Journal Of The Peripheral Nervous System[JOURNAL]
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200 papers
Prognostic Nutritional Index as a Biomarker of Disease Severity and Long-Term Outcome in Guillain-Barré Syndrome.
Biswas PP, Jahan I, Ahmed J … +6 more , Papri N, Ahmed R, Khurshid S, Mohammad QD, Ara G, Islam Z
J Peripher Nerv Syst · 2025 Dec · PMID 41157951 · Full text
BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) exhibits clinical heterogeneity and variable progression. In low-resource settings, malnutrition and limited treatment worsen prognosis, underscoring the need for a simp...
BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) exhibits clinical heterogeneity and variable progression. In low-resource settings, malnutrition and limited treatment worsen prognosis, underscoring the need for a simple prognostic tool. This study evaluated the Prognostic Nutritional Index (PNI) and Nutritional Risk Index (NRI) in relation to GBS severity and long-term outcomes, comparing their predictive value with standard prognostic indicators. METHODS: An observational cohort study of 252 GBS patients enrolled between 2019 and 2024 was conducted. PNI and NRI were calculated using serum albumin, lymphocyte count, and body weight. The GBS-disability score (GBS-DS) assessed baseline severity and 26-week outcomes. Statistical analysis included Chi-square tests, Mann-Whitney U tests, Spearman's ρ, and logistic regression to identify predictors. ROC analysis determined optimal PNI cut-offs, confirmed by Kaplan-Meier survival curves. RESULTS: PNI, unlike NRI, was significantly reduced in severe GBS (GBS-DS > 3) compared to mild/moderate GBS (GBS-DS ≤ 3). PNI correlated with GBS-DS (ρ = -0.62), MRC sum score (ρ = 0.5), hemoglobin (ρ = 0.53), and neutrophil count (ρ = -0.35) (all p < 0.0001). PNI independently predicted disease severity (odds ratio [OR] = 0.91; p = 0.036) and 26-week outcomes (OR = 0.93; p = 0.033). Area under the ROC curve (AUC) was 0.769 for severity and 0.719 for 26-week outcomes. PNI cut-offs of 49.395 and 45.72 predicted severe GBS and long-term poor outcome, respectively. Kaplan Meier analysis confirmed patients with PNI < 45.72 required a longer time to gain independent locomotion (p < 0.0001). INTERPRETATION: Lower PNI, but not NRI, is associated with greater GBS severity and poor long-term outcomes. PNI independently predicted disease severity and 26-week outcomes, with specific cut-offs identifying patients requiring longer recovery, supporting its prognostic utility.
Pseudodominant Inheritance of Biallelic RFC1 Expansions-Revisiting the 3p22-p24 HSN1B Locus.
Grosz BR, Ellis M, Trivedi S … +14 more , Scriba C, Stoll M, Zhu D, Chintalaphani SR, Stevanovski I, Cortese A, Spring PJ, Laing NG, Deveson IW, Reilly MM, Nicholson GA, Kumar KR, Vucic S, Kennerson ML
J Peripher Nerv Syst · 2025 Dec · PMID 41084404 · Publisher ↗
BACKGROUND AND AIMS: Hereditary sensory neuropathies (HSN) are a group of heterogenous peripheral neuropathies presenting primarily with distal sensory loss. Biallelic expansions in intron 2 of RFC1 (replication factor C...
BACKGROUND AND AIMS: Hereditary sensory neuropathies (HSN) are a group of heterogenous peripheral neuropathies presenting primarily with distal sensory loss. Biallelic expansions in intron 2 of RFC1 (replication factor C subunit 1) can cause autosomal recessive HSN. We aimed to reassess two previously reported families (HSN32 and HSN35) with "autosomal dominant HSN1 with cough and gastroesophageal reflux." The phenotype was designated HSN1B and linked to chromosome 3p22-p24, although no causative variant was identified. METHODS: Due to the phenotypic similarities between HSN1B and biallelic RFC1 expansions, targeted long-read sequencing (LRS) of the HSN32 proband was performed. RFC1 expansion analysis was then conducted on available individuals from HSN32 and HSN35 using flanking PCR, repeat-primed PCR (RP-PCR), and targeted LRS. RESULTS: LRS of the proband (Generation III) from HSN32 revealed a novel complex RFC1 expansion (AGGGCAAGGC) in trans with a known pathogenic AAGGG expansion. Extended RFC1 analysis showed the proband's affected father (Generation II) reproduced with an unaffected carrier of the novel RFC1 AGGGCAAGGC expansion to produce the affected proband. Further analysis of the affected father and his four affected siblings (Generation II) identified pathogenic biallelic RFC1 AAGGG expansions inherited from their carrier parents (Generation I). For family HSN35, both affected individuals previously reported in the second HSN1B family had biallelic AAGGG RFC1 expansions. INTERPRETATION: Affected individuals across consecutive generations in HSN32 resulted in the erroneous mapping of an "autosomal dominant" HSN1B chr3p22-p24 locus. The HSN1B locus should therefore no longer be considered a valid locus for HSN.
