) mutations both have a significantly decreased density of the small-nerve fibers. Additionally, larvae overexpressing the p. (I228M) mutation displayed a significant increase in activity induced by temperature change. As these features closely resemble the clinical hallmarks of SFN, our data suggest that transient overexpression of mutant human mRNA provides a model for SFN in zebrafish. This disease model may provide a basis for testing the pathogenicity of novel genetic variants identified in SFN patients. Furthermore, this model could be used for studying SFN pathophysiology in an in vivo model and for testing therapeutic interventions.

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

The association between painful diabetic neuropathy (PDN) and anxiety has been acknowledged using various anxiety scales capturing various fear entities. It has never been examined whether these generally applied anxiety questionnaires could be pooled to construct one overall anxiety metric. After completion by a cohort of 151 patients with PDN, data obtained from seven generally applied fear scales were stacked (n = 88 items) and subjected to Rasch analyses (pre-PART-Q88) to create the PDN overall Anxiety Questionnaire (PART-Q30(©) ). We subsequently examined the impact of the final constructed PART-Q30(©) on disability and Quality of Life (QoL) using the Rasch-Transformed Pain Disability Index (RT-PDI) and the Norfolk Quality of Life Questionnaire, Diabetic Neuropathy version (RT-Norfolk). The pre-PART-Q88 data did not meet Rasch model's expectations. Through stepwise examination for model fit, disordered thresholds, local dependency and item bias, we succeeded in reducing the data and constructing a 30 items overall anxiety scale (PART-Q30(©) ) that fulfilled all model's expectations, including unidimensionality. An acceptable internal reliability was found (person-separation-index: 0.90). PART-Q30(©) explained 36% of disability and combined with RT-PDI 63% of QoL (assessed with RT-Norfolk).

Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na(+)/Ca(2+) exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition.

In a 51-year-old patient of consanguineous parents with a severe neuromuscular phenotype of early-onset ataxia, myoclonia, dysarthria, muscle weakness and exercise intolerance, exome sequencing revealed a novel homozygous variant (c.-264-31delinsCTCACAAATGCTCA) in the mitochondrial FAD-transporter gene SLC25A32. Flavin adenine dinucleotide (FAD) is an essential co-factor for many mitochondrial enzymes and impaired mitochondrial FAD-transport was supported by a reduced oxidative phosphorylation complex II activity in the patient's muscle, decreased ATP production in fibroblasts, and a deficiency of mitochondrial FAD-dependent enzymes. Clinically, the patient showed improvement upon riboflavin treatment, which is a precursor of FAD. Our results confirm the recently reported case of SLC25A32 as a cause of riboflavin-responsive disease. Our patient showed a more severe clinical phenotype compared with the reported patient, corresponding with the (most likely) complete absence of the SLC25A32-encoding MFT (Mitochondrial Folate Transporter) protein.

Pain is a central feature in small fiber neuropathy (SFN), with only moderate effects of pharmacologic treatment. The evaluation of the efficacy of therapies on pain has been driven by static measures, and a circadian cycle has been suggested. The aim of this study is to evaluate the pain dynamics in SFN. A total of 165 patients completed a standardized pain diary 4 times per week over a 4-week period. Patients used the 11-point numeric rating scale for average diurnal, nocturnal, and maximum pain, taking into account the circumstances in which pain emerged most. Medication used, SFN-related complaints, sleep quality, and anatomic location of pain were also assessed. Neuropathic pain showed a length-dependent pattern. For pain intensity, marginal higher pain scores at night than during the day were shown, likely not clinically meaningful, with stable lower pain intensities in weekends compared with weekdays. The average pain intensity was stable during the 4 week period. Maximum pain was experienced mainly at rest and during sleep. Besides, pain intensity at night showed an inverse relationship with quality of sleep. In conclusion, for trials in SFN it is justified to use pain scores from any time of the day during short measurement periods.Perspective: This article presents for the first time the pain dynamics of SFN. The effect of pharmacologic treatment in SFN is often disappointing, partly owing to insufficient trial designs. The results of this study have added value in the development of new proper clinical trials in SFN. (C) 2018 by the American Pain Society

