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Background and Aims Methods Results Interpretation Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late‐onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late‐onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients.The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects.We observe a relatively mild axonal sensory‐motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression.CM2T has been definitively defined as a late‐onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included. [ABSTRACT FROM AUTHOR]

Background and Aims: Prior to next‐generation sequencing (NGS), the evaluation of a patient with neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory. Methods: A cohort of 6849 adult patients underwent clinician‐ordered peripheral neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis. Results: A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines. Interpretation: Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary neuropathy, address the overlap of acquired and hereditary neuropathy, and provide broader access to genetic diagnosis for patients. [ABSTRACT FROM AUTHOR]

Aims: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra‐epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. Methods: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two‐way mixed‐effects model to evaluate inter‐ and intra‐observer variability. Results: The automated staining system reproduced intra‐epidermal nerve fibre density (IENFD) counts consistent with free‐floating sections (mean ± standard deviation: free‐floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at −0.00005 established non‐inferiority against a margin of −0.4 (p =.08). Specifically, the inter‐class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9–1), indicating excellent agreement between free‐floating and automated methods. The inter‐ and intra‐class coefficient between examiners were both 99% (95% CI: 0.9–0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. Interpretation: Automated immunohistochemistry provides high‐throughput reliable and reproducible intra‐epidermal nerve fibre quantification. This method, although currently proof‐of‐concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies. [ABSTRACT FROM AUTHOR]

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

Introduction Methods Results Conclusions Radiation‐induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life‐long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation‐induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model.Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham‐radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham‐radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain‐related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8‐week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves.Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non‐radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls.A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation‐induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition. [ABSTRACT FROM AUTHOR]

Background and Aim: Recreational use of nitrous oxide (N2O) has been associated with the development of severe nitrous oxide‐induced neuropathy (N2On). Follow‐up of these patients poses challenges, and their clinical progression remains largely unknown. The identification of prognostic factors is made difficult by the lack of standardized longitudinal assessments in most studies. The objective was to document the course of neuropathy through systematic follow‐up assessments in N2On patients to identify prognostic factors for persistent disability after 6 months. Methods: We gathered demographic, clinical, biological, and electrophysiological data from N2On patients hospitalized in the Referral center in Marseille, both at baseline and during a standardized follow‐up assessment at 6 months. Results: We retrospectively included 26 N2On patients (mean age 22.6 ± 4.4). Significant improvements were observed in all main clinical scores including Rankin, ONLS, and MRC testing (p <.01). Electrophysiological studies (EDX) revealed a predominantly motor neuropathy with marked reduction in CMAP in the lower limbs at baseline, and no significant improvement in motor parameters (p =.543). Rankin score at 6 months correlated with the initial weekly N2O consumption (r =.43, p =.03) and the CMAP sum score in the lower limbs at the first EDX (r = −.47, p =.02). Patients with and without myelitis showed similar Rankin and ONLS score after 6 months. Interpretation: The clinical course generally improved favorably at 6 months with notable amelioration in the primary disability scores, sensory deficits, and ataxia. However, distal motor impairment associated with peripheral neuropathy persisted, with distal axonal loss emerging as the main prognostic factor for long‐term disability in these young patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Chemotherapy‐induced peripheral neurotoxicity (CIPN) is one of the most common dose‐limiting side effects of paclitaxel (PTX) treatment. Many age‐related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Methods: Twenty‐four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2‐week follow‐up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. Results: At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p <.05) in the caudal nerve of young PTX‐animals, and in both the digital and caudal nerve of adult PTX‐animals (p <.05). A significant decrease in the mechanical threshold was observed only in young PTX‐animals (p <.001), but not in adult PTX‐ones. Nevertheless, both young and adult PTX‐rats had reduced IENF density (p <.0001), which persisted at the end of follow‐up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX‐animals developing peripheral neuropathy and age‐matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration. Interpretation: Our study identifies for the first time multiple related metabolic axes involved in PTX‐induced peripheral neurotoxicity, and suggests age‐related differences in CIPN manifestations and in the metabolic profile. [ABSTRACT FROM AUTHOR]