Correction to "Polyneuropathy in Kidney Transplant Recipients: Accuracy of a New Clinical Diagnostic Scoring System".
J Peripher Nerv Syst · 2025 Dec · PMID 41084271 · Full text
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Insight in the Unmet Needs Encountered During the Management of Chronic Inflammatory Demyelinating Polyradiculoneuropathy.
Allen JA, Lehmann HC, Nobile-Orazio E … +2 more , Querol L, Rajabally YA
J Peripher Nerv Syst · 2025 Dec · PMID 41054275 · Full text
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare acquired immune-mediated disorder affecting peripheral nerves, manifesting most commonly as symmetric, proximal, and distal weakness with sensory...
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare acquired immune-mediated disorder affecting peripheral nerves, manifesting most commonly as symmetric, proximal, and distal weakness with sensory loss. Although the 2021 European Academy of Neurology/Peripheral Nerve Society guidelines provide evidence-based and consensus-driven approaches to the diagnosis and treatment of CIDP, challenges to optimal patient care persist. This report aims to highlight the unmet needs in CIDP management. A structured analysis of existing evidence was conducted to map gaps in CIDP care pathways, emphasizing diagnostic criteria, assessment of the therapeutic response, and disease management. Recognized key gaps and unmet needs in CIDP include (1) the absence of specific biomarkers for CIDP, (2) weighing the relative value of various CIDP metrics and interpreting what those metrics say about disease activity and treatment response, and (3) understanding the optimal timing and approach to assess treatment efficacy (or failure). There exists variability in how diagnostic and treatment guidelines are utilized, as well as how (and if) outcome metrics are utilized to guide informed treatment decisions. At least part of the confusion stems from the absence of terms commonly used during the CIDP treatment journey, including "response," "refractory," "remission," and "relapse." To address these ambiguities, a consensus-driven effort is needed to establish standardized definitions for key treatment milestones in CIDP. Harmonizing terminology will not only facilitate more accurate clinical assessments but also promote more robust and comparable research outcomes, ultimately improving the care of individuals with CIDP. This report underscores the critical unmet needs in CIDP diagnosis and management. By identifying barriers and facilitators within the current CIDP landscape, we hope to optimize clinical decision-making and focus research efforts.
The Easy Handgrip Test as a Tool for Assessing Motor Fatigability in Children With Charcot-Marie-Tooth Disease Type 1A.
Estevam EDS, Martins EJ, Franco CSB … +5 more , Cruz KLT, de Lemos TW, Tomaselli PJ, Junior WM, Mattiello-Sverzut AC
J Peripher Nerv Syst · 2025 Dec · PMID 41042603 · Publisher ↗
BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT), the most common inherited neuromuscular disorder, causes progressive, symmetrical muscle weakness, often affecting distal extremities. Motor fatigability, characterized by...
BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT), the most common inherited neuromuscular disorder, causes progressive, symmetrical muscle weakness, often affecting distal extremities. Motor fatigability, characterized by a decline in maximal muscle force, is common in neuromuscular disorders but remains underexplored in children with CMT. This study aimed to evaluate the feasibility of a motor fatigability test using a bulb dynamometer in children and adolescents with CMT1A, assess test-retest reliability, and compare handgrip pressure, electromyographic parameters, perceived effort, and time to exhaustion between CMT1A and typically developing peers. METHODS: This observational cross-sectional study included 107 children (aged 8-16 years; 19 with CMT1A and 88 typically developing). Participants performed a handgrip motor fatigability test using a bulb dynamometer, involving repetitive maximum voluntary isometric contractions (MVICs) at one-second intervals until exhaustion, with simultaneous electromyographic monitoring. Test-retest reliability was assessed using Bland-Altman plots and the Intraclass Correlation Coefficient (ICC). For comparisons between groups and test phases, ANCOVA and linear mixed-effects models were adjusted for sex, age, height, and weight. RESULTS: A hundred and four children completed the test. The protocol was feasible, with both groups reaching significant exhaustion in 4 min and showing a significant decline in handgrip pressure (p < 0.05). The decline in median power frequency observed during the fatigue test indicated reduced neural activation in both groups. The ICC was 0.824, indicating good test-retest reliability. INTERPRETATION: The protocol shows promise for monitoring disease progression and treatment effects in children with CMT1A, and may serve as a functional marker. Future studies should include other CMT types.
Identifying Predictors of Idiopathic Small-Fiber Neuropathy in Adolescent Patients With Chronic Pain.
Frye WS, Ward SR, Nguyen ATH … +2 more , Cucchiaro G, Hart DA
J Peripher Nerv Syst · 2025 Dec · PMID 41028910 · Publisher ↗
INTRODUCTION: Small-fiber neuropathy (SFN) affects thinly myelinated and unmyelinated nerve fibers and often presents with pain. While this condition is observed in pediatric chronic pain settings, it is unclear which pa...
