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Objective Compare the diagnostic characteristics of intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM) for distal symmetric polyneuropathy (DSP) and small fiber neuropathy (SFN). Methods Participants with obesity were recruited from bariatric surgery clinics and testing was performed prior to surgery. DSP and SFN were determined using the Toronto consensus definitions of probable neuropathy. IENFD was assessed from 3 mm punch biopsies of the distal leg and proximal thigh. CCM was performed on both eyes with manual and automated counting. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was also completed. Diagnostic capability was determined using areas under the receiver operating characteristics curve (AUC) from logistic regression. Results We enrolled 140 participants (mean [standard deviation [SD]] age: 50.3 years [7.1], 77.1% female, BMI: 44.4 kg/m2 [6.7]). In this population, 22.9% had DSP and 14.3% had SFN. Distal leg IENFD had the largest AUC (95% confidence interval) for DSP (0.78, 0.68–0.89) and SFN (0.85, 0.75–0.96). Proximal thigh IENFD (DSP: AUC: 0.59, 0.48–0.69, SFN: AUC: 0.59, 0.46–0.73) and CCM metrics (DSP: AUC range: 0.55–0.60, SFN: AUC range: 0.45–0.62) had poorer diagnostic capability than distal leg IENFD for DSP/SFN (P < 0.05). MNSIq had similar diagnostic capability to distal leg IENFD for both DSP/SFN (DSP: AUC: 0.76, 0.68–0.85, SFN: AUC: 0.81, 0.73–0.88). More participants (52%) preferred skin biopsies to CCM. Interpretation Distal leg IENFD was the best quantitative measure of DSP/SFN. CCM had poor diagnostic characteristics and fewer patients preferred this test to IENFD. The MNSIq had similar diagnostic characteristics to distal leg IENFD, indicating its value as a diagnostic tool in the clinical setting. Clinical Trial Registration clinicaltrials.gov: NCT03617185.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9‐month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50‐mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double‐blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4‐week loading dose of 200 mg QD or placebo for 9 months (placebo‐controlled phase); they then entered the active‐therapy extension and received ritlecitinib 50 mg QD (with a 4‐week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I–V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans. Results of this placebo‐controlled study, which assessed the neurological and neuroaudiological effects of ritlecitinib in adults with alopecia areata, provide evidence that the brainstem auditory evoked potential (BAEP) changes and axonal swelling finding in standard chronic toxicology studies in dogs are not clinically relevant in humans.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.

Objective Experimental therapies under development for Friedreich’s Ataxia (FRDA) require validated biomarkers. In‐vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner’s corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross‐sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA. Methods Sixteen individuals with FRDA and 16 age‐ and gender‐matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds. Results MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich’s Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset. Interpretation MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

BackgroundLower limb muscle magnetic resonance imaging (MRI) obtained fat fraction (FF) can detect disease progression in patients with Charcot-Marie-Tooth disease 1A (CMT1A). However, analysis is time-consuming and requires manual segmentation of lower limb muscles. We aimed to assess the responsiveness, efficiency and accuracy of acquiring FF MRI using an artificial intelligence-enabled automated segmentation technique.MethodsWe recruited 20 CMT1A patients and 7 controls for assessment at baseline and 12 months. The three-point-Dixon fat water separation technique was used to determine thigh-level and calf-level muscle FF at a single slice using regions of interest defined using Musclesense, a trained artificial neural network for lower limb muscle image segmentation. A quality control (QC) check and correction of the automated segmentations was undertaken by a trained observer.ResultsThe QC check took on average 30 seconds per slice to complete. Using QC checked segmentations, the mean calf-level FF increased significantly in CMT1A patients from baseline over an average follow-up of 12.5 months (1.15%±1.77%, paired t-test p=0.016). Standardised response mean (SRM) in patients was 0.65. Without QC checks, the mean FF change between baseline and follow-up, at 1.15%±1.68% (paired t-test p=0.01), was almost identical to that seen in the corrected data, with a similar overall SRM at 0.69.ConclusionsUsing automated image segmentation for the first time in a longitudinal study in CMT, we have demonstrated that calf FF has similar responsiveness to previously published data, is efficient with minimal time needed for QC checks and is accurate with minimal corrections needed.