Background and Aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. Methods: We conducted unbiased mass‐spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross‐validation and bootstrapping. Results: In the univariate analysis, 73 proteins showed a p‐value <.05 and 12 proteins showed a p‐value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false‐negative rate 0.10, false‐positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p‐value =.0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin‐like growth factor‐binding protein 2 (IGFBP2), complement factor H‐related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN. [ABSTRACT FROM AUTHOR]

Background and Aims: X‐linked Charcot–Marie–Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. Methods: We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole‐exome sequencing in the probands to investigate the genetic basis of the disease. Results: Males in the family carrying the Arg162His mutation displayed early‐onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. Interpretation: We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co‐segregates with the disease as expected in a X‐linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary transthyretin amyloidosis polyneuropathy (ATTRv‐PN) presymptomatic carriers often show preclinical abnormalities at small fiber‐related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic carriers' follow‐up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late‐onset ATTRv presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO). Methods: Late‐onset ATTRv presymptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fiber density (IENFD) evaluation from a distal and a proximal site. Douleur Neuropathique‐4 (DN4) and Small Fiber Neuropathy‐Symptoms Inventory (SFN‐SIQ) were used to assess painful and small fiber neuropathy‐related symptoms. PADO and time‐to‐PADO (delta‐PADO) were estimated for each carrier, and correlations with diagnostic test measures were analyzed. Results: Forty presymptomatic ATTRv subjects were enrolled. Twenty carriers (50%) had distal IENFD reduction, with a non‐length‐dependent distribution in 73% of cases. Eleven subjects (27.5%) had cold and/or warm detection threshold (CDT and/or WDT) abnormalities at QST. Delta‐PADO positively correlated with sural sensory nerve action potential (SNAP) amplitude (r =.416, p =.004), and z‐values of QST parameters like CDT (r =.314, p =.028), WDT (r = −.294, p =.034), and mechanical detection threshold (MDT; r = −.382, p =.012). Simple linear regression models showed a linear relation between delta‐PADO and sural SAP, CDT, and MDT. Conclusions: Our findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv presymptomatic carriers, often with a non‐length‐dependent pattern. However, only sural SAP amplitude and QST parameters correlated with delta‐PADO, suggesting that serial combined QST and NCS evaluation could be useful in ATTRv presymptomatic carriers' follow‐up. [ABSTRACT FROM AUTHOR]

Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short‐term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow‐up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy‐six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

Background and Aims: Cisplatin is a chemotherapeutic agent for many types of cancer. The neurotoxicity of cisplatin includes neuropathy and allodynia. We aimed to study structural changes by using CYM54‐78, attenuating cisplatin‐induced neuropathy and blocking the pathogenesis in neurons, and promoting axonal regeneration. Methods: TEM (transmission electron microscopy) was used to distinguish ultrastructural changes in dorsal root ganglion (DRG) and dorsal rootlets (DR) between rats treated with cisplatin alone and rats co‐treated with cisplatin and sphingosine ‐1‐phosphate receptor2 (S1P2) agonist, CYM‐5478. Results: In DRG of rats treated with cisplatin alone, TEM micrographs showed necrosis and apoptotic cells. Neuronal cytoplasm showed numerous vacuole (stage C) and swelling (stage B➔C) mitochondrial degeneration. Neurons in DRG from cisplatin+CYM‐5478 group showed a higher percentage of healthy mitochondria (from 5.3% to 75.6%) than those treated with cisplatin alone. DR of cisplatin only group showed abnormal axoplasm, axolemma, and focal detached myelin sheaths, especially in Aδ (fast pain) and Aβ (touch) fibers, and revealed collateral branches that sprouted from Aβ fibers, which is characteristic of allodynia. Moreover, vasoconstriction was observed in DRG and DR. Rats in cisplatin+CYM‐5478 group showed not only fewer abnormal structures than those in cisplatin only group, but also showed Bands of Büngner and onion bulb‐like structures, which are characteristic of nerve regeneration. Interpretation: Together with our previous study, showed that CYM‐5478 attenuated neuropathy and allodynia in a rat model of cisplatin‐induced neuropathy, these results suggest S1P2 agonists as a potential approach the for treatment of cancer due to the reduction of side effects of cisplatin. [ABSTRACT FROM AUTHOR]