INTRODUCTION: Small-fiber neuropathy (SFN) affects thinly myelinated and unmyelinated nerve fibers and often presents with pain. While this condition is observed in pediatric chronic pain settings, it is unclear which patients are most appropriate for SFN testing, particularly for idiopathic cases. Skin biopsy is the most accurate diagnostic tool, but guidelines for its use are lacking. This study aimed to identify clinical and laboratory variables predictive of a positive skin biopsy for SFN in adolescents with chronic pain. METHODS: This retrospective study analyzed clinical, demographic, and laboratory characteristics of 104 adolescents with chronic pain who had undergone PGP9.5-immunolabeled distal-leg skin biopsy to assess for SFN. Fisher's exact tests, ANOVA, and logistic regression were used to identify predictive factors. RESULTS: Patient mean age was 15 years old and 51.9% had positive diagnostic skin biopsies. Results indicated adolescents with positive biopsies were more likely to have Juvenile Idiopathic Arthritis (JIA) compared to those without (33.3% vs. 14.3%, p = 0.02) and had higher median angiotensin-converting enzyme (ACE) levels (p < 0.01) and thyroid free T4 levels (p = 0.02). Logistic regression only showed increased odds of positive skin biopsies with JIA (OR = 3.27, p = 0.02). No clinical symptoms were predictive of positive skin biopsies. DISCUSSION: Findings suggest that common clinical observations and laboratory tests used to guide referrals for skin biopsies were not predictive of SFN diagnosis. Clinicians should consider the risks and benefits of skin biopsies for adolescents with chronic pain. Additional research is warranted to validate potentially predictive markers and improve diagnostic pathways for SFN in pediatric chronic pain settings.
Epidemiology, Presentation, Management and Outcomes in Chronic Inflammatory Demyelinating Polyneuropathy in Birmingham, UK: The Impact of Ethnicity.
Rajabally Z, Spencer L, Mistry N … +1 more , Rajabally YA
J Peripher Nerv Syst · 2025 Dec · PMID 41020729 · Full text
BACKGROUND: Whether ethnicity impacts on epidemiology, presentation, management, and outcome is unknown in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We studied the prevalence/incidence of CIDP in...
BACKGROUND: Whether ethnicity impacts on epidemiology, presentation, management, and outcome is unknown in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We studied the prevalence/incidence of CIDP in Asian (Indian/Pakistani/Bangladeshi) and white subjects in Birmingham, UK, and associations of ethnicity with demographics/deprivation/phenotype/treatment and outcomes. RESULTS: On 10th July 2025, CIDP prevalence was 6.18 per 100 000 (95% CI: 4.66-8.05). Prevalence was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (2.64 per 100 000 vs. 10.15 per 100 000; RR: 0.260, 95% CI: 0.111-0.609; p < 0.001). Prevalence in ≥ 50-year-olds was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (8.00 per 100 000 vs. 46.68 per 100 000; RR: 0.172; 95% CI: 0.061-0.479; p < 0.001) but similar in 18-49-year-olds (2.48 per 100 000 vs. 1.83 per 100 000; RR: 1.355, 95% CI: 0.273-6.712; p = 0.661). Mean incidence of CIDP was 0.54 per 100 000 per year (95% CI: 0.404-0.713). CIDP incidence was lower in Asian (Indian/Pakistani/Bangladeshi) than in white subjects (0.24 per 100 000 per year vs. 0.86 per 100 000 per year, RR: 0.278; 95% CI: 0.118-0.654; p = 0.002). Asian (Indian/Pakistani/Bangladeshi) ethnicity was independently associated with younger age (p = 0.037), greater social deprivation (p = 0.045), and noncompliance to treatment (p = 0.016). No association of Asian (Indian/Pakistani/Bangladeshi) ethnicity was found with CIDP sub-type, diagnostic delay, pretreatment disability, access to high-cost therapies, or posttreatment outcomes. CONCLUSIONS: Subjects of Asian (Indian/Pakistani/Bangladeshi) ethnicity in the UK may have a lower risk of CIDP after 50 years of age, but an equivalent risk between 18 and 49 years, compared to white subjects. They may present younger, be more socially deprived, and be more likely noncompliant to treatment, compared to white subjects.
Serum Neurofilament Light Chain Level as an Indicator of Axonal Injury in Parsonage-Turner Syndrome (Neuralgic Amyotrophy).
Queler SC, Tsoon Tan E, Green A … +3 more , Milani C, Abdelhak A, Sneag DB
J Peripher Nerv Syst · 2025 Dec · PMID 41020719 · Publisher ↗
BACKGROUND AND AIMS: Parsonage-Turner syndrome (PTS), also known as neuralgic amyotrophy, is a peripheral neuropathy resulting in severe axonal loss. This study aimed to characterize initial elevation and longitudinal tr...