A 31-year-old man presented with intermittent vertical diplopia, lasting for seconds to hours. He described a sensation of movement of his right eye, comparable to that of involuntary eyelid contractions. Fatigue induced the symptoms. Self-recorded videos (videos 1 and 2, [links.lww.com/WNL/A195][1] and [links.lww.com/WNL/A196][2]; video legends, [links.lww.com/WNL/A269][3]) showed involuntary paroxysmal, intorsional movements of the right eye, consistent with superior oblique myokymia.1,2 This condition can be caused by trochlear neuropathy, for example due to microvascular compression, tumor in the tectal region, or trauma.1,2 Brain MRI did not reveal any abnormalities. Carbamazepine, which is recommended as first-line treatment,1,2 only slightly reduced the symptoms, making this essentially benign condition quite disabling. [1]: http://links.lww.com/WNL/A195 [2]: http://links.lww.com/WNL/A196 [3]: http://links.lww.com/WNL/A269

Background and purpose Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. Methods A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. Results No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. Conclusions Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

Interval measures at the impairment level addressing symptoms and at the activity/participation level addressing daily and social restrictions have not been developed for small fiber neuropathy (SFN). We developed an SFN-specific Rasch-built overall disability scale (SFN-RODS©), an activity/participation scale at the interval level. A preliminary SFN-RODS containing 146 activity/participation items was assessed twice (reliability studies) in 238 patients with SFN. The ordinal-based 13-item SFN-symptoms inventory questionnaire (SFN-SIQ©) and pain-visual-analogue-scale were also assessed (validity studies). The pre-SFN-RODS and SFN-SIQ data were subjected to the Rasch analyses. The pre-SFN-RODS did not meet Rasch model expectations. Based on requirements, such as misfit statistics, differential item functioning, and local dependency, items were systematically removed and model fit improved. Finally, a 32-item SFN-RODS© scale was constructed that fulfilled all Rasch requirements, demonstrating acceptable reliability and validity scores. The 13-item SFN-SIQ© was successfully transformed to an interval Rasch-built measure fulfilling model's requirements. In conclusion, the 32-item SFN-RODS© is a disease-specific interval measure suitable for detecting activity limitations and participation restrictions in patients with SFN. The 13-item SFN-SIQ© was transformed through Rasch to an interval measure. The use of these scales is recommended in future clinical interventional trials involving patients with SFN.

This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na+ concentration ([Na+]) and intracellular [Ca2+] following stimulation with high [K+] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca2+] transients evoked by high [K+] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K+] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K+] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca2+ or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K+] and 2-DG. These results point to [Na+] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca2+ toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

Over the last 10 years, the diagnosis small fiber neuropathy (SFN) has gained recognition worldwide. Patients often suffer from severe neuropathic pain that may be difficult to treat. A substantial subset of patients with SFN is aged 65 years or older, and these patients often exhibit comorbidities and usage of multiple drugs, making neuropathic pain treatment more challenging. In this review, we highlight relevant pathophysiological aspects and discuss currently used therapeutic strategies for neuropathic pain. Possible pitfalls in neuropathic pain treatment in the elderly will be underlined.

Introduction: We examined optimization of a temperature threshold testing (TTT) protocol for patients with suspected small-fiber neuropathy (SFN) to lessen the burden for both patients and technicians, without sacrificing accuracy. Methods: Data from 81 patients with SFN (skin biopsy and TTT abnormal) and 81 without SFN (skin biopsy and TTT normal) were used. Warm, cold, and heat pain sensation thresholds were determined bilaterally on the thenar eminence and foot dorsum by methods of limits and levels. Diagnostic accuracy was determined for various sensory modality combinations through comparative corresponding area under the receiver-operator characteristic curves. Results: Assessment of warm and cold thresholds in all extremities by the method of levels showed the best discriminatory ability (area under the curve 0.95, sensitivity 84.2%, specificity 93.8%). Conclusions: These assessments are suggested for TTT examination in possible SFN patients. By applying this combination, the time needed for TTT can be reduced, maintaining diagnostic accuracy. Muscle Nerve 51: 870–876, 2015

The aetiology of painful peripheral neuropathy is often unknown. Huang et al. sequence the gene encoding sodium channel Na(v)1.9 in 393 patients with small fibre neuropathy and identify eight variants in 12 individuals. Functional analysis of two variants reveals that they confer gain-of-function attributes to Na(v)1.9, and induce nociceptor hyperexcitability.Sodium channel Na(v)1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Na(v)1.7 and Na(v)1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Na(v)1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Na(v)1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Na(v)1.9 as a cause of painful peripheral neuropathy.