Background and Aims: Comprehensive study of sural nerve biopsy utility based on individual histopathologic preparations is lacking. We aimed to quantify the value of different histologic preparations in diagnosis. Methods: One hundred consecutive sural nerves were studied by standard histological preparations plus graded teased nerve fibers (GTNF), immunohistochemistry, and epoxy‐semithin morphometry. Three examiners scored the individual preparations separately by a questionnaire of neuropathic and interstitial abnormalities, masked to the biopsy number, versus a gold‐standard of all preparations. Multivariate modeling was utilized to determine best approach versus the gold‐standard. Results: Highest confidence (range 8–9 of 10) and inter‐rater reliability (99%) for fiber abnormalities came from GTNF, and interstitial abnormalities from paraffin stains (range 7–8, 99%). Vasculitic neuropathy associated with GTNF axonal degeneration (moderate to severe 79%) with OR 3.8, 95% CI (1.001–14.7), p =.04, but not significantly with the other preparations. Clinicopathologic diagnoses associated with teased fiber abnormalities in chronic inflammatory demyelinating polyradiculoneuropathy, 80% (8/10); amyloidosis, 50% (1/2); adult‐onset polyglucosan disease 100% (1/1). GTNF and paraffin stains significantly correlated with fiber density determined by morphometric analysis (GTNF: OR 9.9, p <.0001, paraffin: OR 3.8, p =.03). GTNF combined with paraffin sections had highest accuracy for clinicopathologic diagnoses and fiber density with 0.86 C‐stat prediction versus morphometric analysis. Pathological results lead to initiation or changes of immunotherapy in 70% (35/50; initiation n = 22, reduction n = 9, escalation n = 4) with the remaining having alternative intervention or no change. Interpretation: Nerve biopsy paraffin stains combined with GTNF have highest diagnostic utility, confidence, inter‐rater reliability, improving accuracy for a pathologic diagnosis aiding treatment recommendations. Immunostains and epoxy preparations are also demonstrated useful supporting consensus guidelines. This study provides class II evidence for individual nerve preparation utility. [ABSTRACT FROM AUTHOR]

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non‐specialist centers are warranted to identify patients who require second‐level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN‐SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN‐SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN‐SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN‐SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second‐level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials. [ABSTRACT FROM AUTHOR]

Patient‐reported outcome measures engage patients in disease severity measurement and the metrics reported can be meaningful to their lives. The Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome (POEMS) is a complex multisystem disorder with disabling neuropathy which is distinct from other acquired inflammatory neuropathies. No current POEMS‐specific validated disability scales exist. To address this, we have produced a Rasch‐built overall disability scale (RODS) specific to POEMS. A 146‐item preliminary questionnaire containing relevant activity and participation items for neuropathic disability was applied to 49 clinically stable patients with POEMS from the UK national POEMS cohort. A total of 123 items not fulfilling Rasch model expectations were sequentially removed. The final 23‐item POEMS‐RODS fulfilled Rasch model expectations and showed acceptable test‐retest reliability. The 23‐item POEMS‐RODS is a disease‐specific patient‐reported outcome measure able to detect activity limitations within the range of ability demonstrated by the UK POEMS cohort. Larger international studies are needed to confirm the broader applicability and responsiveness of this scale in other countries. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Small fiber neuropathy usually presents with gradual and progressive chronic length‐dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra‐epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra‐epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. At follow up, neuropathic pain was present in two of the patients. [ABSTRACT FROM AUTHOR]

The early clinical features of nitrous oxide (N2O)‐induced neuropathy were mimicking that of Guillain‐Barré syndrome (GBS). We aimed to explore clinical and laboratory characteristics of N2O‐induced neuropathy in comparison with GBS. We retrospectively reviewed data of 15 patients with N2O‐induced neuropathy and compared them with 15 GBS patients. The age of the N2O‐induced neuropathy group was significantly younger than that in the GBS group (22 ± 5 vs 45 ± 17). Paresthesia was more common in N2O‐induced neuropathy group (100% vs 53.3%). The proportion of distal upper limbs weakness was lower than that in GBS group (20.0% vs 93.3%). There was no significant difference in the distal weakness of the lower limbs (100% vs 80.0%). The incidence of motor conduction block and compound muscle action potential amplitude reduction in upper limbs was lower than that in GBS group (6.7% vs 60.0%; 26.7% vs 80.0%). The sensory nerve action potential amplitude drop in the lower limbs was more severe than that in GBS group (53.3% vs 0). The increase of Mean corpuscular volume (MCV) was more pronounced compared to GBS group (96.97 ± 6.00 vs 88.55 ± 5.41). High homocysteine levels were more common in N2O‐related group [29.80(11.60, 70.50) vs 14.35(9.22, 19.30)]. Typical clinical features of the acute N2O neuropathy appears to be a myeloneuropathy, affecting the lower limbs more than the upper limbs, mixed axonal‐demyelinating electrophysiological performance, higher homocysteine level, and larger MCV and common posterior spinal cord involvement in cervical segment. [ABSTRACT FROM AUTHOR]