BACKGROUND AND AIMS: Parsonage-Turner syndrome (PTS), also known as neuralgic amyotrophy, is a peripheral neuropathy resulting in severe axonal loss. This study aimed to characterize initial elevation and longitudinal trends of serum neurofilament light chain (sNfL), a marker of neuro-axonal damage, in PTS. METHODS: This prospective cohort included 29 adults with electromyography (EMG)-confirmed PTS ≤ 6 months from symptom onset. Patients underwent sNfL testing and EMG at baseline (median 86 days from symptom onset) and again at 3- and 6-month follow-up intervals. Age- and BMI-adjusted Z-scores were analyzed. Linear mixed-effects models assessed associations between sNfL and time from onset, number of nerves involved, EMG metrics, and corticosteroid use. RESULTS: Mean sNfL Z-scores were significantly elevated (1.64, SD 1.32, p < 0.001) compared with healthy controls at 0 (1.64, p < 0.001) and 3 months (0.49, SD 1.06, p = 0.020). At 6 months, statistically significant elevations were not detected (0.39, SD 0.96, p = 0.106). sNfL declined by 0.17 Z-scores per month (95% CI: 0.11-0.23; p < 0.001). On EMG, the presence of nascent motor units, reflecting reinnervation, was associated with lower sNfL (p = 0.043). INTERPRETATION: sNfL elevation was detected in PTS patients within the first 6 months from symptom onset and decreased as reinnervation ensued. These findings suggest sNfL deserves further consideration as a blood-based biomarker for detection and monitoring of PTS.
Rasch-Built Overall Disability Scale for IgM-Associated Polyneuropathy With and Without Anti-MAG Antibodies: IgM-RODS.
Hamadeh T, van de Mortel JPM, Hoeijmakers JGJ … +7 more , Cornblath DR, Vrancken AFJE, Faber CG, Notermans NC, van Doormaal PTC, Merkies ISJ, IMAGiNe Consortium
J Peripher Nerv Syst · 2025 Sep · PMID 40984806 · Publisher ↗
BACKGROUND AND AIM: IgM monoclonal gammopathy-associated polyneuropathy with(out) anti-myelin associated glycoprotein (±anti-MAG) is a rare immune-mediated disease that may cause severe limitations in daily activities an...
BACKGROUND AND AIM: IgM monoclonal gammopathy-associated polyneuropathy with(out) anti-myelin associated glycoprotein (±anti-MAG) is a rare immune-mediated disease that may cause severe limitations in daily activities and quality of life. The absence of a systematic comparison between patients with/without anti-MAG IgM polyneuropathy, no disease-specific functional metric, and lack of international consensus regarding assessment and treatment of these patients are factors obstructing future clinical trials. Therefore, it was decided to develop an interval Rasch-built activity/participation scale specifically for IgM polyneuropathy ±anti-MAG (IgM-RODS) and examine its clinimetric properties. METHODS: A pre-phase IgM-RODS questionnaire containing 146 activity/participation items, based on the WHO International Classification of Functioning, Disability and Health, was completed by participants (≥ 18 years) of the IMAGiNe observational registry that fulfilled international criteria for IgM-polyneuropathy ±anti-MAG. Data was subjected to Rasch analyses, and reliability/validity studies were performed as well. RESULTS: The pre-RODS data of 259 subjects (originating from 8 different countries) underwent quality assessment, and 244 remaining records were submitted to the Rasch model, evidencing the model's expectations. Based on requirements like exceeding fit residuals, misfit statistics, item bias, local dependency, and less face validity, we systematically removed items until the final 36-item IgM-RODS fulfilled all Rasch requirements and showed acceptable test-retest reliability, cross-cultural, construct and discriminant validity, and unidimensionality. Compared to the Inflammatory-RODS, the IgM-RODS showed lower standard errors across the metric, indicating greater sensitivity. INTERPRETATION: The 36-item IgM-RODS is a disease-specific interval measure suitable for detecting functional deficits in patients with IgM-polyneuropathy ±anti-MAG. Future studies are needed to determine its responsiveness.
Designing and Implementing a Web-Based Platform for Accurate and Reliable Clinical Outcome Measures and Global Certification for Evaluating Charcot-Marie-Tooth disease.
Cornett KMD, Estilow T, Bray P … +7 more , Mandarakas MR, Donlevy GA, Baldwin JN, Eichinger K, Finkel RS, Burns J, McKay MJ
J Peripher Nerv Syst · 2025 Sep · PMID 40968111 · Full text
BACKGROUND AND AIMS: Accurate, reliable and sensitive clinical outcome measures in rare neurologic conditions, such as Charcot-Marie-Tooth disease (CMT), are essential for monitoring disease progression and evaluating tr...