Hereditary neuropathies represent approximately 40% of undiagnosed neuropathies in a tertiary clinic setting. The Charcot–Marie–Tooth neuropathies (CMT) are the most common. Mutations in more than 40 genes have been identified to date in CMT. Approximately 50% of CMT cases are accounted for by CMT type 1A, due to a duplication within the peripheral myelin protein 22 gene (PMP22). Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically definable CMT. Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component. This review surveys the challenges of developing effective therapies for hereditary neuropathies in terms of past, present, and future experimental therapeutics in CMT.

Peripheral neuropathies are diverse and require a multidimensional approach for detection and monitoring in a clinical and research setting. This review describes non- and minimally-invasive measures of distal predominantly sensory polyneuropathy (DSP), the most common form of neuropathy. A combination of clinical and electrophysiologic assessment with nerve-conduction studies (NCSs) suffices for the detection and characterization of most DSPs. NCS are insensitive to variants of DSP that predominantly affect small diameter sensory nerve fibers (SFNs) and cutaneous nerve terminals that subserve pain and thermal sensation. Skin biopsy with assessment of epidermal nerve fiber density permits objective detection and monitoring of SFNs. Conventional clinical and NCS measures have limitations as outcomes in experimental therapeutics in DSP. For clinical trials, biopsy evaluation of epidermal innervation and emerging noninvasive imaging approaches (in vivo confocal microscopy of corneal innervation and of Meissner corpuscles in the skin) hold promise as surrogate markers that are complementary to traditional DSP measures.

Several approaches exist for quantitative assessment of human immunodeficiency virus (HIV)-associated distal sensory polyneuropathy (DSP). While useful, each has some limitations. This study evaluated non-invasive, in vivo reflectance confocal microscopy (RCM) of Meissner corpuscles (MCs) as a measure of HIV-DSP. Forty-eight adults (29 HIV-infected, 19 controls) underwent RCM of MC density (MCs/mm 2 ) at the arch, fingertip, and thenar eminence (TE); ankle skin biopsy to measure epidermal nerve fiber density (ENFD); electrophysiologic studies; and tactile, vibration, and thermal threshold testing. HIV+ subjects were clinically categorized as having DSP signs or no signs. MC densities were lower in HIV+ subjects with DSP signs than in controls (arch, p  = 0.0003; fingertip, p  < 0.0001; TE, p  = 0.0002). Tactile thresholds in the TE and foot were worse in HIV-DSP than in controls, but in this mild DSP cohort, sural amplitudes, ENFD, and vibration and thermal thresholds did not differ significantly from controls. Fingertip MC densities and tactile thresholds at the foot were also lower in HIV+ subjects without DSP signs than in controls. Other sensory measures were not significantly different in HIV+ subjects without DSP signs than in controls. MC density correlated inversely with tactile thresholds at each imaging location. The results suggest that RCM of MC density complements existing sensory DSP measures and discriminates mild HIV-DSP from controls at a stage when sural amplitudes do not. Further studies are required to determine whether RCM of MC density can establish quantitative changes in DSP, in response to treatment or disease progression.

Here we report biallelic mutations in the sorbitol dehydrogenase gene ( SORD ) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD , in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila , loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila , and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes. Biallelic mutations in the sorbitol dehydrogenase gene SORD are identified as a common cause of hereditary neuropathy. Functional studies suggest that SORD deficiency may be treatable with aldose reductase inhibitors.

This Practice Point commentary discusses a retrospective study conducted by Devigili et al . that sought to establish gold standard diagnostic criteria for small fiber neuropathy (SFN). The chosen gold standard for SFN requires abnormalities on two out of three tests (clinical findings, skin biopsy [epidermal nerve fiber density] and quantitative sensory testing), with nerve conduction studies being normal. A total of 150 patients with sensory symptoms met study inclusion criteria, and 67 were determined to have SFN on the basis of the gold standard criteria. Epidermal nerve fiber density was the single most useful test for SFN with a diagnostic efficiency of 88.4%. This commentary argues in favor of a hierarchical system of levels of diagnostic certainty for SFN, depending on the number and type of abnormal diagnostic tests, in contrast to the dichotomous approach used by Devigili et al . We further highlight methodological limitations of the present study, such as the confounding of diagnostic-efficiency estimates for individual SFN tests through incorporation bias.