Neuropathy is a major cause of morbidity and mortality in individuals with diabetes, with no effective therapy to alter the inevitable progression of nerve damage. We hypothesized that mesenchymal stroma cell‐like populations, that are characterized as immune modulators also have the potential of inducing angiogenesis and neurite outgrowth, might be useful in treating diabetic peripheral neuropathy (DPN). The aims of this study were to investigate the efficacy and safety of mesenchymal stem cell‐like product (PDA‐002) in treating DPN. A phase‐2 randomized placebo‐controlled trial was conducted in 26 patients with DPN. Treatment consisted of three rounds of intramuscular injections in one lower limb using one of the three randomized treatment arms PDA‐002 (low‐dose 3 × 106 cells), PDA‐002 (high‐dose 30 × 106 cells), or placebo. Three treatments per patient occurred on days 1, 29, and 57. Study endpoints included efficacy and safety of PDA‐002 in treating DPN in both lower extremities following unilateral local injection. Outcome measures included intra‐epidermal nerve fiber density (IENFD) up to 1 year from the day of treatment with 6‐month as the primary outcome measurement. In this phase 2 study of DPN, PDA‐002 was well tolerated in both doses. No significant changes were noted in IENFD in both the treated and untreated leg in the NIS‐LL, NTSS‐6, or UENS. Mesenchymal stem cells represent a novel mechanism for treating diabetic neuropathy and are well tolerated. Preliminary results highlight the need of further investigation of PDA‐001 as a disease modifying agent for treatment of DPN. [ABSTRACT FROM AUTHOR]

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m2) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age‐matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB‐HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1‐month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P =.1), NDS (P =.3), VPT (P =.6), CST (P =.2), CIP (P =.08), HIP (P =.1), DB‐HRV (P =.9) and sural (P =.4) and peroneal (P =.1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P =.04), peroneal (P =.002) and tibial (P =.007) nerve conduction velocity and tibial nerve amplitude (P =.03) were significantly lower, WST (P =.02) was significantly higher and corneal nerve fibre density (P =.004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB‐HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation. [ABSTRACT FROM AUTHOR]