BACKGROUND AND AIMS: Accurate, reliable and sensitive clinical outcome measures in rare neurologic conditions, such as Charcot-Marie-Tooth disease (CMT), are essential for monitoring disease progression and evaluating treatment efficacy. Ensuring measures such as the CMTPedS, CMTInfS and CMT-FOM are easily accessible removes a barrier to implementation. The aims of this project were to: (1) design a web-based platform to enable real-time scoring of CMT outcome measures; (2) implement co-designed training and quality assurance resources; and (3) establish a Global Certification Standard for clinical evaluators. METHODS: A consultation process informed the design of the web-based platform and included a process evaluation of current users (n = 65). Training resources were co-designed with key stakeholders (n = 51) including CMT physicians and scientists, clinical evaluators, pharmaceutical representatives, and patients through a mixed-methods approach. A Global Certification Standard was developed through the co-design process and Master Trainer expertise. RESULTS: A web-based platform, www.ClinicalOutcomeMeasures.org was designed and implemented in June 2020 as a freely available trial readiness resource for clinicians and researchers. The platform now has > 1400 registered users from > 45 countries. Clinical evaluators identified a lack of accessible training resources as the top barrier to accurate and reliable administration of CMT outcome measures. Video demonstrations, online workshops, and labelled photographs were ranked as the top training methods. Five guiding principles for the Global Certification Standard for CMT outcome measures were established. INTERPRETATION: The web-based platform provides real-time scoring of CMT outcome measures, access to standardized training, and a Global Certification Standard to support accurate and reliable assessment of disease severity, progression, and treatment efficacy.
Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature.
Mandia D, Benoit C, Stojkovic T … +1 more , Nadjar Y
J Peripher Nerv Syst · 2025 Sep · PMID 40946707 · Publisher ↗
BACKGROUND AND AIMS: TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cer...
BACKGROUND AND AIMS: TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cerebellar ataxia, neuropsychiatric symptoms, and characteristic brain MRI findings within the Leigh syndrome spectrum. Peripheral motor involvement has been described in a minority of cases but has rarely been documented with detailed neurophysiological data. We report a novel TTC19 variant in a patient presenting with a distinctive combination of central and peripheral motor involvement. CASE REPORT: A male patient of Malian origin presented with cerebellar ataxia and attention deficits from early childhood. During adolescence, he developed additional features including dysarthria, dysphagia, dysexecutive syndrome, and signs of peripheral motor neuropathy. Brain MRI revealed T2-FLAIR hyperintensities in the basal ganglia and brainstem. Genetic testing identified a novel homozygous nonsense variant in TTC19 (c.235G>T, p.(Gly79*)). At age 19, he experienced two acute deteriorations associated with respiratory infections, leading to severe tetraparesis and diaphragmatic weakness. Neurophysiological studies confirmed a diffuse, axonal, pure distal motor neuropathy. Follow-up imaging showed progression and cavitation of brainstem lesions. The patient died from respiratory failure at age 20. INTERPRETATION: This case, featuring a novel TTC19 variant and detailed electrophysiological data, further supports the presence of pure motor neuropathy within the phenotypic spectrum of TTC19-related disease. The co-occurrence of Leigh syndrome MRI findings and motor neuropathy represents a specific diagnostic clue that may help prioritize genetic testing in patients with overlapping central and peripheral motor involvement.
Polyneuropathy in Kidney Transplant Recipients: Accuracy of a New Clinical Diagnostic Scoring System.
Nolte S, Shehab NBN, Berger SP … +10 more , Oldag C, Nolte IM, de Greef BTA, Lange F, van Londen M, Faber CG, Bakker SJL, van Doorn PA, Moes HR, Drost G
J Peripher Nerv Syst · 2025 Sep · PMID 40915314 · Full text
BACKGROUND AND AIMS: Polyneuropathy is highly prevalent among kidney transplant recipients (KTR), underscoring the need for an accurate yet easy-to-perform diagnostic method to improve understanding and enable early iden...
BACKGROUND AND AIMS: Polyneuropathy is highly prevalent among kidney transplant recipients (KTR), underscoring the need for an accurate yet easy-to-perform diagnostic method to improve understanding and enable early identification of treatable cases. METHODS: This study included KTR at least 12 months post-transplant at the University Medical Centre Groningen, the Netherlands. An expert panel assessed polyneuropathy through a structured neurological examination, quantitative sensory testing, and nerve conduction studies. The modified Toronto Clinical Neuropathy Score (mTCNS) was obtained from all participants. Logistic regression analyses with Firth penalization validated the mTCNS components. A new model, the Kidney Transplant Neuropathy Score (KTNS), was developed through stepwise elimination. Diagnostic performance was evaluated with bootstrapped metrics and ROC curve analyses. RESULTS: Among 160 KTR, 91 (57%) were diagnosed with polyneuropathy. All 10 mTCNS components were univariably associated with polyneuropathy; numbness (OR = 4.9 [1.8-18.0]), tingling (OR = 2.5 [1.2-5.9]), impaired nociception (OR = 1.5 [1.1-2.2]), and reduced vibration perception (OR = 1.5 [1.0-2.4]) remained independently associated in multivariable analysis. The mTCNS achieved an area under the curve (AUC) in ROC analysis of 0.83 [0.76-0.89]. Two KTNS were derived: the KTNS, including history of numbness, tingling in the feet, and pinprick and vibration perception testing (AUC-ROC: 0.85 [0.79-0.90]); and the KTNS, replacing vibration perception with Achilles and patellar deep tendon reflex testing (AUC-ROC: 0.90 [0.85-0.94]). INTERPRETATION: The mTCNS is a valid diagnostic tool for polyneuropathy in KTR. The KTNS offers a simplified alternative based on key symptoms and sensory tests, with reflex testing included in the KTNS for settings with neurological expertise. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04664426.