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.

Objective Painful small fibre neuropathy (SFN) represents a significant public health problem, with no cause apparent in one-half of cases (termed idiopathic, I-SFN). Gain-of-function mutations of sodium channel Na V 1.7 have recently been identified in nearly 30% of patients with biopsy-confirmed I-SFN. More recently, gain-of-function mutations of Na V 1.8 have been found in patients with I-SFN. These Na V 1.8 mutations accelerate recovery from inactivation, enhance the response to slow depolarisations, and enhance activation at the channel level, thereby producing hyperexcitability of small dorsal root ganglion (DRG) neurons, which include nociceptors, at the cellular level. Identification and functional profiling of additional Na V 1.8 variants are necessary to determine the spectrum of changes in channel properties that underlie DRG neuron hyperexcitability in these patients. Methods Two patients with painful SFN were evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for mutations in SCN9A and SCN10A and electrophysiological functional analysis. Results A novel sodium channel Na V 1.8 mutation G1662S was identified in both patients. Voltage-clamp analysis revealed that the Na V 1.8/G1662S substitution impairs fast-inactivation, depolarising the midpoint (V 1/2 ) by approximately 7 mV. Expression of G1662S mutant channels within DRG neurons rendered these cells hyperexcitable. Conclusions We report for the first time a mutation of Na V 1.8 which impairs inactivation, in patients with painful I-SFN. Together with our earlier results, our observations indicate that an array of Na V 1.8 mutations, which affect channel function in multiple ways, can contribute to the pathophysiology of painful peripheral neuropathy.

Small fiber neuropathy (SFN) is a debilitating condition that often leads to pain and autonomic dysfunction. In the last few decades, SFN has been gaining more attention, particularly in adults. However, literature about SFN in children remains limited. The present article reports the cases of 2 adolescent girls diagnosed with SFN. The first patient (14 years of age) complained about painful itch and tingling in her legs, as well as dysautonomia symptoms for years. She also reported a red/purple-type discoloration of her legs aggravated by warmth and standing, compatible with erythromelalgia. The diagnosis of SFN was confirmed by a reduced intraepidermal nerve fiber density (IENFD) in skin biopsy sample. No underlying conditions were found. Symptomatic neuropathic pain treatment was started with moderate effect. The second patient (16 years of age) developed painful sensations in both feet and hands 6 weeks after an ICU admission for diabetic ketoacidosis, which included dysautonomia symptoms. She also exhibited some signs of erythromelalgia. The patient was diagnosed with predominant SFN (abnormal IENFD and quantitative sensory testing) as well as minor large nerve fiber involvement. Treatment with duloxetine, combined with a rehabilitation program, resulted in a marked improvement in her daily functioning. Although the SFN diagnosis in these 2 cases could be established according to the definition of SFN used in adults, additional diagnostic tools are needed that may be more appropriate for children. Additional information about the course of SFN in children may result in better treatment options.

Objective: To determine the minimum incidence and minimum prevalence rates of small-fiber neuropathy (SFN) in a well-defined region in the southern part of the Netherlands. Methods: In this cross-sectional study with retrospective data collection, we used data of patients diagnosed with pure SFN at our Small Fiber Neuropathy Center between January 2006 and December 2011 to calculate minimum incidence and prevalence rates. Results: A total of 88 patients were diagnosed with SFN (mean age 56.9 years, SD 11.8, range 34–81; 44.3% women, 55.7% men). The overall minimum incidence over 2010 and 2011 was 11.73 (95% confidence interval 7.12–18.22) cases/100,000 inhabitants/year. The overall minimum prevalence was 52.95 (95% confidence interval 42.47–65.23) cases/100,000. Incidence and prevalence rates were higher in men than in women, as were the rates in elderly patients compared with younger patients. Conclusions: The minimum incidence and prevalence rates of SFN are presented. We found that SFN is more frequently seen in men and more often diagnosed in elderly patients. These rates probably are an underestimation and are expected to increase in the coming years, since the awareness of SFN is increasing worldwide.

Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Na(v)1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Na(v)1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Na(v)1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Na(v)1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.

Introduction: The impact of small-fiber neuropathy (SFN) on patients' quality of life (QOL) has not been studied extensively. Our aim was to determine the impact of SFN on QOL and examine possible determinants. Methods: We exam- ined a total of 265 patients diagnosed with SFN. The SFN Symptoms Inventory Questionnaire (SFN-SIQ), the pain Visual Analog Scale (VAS), and the generic SF-36 Health Survey were assessed. Regression studies were undertaken to evalu- ate determinants of functioning. Results: SFN patients demon- strated a severe overall reduction in QOL. The biggest deficits were in Role Functioning-Physical, Body Pain, and Physical Component Summary (PCS) scores. VAS scores, changed sweating pattern, dry mouth, and age were the strongest pre- dictors for PCS, explaining 32% of the QOL decrease. Conclu- sions: SFN leads to a reduction in overall QOL. The presence of pain and some autonomic symptoms explained only a small portion of the findings. Muscle Nerve 000:000-000, 2013 Small-fiber neuropathy (SFN), a disorder of thinly myelinated A-d and unmyelinated C fibers, is char- acterized by chronic and severe complaints, such as neuropathic pain and autonomic symptoms. SFN is associated with various disorders, such as metabolic (diabetes mellitus), infectious (human immunodeficiency virus), inflammatory (Sj€ ogren's syndrome), and genetic (Fabry disease) diseases, but the cause is often idiopathic. The incidence and prevalence of SFN is unknown, 1,2 but probably not rare. In patients with diabetes mellitus, for example, a disease with increasing incidence and prevalence, 3 an estimated 16-20% have painful neuropathy. 4,5 This has been largely attributed to small-fiber involvement. 6

Background Small fiber neuropathy is the most common cause of neuropathic pain in peripheral neuropathies, with a minimum prevalence of 53/100,000. Patients experience excruciating pain, and currently available anti-neuropathic and other pain drugs do not relieve the pain substantially. Several open-label studies have suggested an immunological basis in small fiber neuropathy and have reported efficacy of treatment with intravenous immunoglobulin. Therefore, immunological mechanisms conceivably may play a role in small fiber neuropathy. To date, no randomized controlled study with intravenous immunoglobulin in patients with small fiber neuropathy has been performed. Methods/design This study is a randomized, double-blind, placebo-controlled, clinical trial in patients with idiopathic small fiber neuropathy. The primary objective is to investigate the efficacy of intravenous immunoglobulin versus placebo on pain alleviation. A 1-point change in the PI-NRS compared to baseline is considered the minimum clinically important difference. In the IVIg-treated group, we assume a response rate of approximately 60 % based on the criteria composed by the IMMPACT group for measurement of pain. Based on this, a sample size of 60 patients is needed. Eligible patients fulfilling the inclusion/exclusion criteria will be randomized to receive either intravenous immunoglobulin or placebo (0.9 % saline). The treatment regimen will start with a loading dose of 2 g/kg body weight over 2–4 consecutive days, followed by a maintenance dose of 1 g/kg body weight over 1–2 consecutive days given three times at a 3-week interval. The primary endpoint is the comparison of the percentage of responder subjects between the two treatment groups from the first randomization during the 12 weeks of treatment. A responder is defined as ≥ 1-point Pain Intensity Numerical Rating Scale improvement on the mean weekly peak pain relative to baseline. The secondary outcomes are pain intensity, pain qualities, other small fiber neuropathy-related complaints, daily and social functioning, as well as quality of life. In addition, safety assessments will be performed for adverse events, vital signs, and laboratory values outside the normal range. Responders during the 12-week treatment period will be followed during a 3-month extension phase. Discussion This is the first randomized, double-blind, placebo-controlled clinical trial with intravenous immunoglobulin in patients with idiopathic small fiber neuropathy. Positive findings will result in a new treatment option for small fiber neuropathy and support an immunological role in this condition. Trial registration ClinicalTrials.gov, NCT02637700. Registered on 16 December 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1450-x) contains supplementary material, which is available to authorized users.