Mutations in Myelin Protein Zero (MPZ) cause CMT1B, the second leading cause of CMT1. Many of the >200 mutations cause neuropathy through a toxic gain of function by the mutant protein such as ER retention, activation of the Unfolded Protein Response (UPR) or disruption of myelin compaction. While there is extensive literature on the loss of function consequences of MPZ in heterozygous Mpz +/− null mice, there is little known of the consequences of MPZ haploinsufficiency in humans. We identified six patients from different families with p.Tyr68Ter or p.Asp104fs heterozygous mutations of MPZ that are predicted to cause a premature termination and nonsense mediated decay of the mutant allele. Five patients were evaluated in Milan and one in Iowa City; all should be haploinsufficient for MPZ. Patients were evaluated clinically and by electrophysiology. Sensory ataxia dominated the clinical presentation with only mild weakness present in five of the six patients. Symptoms presented in adulthood in all patients and only one individual had a CMTNSv2 >5. Deep tendon reflexes were absent in all patients. Patients with likely MPZ loss of function due to mutations that cause haplodeficiency in MPZ have a mild, predominantly large fiber sensory neuropathy that serves as a human equivalent to the neuropathy observed in heterozygous Mpz null mice. Successful therapeutic approaches in treating Mpz deficient mice may be candidates for trials in these and similar patients. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis (ATTRv) is a condition with adult onset, caused by mutation of the transthyretin (TTR) gene and characterized by extracellular deposition of amyloid fibrils in tissue, especially in the peripheral nervous system (PNS) and heart. PNS involvement leads to a rapidly progressive and disabling sensory‐motor axonal neuropathy. Although awareness among neurologists increased in recent years thanks to new treatment options, ATTRv is frequently misdiagnosed, and thus a correct diagnosis can be delayed by several years. This review aims to draw the history and features of polyneuropathy in ATTRv based on pathological and electrophysiological correlates. We assessed original articles and case reports based on their relevance to ATTRv neuropathy and we included those appropriate for the scheme of this narrative review. Amyloid fibrils initially deposit in ganglia, causing an axonal neuropathy without amyloid deposits in distal segments (eg, sural nerve biopsy). Over time, amyloid fibrils spread along the nerves, leading to some demyelinating features in the context of severe axonal loss. This review highlights how the features of neuropathy change based on type of ATTRv (early vs late onset) and stage of disease. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is a common side effect of paclitaxel. Clinical studies suggest that different paclitaxel formulations influence the severity and time course of paclitaxel‐induced peripheral neuropathy. We compared two paclitaxel formulations, nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) and Cremophor EL paclitaxel (CreEL‐paclitaxel), for their toxicity, distribution, and clearance in the peripheral nervous system. Neuronal F11 cells were used to detect changes in morphology, cell nuclei size, and cell viability after nab‐ or CreEL‐paclitaxel treatment via MTT Assay and immunohistochemistry. C57BL/6 mice were treated with 50 mg/kg of nab‐paclitaxel or CreEL‐paclitaxel. Paclitaxel levels in serum, liver, dorsal root ganglia (DRG), and sciatic nerve (SCN) were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Accumulation of paclitaxel in DRG neurons and SCN was visualized by immunostainings. Neurotoxicity was evaluated after a 4‐week treatment regime with nab‐ or CreEL‐paclitaxel by nerve morphology, behavioral, and functional assays. In vitro cell nuclei size and morphology were similar between the two treatment groups. Viability was increased in neurons exposed to nab‐paclitaxel compared to CreEL‐paclitaxel. In vivo paclitaxel mostly accumulated in DRG. SCN displayed lower paclitaxel uptake. The two paclitaxel formulations mainly accumulated in neurofilament 200‐positive large‐caliber neurons and less in Isolectin B4‐, or calcitonin gene‐related peptide‐positive small‐caliber neurons. Sensory nerve conduction studies demonstrated increased sensory latencies after 11 days in nab‐paclitaxel treated animals, while an increase occurred after 22 days in CreEL‐paclitaxel treated animals. Behavioral testing did not reveal significant differences between the different groups. Skin denervation, axon count, myelin thickness, and F4/80‐positive cell accumulation were comparable between the two treatment groups. Our findings indicate that different drug formulations impact the severity of neuropathy induced by paclitaxel via different tissue uptake. Neurotoxicity was comparable between the two paclitaxel formulations. [ABSTRACT FROM AUTHOR]

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

A proportion of individuals with type 1 diabetes mellitus for more than 50 years (medallists) may be protected from developing nephropathy, retinopathy and neuropathy. Detailed neuropathy phenotyping was undertaken in a cohort of 33 medallists aged 63.7 ± 1.4 years with diabetes for 58.5 ± 0.8 years and HbA1c of 65.9 ± 2.1 mmol/mmol. Medallists had a significantly higher HbA1c (P <.001), lower estimated glomerular filtration rate (eGFR) (P =.005) and higher albumin creatinine excretion ratio (ACR) (P =.01), but a lower total cholesterol (P <.001), triacylglycerols (P =.001), low density lipoprotein‐cholesterol (P <.001) and higher high density lipoprotein‐cholesterol (P =.03), compared to controls. Twenty‐four percent of participants were identified as "escapers" without confirmed diabetic neuropathy. They had a lower neuropathy symptom profile (P =.002), vibration perception threshold (P =.02), warm threshold (P =.05), higher peroneal amplitude (P =.005), nerve conduction velocity (P =.03), heart rate variability (P =.001), corneal nerve fibre density (P = 0.001), branch density (P <.001) and length (P =.001), compared to medallists with diabetic neuropathy. Escapers had a shorter duration of diabetes (P =.006), lower alcohol consumption (P =.04), lower total cholesterol (P =.04) and LDL (P =.02), higher eGFR (P =.001) and lower ACR (P <.001). Patients with extreme duration diabetes without diabetic neuropathy have a comparable HbA1c, blood pressure and body mass index, but a more favourable lipid profile and consume less alcohol compared to those with diabetic neuropathy. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the presence and characterization of chemotherapy‐induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty‐one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life. [ABSTRACT FROM AUTHOR]