A Novel Case of Nerve Biopsy Proven Wild Type Transthyretin (TTR) Amyloidosis.
Daley CM, Skolka MP, Engelstad JK … +2 more , Rech KL, Dyck PJB
J Peripher Nerv Syst · 2025 Sep · PMID 40899218 · Publisher ↗
AIM: To report a novel case of biopsy-proven, mass spectrometry-confirmed, wild-type transthyretin amyloidosis (ATTRwt) in nerve. METHODS: The patient was identified and evaluated in the peripheral nerve clinic. Our nerv...
AIM: To report a novel case of biopsy-proven, mass spectrometry-confirmed, wild-type transthyretin amyloidosis (ATTRwt) in nerve. METHODS: The patient was identified and evaluated in the peripheral nerve clinic. Our nerve laboratory's pathology database and the literature were searched for prior evidence of pathologically confirmed cases of ATTRwt. RESULTS: A 94-year-old man with a history of lumbar spinal stenosis presented to the neurology clinic with subacute-on-chronic progressive, upper limb predominant weakness along with numbness and tingling paresthesia. Electromyography (EMG) revealed multiple mononeuropathies involving the right median nerve at the wrist, right ulnar nerve, and right distal radial nerve superimposed upon an axonal predominant peripheral neuropathy along with multilevel lumbosacral radiculopathies. Extensive serology for causes of neuropathy and multiple mononeuropathies returned unremarkable. A diagnostic right superficial radial nerve biopsy was performed and showed congophilic material within a small epineurial vessel wall in the nerve tissue. Amyloid typing by mass spectrometry was performed and revealed ATTRwt. TTR gene sequencing returned normal. The patient was diagnosed with ATTRwt neuropathy and started on diflunisal therapy for neuropathy treatment. CONCLUSION: This case confirms the presence of ATTRwt deposition directly in nerve tissue as the likely cause of the patient's large fiber and multiple mononeuropathies, expanding our current understanding of ATTRwt-associated disease. Proving the direct association of ATTRwt and neuropathy may open up amyloid-specific treatments for this disease.
Intrathecal Antibody Synthesis in Autoimmune Nodopathy.
Min YG, Ko BK, Han HJ … +5 more , Kim M, Lee DH, Kim SW, Sung JJ, Shin HY
J Peripher Nerv Syst · 2025 Sep · PMID 40887769 · Full text
BACKGROUND: Autoimmune nodopathy (AN) is caused by autoantibodies targeting the nodes of Ranvier or paranodes. AN frequently affects cranial nerves and spinal nerve roots and may accompany central demyelination, all of w...
BACKGROUND: Autoimmune nodopathy (AN) is caused by autoantibodies targeting the nodes of Ranvier or paranodes. AN frequently affects cranial nerves and spinal nerve roots and may accompany central demyelination, all of which belong to the intrathecal compartment. We aimed to ascertain the frequency of intrathecal antibody synthesis and blood-CSF barrier (BCSFB) dysfunction in AN and their clinical correlates. METHODS: We analyzed paired cerebrospinal fluid (CSF) and serum samples from 110 patients with AN, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain-Barré syndrome (GBS). BCSFB dysfunction and intrathecal total IgG synthesis were assessed using Q, Q, and IgG index. Flow cytometry was used to evaluate intrathecal autoantibody synthesis. RESULTS: Compared to CIDP and GBS, AN patients more frequently exhibited BCSFB dysfunction (87.5%) and intrathecal total IgG synthesis (68.8%). Among AN patients with cranial nerve or brain involvement (8/16, 50%), all had either an elevated IgG index (n = 7) or CSF-specific oligoclonal bands (n = 1). Intrathecal autoantibody synthesis was confirmed in 2 patients. Notably, both patients initially presented with cranial neuropathies. No CSF-restricted AN autoantibodies were found in the 39 seronegative CIDP and GBS patients. CONCLUSIONS: AN exhibits distinct immunopathogenesis compared to CIDP and GBS. Intrathecal synthesis of total IgG is associated with cranial nerve or central nervous system involvement, while that of AN-specific autoantibodies relates to cranial nerve onset diseases.
Neuroprotective Effect of Mas Activation by BIO101 in Vincristine-Induced Small Fiber Neuropathy.
Frachet S, Danigo A, Latil M … +6 more , Dilda PJ, Bessaguet F, Richard L, Sturtz F, Magy L, Demiot C
J Peripher Nerv Syst · 2025 Sep · PMID 40833359 · Full text
BACKGROUND AND AIMS: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect that limits the dosage of many anticancer therapies, such as vincristine. At present, there are no effective pharmacolog...
BACKGROUND AND AIMS: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect that limits the dosage of many anticancer therapies, such as vincristine. At present, there are no effective pharmacological treatments to prevent CIPN. The Mas receptor (MasR) is expressed in the peripheral nervous system and plays a role in pain modulation. While the antinociceptive properties of MasR activation in CIPN have been documented, its potential neuroprotective effects have not been explored in the peripheral nervous system. BIO101, a highly purified form of the MasR activator 20-hydroxyecdysone, exhibits a positive safety profile in a Phase 1 study without any serious adverse events. METHODS: This study aimed to investigate the neuroprotective effects of BIO101 in a mouse model of vincristine-induced peripheral neuropathy (VIPN). Swiss mice were treated with daily doses of vincristine. VIPN was evaluated through repeated measurements of tactile sensitivity, quantification of intraepidermal nerve fibers (IENF) and dorsal root ganglion (DRG) neurons, and ultrastructural analysis of the sciatic nerve. RESULTS: Vincristine led to mechanical allodynia and reduced the density of IENF, DRG neurons, and unmyelinated nerve fibers in the sciatic nerve. Prophylactic administration of BIO101 mitigated vincristine-induced symptoms and nerve damage. The neuroprotective effect of BIO101 was nullified when the MasR antagonist A779 was administered; confirming the involvement of MasR. INTERPRETATION: Therefore, BIO101 emerges as a safe and promising preventive treatment against vincristine-induced small fiber neuropathy.
SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.
Rice AD, Tadenev ALD, Hines TJ … +2 more , Funke JR, Burgess RW
J Peripher Nerv Syst · 2025 Sep · PMID 40833344 · Full text
BACKGROUND: Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is...
BACKGROUND: Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear. AIMS: Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: Gars/CTM2D, Nefl/CMT2E, and Ighmbp2/CMT2S. METHODS: For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes. RESULTS: We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology. INTERPRETATION: Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.
Real-World Multinational Survey of Chronic Inflammatory Demyelinating Polyneuropathy: Disease Characteristics and Therapeutic Landscape.
Querol L, Rinaldi S, Borsi A … +8 more , Boggia GM, de Courcy J, Taylor Y, Wright J, Karmous W, Noel W, Gary C, Meyer Zu Hörste G
J Peripher Nerv Syst · 2025 Sep · PMID 40826893 · Full text
BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated syndrome characterized by progressive muscle weakness and sensory impairment. Clinical similarities with other neuropath...
BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated syndrome characterized by progressive muscle weakness and sensory impairment. Clinical similarities with other neuropathies can cause misdiagnoses and delayed diagnoses. Additionally, a large proportion of patients appropriately treated according to current guidelines still show residual disability. This real-world study aimed to characterize a global cohort of patients with CIDP. METHODS: Data were drawn from the Adelphi CIDP Disease Specific Programme, a cross-sectional survey with retrospective data collection, conducted in China, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States between September 2022 and April 2023. Neurologists and neuromuscular specialists reported on patient demographic and clinical characteristics at the time of the survey. Patients self-reported treatment satisfaction, disease control, and health-related outcome measures. RESULTS: Overall, 164 physicians provided data for 1056 patients, with 428 (40.5%) providing self-reported data. Patients were diagnosed with typical CIDP (69.2%) and variant CIDP (30.8%). Overall, initial misdiagnosis occurred in 37.2% of patients, with a median (interquartile range) diagnostic delay of 6.0 (3.0-12.0) months. Maintenance therapy was prescribed for 81.6% of patients, with corticosteroid use ranging from 25.7% in the United States to 80.0% in China. Some patients were dissatisfied by treatment outcomes (11.0%) and symptom control (12.2%). Overall, mean (SD) patient-reported scores were 62.1 (20.4) for I-RODS, 35.0 (11.1) for FACIT fatigue, and 0.662 (0.253) for EQ-5D-5L. INTERPRETATION: Diagnostic delay and misdiagnoses were common occurrences across typical CIDP and variant CIDP. Despite the use of guideline treatments, there were unmet needs and a continued disease burden for patients.
Impact of Social Deprivation on Diagnosis, Management and Outcome of Chronic Inflammatory Demyelinating Polyneuropathy at a Tertiary UK Centre.
Rajabally Z, Mohamed MA, Spencer L … +2 more , Mistry N, Rajabally YA
J Peripher Nerv Syst · 2025 Sep · PMID 40801213 · Full text
BACKGROUND: Whether social deprivation may affect diagnosis, management, and outcomes of subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) is unknown. METHODS: We conducted a retrospective study of s...
BACKGROUND: Whether social deprivation may affect diagnosis, management, and outcomes of subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) is unknown. METHODS: We conducted a retrospective study of subjects with CIDP attending University Hospitals Birmingham, UK. Demographics, clinical characteristics, treatment data, post-treatment outcomes and Index of Multiple Deprivation 2019 were collected. Postcodes were categorised in local vs. non-local and travelling distances to the hospital were ascertained. RESULTS: We included 155 consecutive subjects with CIDP. Mean age was 62.2 years (SD: 15.1). Male to female ratio was 1.67:1. One-hundred and eighteen subjects (76.1%) had typical CIDP. Greater pre-treatment disability was independently associated with greater social deprivation (p = 0.031) and longer pre-treatment disease duration (p = 0.001). Neither use of high-cost first-line therapies, nor immunosuppressant usage, were associated with social deprivation. Post-treatment outcomes were not associated with social deprivation. Greater social deprivation was independently associated with younger age (p = 0.002), having a local post-code (p = 0.001) and living closer to the hospital (p < 0.001). Subjects from the two most socially deprived deciles were younger (p = 0.025) and more disabled pre-treatment (p = 0.028) than those from the two least deprived deciles. Significantly fewer tertiary referrals were received for the two most socially deprived deciles compared to the two least deprived deciles (9.9% vs. 31.3%; p = 0.001). CONCLUSIONS: Despite a publicly funded healthcare system with universal access, social deprivation independently contributed to greater pre-treatment disability in subjects with CIDP in this UK cohort. Social deprivation did not impact on treatments administered and post-treatment outcomes but may have influenced tertiary referral decisions to our centre.