To propose a correlation between polyneuropathy and ATTRwt based on retrospective analysis of patients with ATTRwt. We reviewed 151 ATTRwt patients followed by the amyloid cardiac clinic (group A) for symptoms of neuropathy and 12 patients with ATTRwt evaluated in the Neurology Department (group B) with objective measures of neuropathy. Medical history, electrodiagnosis, laboratory and skin biopsies were assessed; 30.5% of group A had neuropathy symptoms. Alternative explanations for neuropathy symptoms were explored, including, age, gender, BMI, diabetes mellitus, B12 deficiency. No difference was observed for BMI, age, gender and spine disease for those with and without neuropathic symptoms (P >.05). All of group B (n = 12) were diagnosed with neuropathy, confirmed by electrodiagnostic testing or skin biopsy, while two patients had not yet developed cardiac symptoms. We observe a higher prevalence of neuropathic symptoms in ATTRwt patients than previously believed. Neuropathic symptoms may precede cardiac symptoms. Our findings suggest a possible causative relationship that requires further investigation. [ABSTRACT FROM AUTHOR]

The peripheral nervous system may be involved at any stage in the course of several hematological diseases, the most common being monoclonal gammopathies (of undetermined significance or malignant) or lymphomas. The underlying pathogenic mechanisms are different and therapies aim at targeting the dangerous either B‐cell or plasma cell clones. Recently, high‐throughput technologies, and next‐generation sequencing have increased our knowledge of hematological diseases pathogenesis by the identification of somatic mutation affecting pivotal signaling pathways. Accordingly, new target therapies are used that may also be borrowed for treatment of neuropathies in hematological diseases. [ABSTRACT FROM AUTHOR]

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot‐Marie‐Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in‐frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT‐associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic‐addressing additional features. [ABSTRACT FROM AUTHOR]

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits. [ABSTRACT FROM AUTHOR]

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One‐hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns—COMPASS 31+ESC and COMPASS 31 and/or ESC—were associated with CAN and DPN (P <.01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality. [ABSTRACT FROM AUTHOR]

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P <.01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P <.05 each), CNFD was lower only in FMS patients (P <.05), and CNBD was lower only in SFN patients (P <.001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling. [ABSTRACT FROM AUTHOR]

The use and utility of targeted gene panels for diagnosing the type of Charcot‐Marie‐Tooth have grown rapidly because commercial gene panels that contain most of the relevant genes are available and affordable for many patients. We used a targeted gene panel to analyze 175 patients who had an unexplained axonal polyneuropathy affecting large myelinated axons, 86 of whom reported a family history of neuropathy, and 89 of whom did not. In patients reporting a family history, the panel identified a pathogenic variant causing the neuropathy in six cases (7%); in patients not reporting a family history, the gene panel identified pathogenic variants causing neuropathy in two patients (2%). Interpretation in a tertiary referral setting, current gene panels identify the genetic cause of neuropathy in a small minority of patients who have an unexplained axonal neuropathy, even in those reporting a family history. [ABSTRACT FROM AUTHOR]

We found a p.Ala406Val (c.1217C > T) mutation in MORC2 in three individuals, from two families. All three individuals were evaluated and clinical electrophysiology was completed. The neuropathy began in childhood to early adulthood, with distal weakness progressing to proximal weakness. Vinblastine (for Hodgkin lymphoma) acutely worsened the weakness in one patient. This finding confirms that that the p.Ala406Val mutation in MORC2 causes severe neuropathy. In addition, we report the first case of vinblastine neurotoxicity in Charcot‐Marie‐Tooth disease type 2Z. [ABSTRACT FROM AUTHOR]

Platinum‐induced peripheral neurotoxicity (PIPN) is a common side effect of platinum‐based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non‐length‐dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking‐and‐glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum‐based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN. [ABSTRACT FROM AUTHOR]

Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a major toxicity of cancer treatment, leading to dose reduction and premature treatment cessation, potentially affecting patient function, and quality of life. The development of accurate and sensitive assessment tools for CIPN is essential to enable clinical monitoring during treatment, follow‐up of long‐term outcomes and measurement of toxicity in clinical trials. This review examines CIPN clinical assessment scales incorporating clinician‐based, composite, and patient‐reported outcomes (PROs), providing a systematic review of their properties and an updated critical analysis of recommendations on current evidence for their use. This systematic review of CIPN assessment tools identified 50 papers containing 41 assessment tools, across 4 categories (common toxicity criteria; composite neurological scale; PROs; pain scale). The majority of these tools were PROs, underscoring the importance of patient‐based assessment of symptoms. While there has been considerable work in the field over the past 10 years, this review highlights significant gaps, including a lack of evaluation of responsiveness and problematic neuropathic pain evaluation. There remains a need for consensus on the best available tool and the need to modify existing instruments to improve utility. [ABSTRACT FROM AUTHOR]

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot‐Marie‐Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations. [ABSTRACT FROM AUTHOR]

Neurofilaments are neuron‐specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot‐Marie‐Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype‐phenotype correlations have yet been established. Here, we report an additional case: a 69‐year‐old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next‐generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly). Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein. [ABSTRACT FROM AUTHOR]

The peripheral nervous system may be involved at any stage in the course of lymphoproliferative diseases. The different underlying mechanisms include neurotoxicity secondary to chemotherapy, direct nerve infiltration (neurolymphomatosis), infections, immune‐mediated, paraneoplastic or metabolic processes and nutritional deficiencies. Accordingly, the clinical features are heterogeneous and depend on the localization of the damage (ganglia, roots, plexi, and peripheral nerves) and on the involved structures (myelin, axon, and cell body). Some clinical findings, such a focal or diffuse involvement, symmetric or asymmetric pattern, presence of pain may point to the correct diagnosis. Besides a thorough medical history and neurological examination, neurophysiological studies, cerebrospinal fluid analysis, nerve biopsy (in selected patients with suspected lymphomatous infiltration) and neuroimaging techniques (magnetic resonance neurography and nerve ultrasound) may be crucial for a proper diagnostic workup. [ABSTRACT FROM AUTHOR]

Small‐fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ 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 Nav1.7, Nav1.8 and Nav1.9 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. [ABSTRACT FROM AUTHOR]

We aimed to elucidate characteristics of beriberi neuropathy (BB) in a general hospital (GH) setting. Nerve conduction studies (NCS), cross‐referenced with clinical records of patients admitted to a GH (May 2011‐July 2017), were reviewed for diagnosis of BB. Thirteen patients (age range 23‐64 years; five women) were diagnosed with BB. Eleven were incarcerated (2‐24 months) at time of index event. Eleven reported prior, severe anorexia (2‐6 months); five reported significant weight loss, three had recurrent vomiting, and three reported alcohol misuse. Commonest presentation was weakness (12/13); nine had symptom evolution over ≥3 weeks. At nadir, 11/13 could not walk independently. Other features included numbness/paraesthesiae (10/13), dysautonomia (6/13), vocal cord dysfunction/dysphagia (4/13), nystagmus (3/13). Pain was not prominent. Cerebrospinal fluid, tested in five patients, was acellular; one showed mildly increased protein. NCS showed predominantly sensorimotor, axonal polyneuropathy, rarely asymmetric. Only one patient had sural‐sparing pattern. All received high dose thiamine. Two of the thirteen received intravenous immunoglobulin for suspicion of Guillain‐Barré syndrome (GBS). Eleven improved to independent ambulation. One patient died from pulmonary embolism; one was lost to follow‐up. Two of the thirteen had residual neurocognitive effects; both misused alcohol. Besides GBS, BB is an important cause of acute to subacute flaccid paralysis, especially in incarcerated patients and those with significant dietary deprivation. Features favoring BB over GBS are ≥3 weeks of symptoms, nystagmus, confusion, vocal cord dysfunction, volume overload, normal spinal fluid, elevated lactate, and absence of sural‐sparing pattern in NCS. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is a common side effect of many chemotherapeutic agents including paclitaxel. We prospectively evaluated demographic and laboratory data in a cohort of 61 woman with breast cancer prior to paclitaxel exposure to explore factors that predispose to neuropathy development. Neuropathy was graded based on the total neuropathy score reduced version (rTNS) at baseline and at 4 months after initiation of chemotherapy. A multivariate analysis identified predictors with the strongest association with a change in rTNS. Serum albumin (P = .002), paclitaxel dose (P = .001), and body surface area (P = .006) were statistically significantly associated with a positive rTNS change (worsening neuropathy). These results suggest that poor nutritional status and obesity increase the risk of paclitaxel induced neuropathy, and that screening for these factors prior to chemotherapy exposure may improve early neuropathy detection or decrease risk with dietary modifications. [ABSTRACT FROM AUTHOR]