Influence of Genomic Ancestry and Other Traditional Risk Factors on the Prevalence of Diabetic Peripheral Neuropathy in Admixed Individuals With Type 1 Diabetes in Brazil: A Pioneer Multicenter Study.
Aguiar CH, Pedrosa HC, Tannus LRM … +5 more , Ferreira LL, Silva D, Porto LC, Negrato CA, Gomes MB
J Peripher Nerv Syst · 2025 Sep · PMID 40801171 · Full text
AIMS: To assess the influence of genomic ancestry (GA) and other traditional risk factors on the prevalence of diabetic peripheral neuropathy (DPN) in admixed Brazilian individuals with type 1 diabetes (T1D). METHODS: Th...
AIMS: To assess the influence of genomic ancestry (GA) and other traditional risk factors on the prevalence of diabetic peripheral neuropathy (DPN) in admixed Brazilian individuals with type 1 diabetes (T1D). METHODS: This cross-sectional, multicenter, pioneer study was conducted in 14 public clinics in 10 Brazilian cities. From 1760 individuals, 1732 were included (98.4%), aged 29.9 ± 11.9 years, diabetes duration 15.4 ± 9.2 years, 968 females (55.9%), 939 (55.7%) self-reported as White. DPN was evaluated by the validated neuropathy disability score (NDS) and neuropathy symptoms score (NSS). RESULTS: The prevalence of DPN was 14.8%. In hierarchical multivariate logistic regression, the covariates associated with DPN were age, diabetes duration, HbA1c, type of health care insurance, insulin therapeutic regimen, number of yearly clinical visits, low exercise practice rates, hypertension, dyslipidemia, heart rate, statin use, uric acid levels, lower health-related quality of life, presence of diabetic retinopathy, and amputations. Among the sociodemographic characteristics, African GA, a contemporary emerging factor, showed the highest association. CONCLUSIONS: DPN was related to several comorbidities, diabetes-related complications, and lower health-related quality of life. These individuals were young, implying a high lifetime cost of this disease. The association with the emerging factor African GA warrants further studies involving other admixed populations.
Neurofilament Light Chain Levels in a Large Idiopathic Peripheral Neuropathy Cohort.
Thomas S, Khan M, Sari MC … +9 more , Hu X, Lewis A, Lobana J, Mukherjee-Clavin B, Moghekar A, Morrison BM, Sumner C, Xie S, Höke A
J Peripher Nerv Syst · 2025 Sep · PMID 40799056 · Publisher ↗
BACKGROUND: Neurofilament light chain (Nf-L) has been identified as a biomarker of neurodegeneration in many neuromuscular conditions, including several subtypes of polyneuropathies. The purpose of this research was to i...
BACKGROUND: Neurofilament light chain (Nf-L) has been identified as a biomarker of neurodegeneration in many neuromuscular conditions, including several subtypes of polyneuropathies. The purpose of this research was to investigate whether Nf-L is also a promising biomarker for idiopathic peripheral neuropathy (IPN), the second most common subtype of axonal polyneuropathy. METHODS: Nf-L levels were quantified using an ultrasensitive digital immunoassay SiMoA in plasma samples from 294 subjects. Participant inclusion required a diagnosis of IPN confirmed by electrodiagnostic testing, intraepidermal nerve fiber density (IENFD), and/or neuromuscular examination. Laboratory testing recommended by the American Academy of Neurology for the evaluation of polyneuropathy was normal in all subjects. RESULTS: In our cohort, the majority of participants (78.1%, N = 228) had Nf-L levels in the age-adjusted normal range. Those with elevated Nf-L levels had higher scores on two different neuropathy severity scores and were more likely to have abnormal electrodiagnostic testing, including reduced action potential amplitude in peroneal motor and sural sensory nerves. No differences in blood Nf-L levels were observed in those participants with a short duration (≤ 1.5 years) versus long duration (≥ 5 years) of disease. Nf-L levels were also not correlated with the presence of neuropathic pain, nor the location of paresthesia. Nf-L expression had the strongest correlation with age. CONCLUSIONS: In this cohort with IPN, Nf-L levels correlated with disease severity as assessed by clinical examination and electrophysiology. However, given that Nf-L was in the normal range for the majority of subjects in our cohort, its use as a biomarker for clinical trials evaluating new treatments for IPN will be limited.
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