Abstract: A 59‐year‐old woman presented with progressive paresthesias of all of her limbs for 4 years, associated with neuropathic pain, tingling in the tongue and allodynia, consistent with small fiber neuropathy (SFN). Several systemic symptoms and signs were found on clinical examination and laboratory work‐up. Neurological investigations including neurophysiologic test and skin biopsy supported the diagnosis of SFN. Chronic exposure to N‐hexane was then disclosed and suspected to be the cause of the disease. Following the discontinuation of chronic N‐hexane exposure, the patient had a progressive improvement of all signs and symptoms, reinforcing the correlation between exposure to N‐hexane, and development of SFN. Exposure to N‐hexane may be considered as a novel reversible cause of SFN, which underlines the need to look for toxic etiologies in the diagnosis of SFN. [ABSTRACT FROM AUTHOR]

Abstract: Dominant mutations in MFN2 cause a range of phenotypes, including severe, early‐onset axonal neuropathy, “classical CMT2,” and late‐onset axonal neuropathies. We report a large family with an axonal polyneuropathy, with clinical onset in the 20s, followed by slow progression. [ABSTRACT FROM AUTHOR]

PHARC syndrome (MIM612674) is an autosomal recessive neurodegenerative pathology that leads to demyelinating Polyneuropathy, Hearing loss, cerebellar Ataxia, Retinitis pigmentosa, and early-onset Cataracts (PHARC). These various symptoms can appear at different ages. PHARC syndrome is caused by mutations in ABHD12 (α-β hydrolase domain 12), of which several have been described. We report here a new complex homozygous mutation c.379_385delAACTACTinsGATTCCTTATATACCATTGTAGTCTTACTGCTTTTGGTGAACACA (p.Asn127Aspfs*23). This mutation was detected in a 36-year-old man, who presented neuropathic symptoms from the age of 15, using a next-generation sequencing panel. This result suggests that the involvement of ABHD12 in polyneuropathies is possibly underestimated. We then performed a comparative study of other patients presenting ABHD12 mutations and searched for genotype-phenotype correlations and functional explanations in this heterogeneous population. [ABSTRACT FROM AUTHOR]

Hand weakness and impaired manual dexterity have been reported in children with Charcot-Marie-Tooth disease type 1A ( CMT1A). This early onset of upper limb involvement might explain frequent clinical referrals for assessment and treatment of impaired handwriting performance. The aim of this study was to examine the impact of CMT1A on handwriting speed and legibility, and identify demographic, anthropometric, and physical measures that might relate to handwriting performance. Handwriting speed (Handwriting Speed Test), handwriting legibility (Evaluation Tool of Children's Handwriting-Cursive), and hand strength (hand-held dynamometry of tip pinch, lateral pinch and grip) were assessed in 30 children with CMT1A (aged 8-17 years) and 30 age- and sex-matched controls. Children with CMT1A exhibited 34% slower handwriting speed (p < 0.0001) with 4% reduced legibility (p = 0.001) and 37-48% lower hand strength (p < 0.0001). All measures of strength, age, height, and weight were positively associated with handwriting speed (r = 0.39-0.79, p < 0.01). None of these factors related to handwriting legibility (p > 0.05). Regression modelling identified a diagnosis of CMT1A, lateral pinch weakness and younger age as significant independent predictors of slower handwriting speed, explaining 78% of the variance. Children with CMT1A have considerable handwriting difficulties, primarily with speed, and substantial associated hand and finger weakness. Understanding the cause-effect relationship between strength and function might provide modifiable targets for upper limb intervention. [ABSTRACT FROM AUTHOR]