Oberoi V, Campbell JO, Akpabli-Tsigbe N
… +10 more, Imran F, Bond S, Tenlep SN, Brennan CD, Wang M, Saxena S, Moss KR, Li DP, Arnold WD, Castoro R
J Peripher Nerv Syst
· 2026 Mar · PMID 41795901
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BACKGROUND: Thermoceptive dysfunction is a frequent but understudied feature of peripheral neuropathies and aging. Patients often report abnormal heat perception, yet the underlying sensory mechanisms remain unclear. Thi...BACKGROUND: Thermoceptive dysfunction is a frequent but understudied feature of peripheral neuropathies and aging. Patients often report abnormal heat perception, yet the underlying sensory mechanisms remain unclear. This study evaluated thermoceptive behavior and corresponding structural changes in mouse models of inherited dysmyelinating neuropathy and natural aging to identify shared and divergent mechanisms. METHODS: Thermal preference was assessed using a user-independent gradient apparatus spanning physiological to noxious temperatures, with automated quantification of time in zone, distance traveled, and velocity. Nocifensive responses were evaluated by hot plate latency. Intraepidermal nerve fiber density (IENFD) was measured in paw pads, and TRPV1-positive dorsal root ganglion (DRG) neurons were analyzed by immunofluorescence and confocal imaging. RESULTS: Thermal gradient testing revealed preserved temperature preference in CMT1A and HNPP mice but significantly altered behavior in aged animals, which spent less time in warmer zones. Hot plate testing showed prolonged times to nocifensive behavior in aged and CMT1A mice, whereas HNPP mice exhibited variable responses. IENFD was markedly reduced in aged mice but preserved in CMT1A and HNPP. DRG analysis revealed smaller soma diameters and reduced proportions of TRPV1-positive Aδ neurons in aged mice, while CMT1A animals maintained normal morphology. INTERPRETATION: Aging produces thermoceptive deficits through axonal degeneration and selective Aδ-fiber vulnerability, whereas CMT1A mice display conduction-related impairment due to dysmyelination. Both models reproduce key human sensory phenotypes and provide translational platforms for studying small-fiber dysfunction and therapeutic interventions in peripheral neuropathies.
Koutsis G, Kontogeorgiou Z, Tzempetzis C
… +9 more, Ragazos N, Efthymiou E, Kartanou C, Koniari C, Giagkou N, Chatzistefanou K, Velonakis G, Karadima G, Zouvelou V
J Peripher Nerv Syst
· 2026 Mar · PMID 41782179
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BACKGROUND AND AIMS: CMT1H is a rare, autosomal dominant, demyelinating subtype of CMT caused by variants in FBLN5. Symptomatic cranial nerve involvement has never been reported in patients with CMT1H. CASE REPORT: We re...BACKGROUND AND AIMS: CMT1H is a rare, autosomal dominant, demyelinating subtype of CMT caused by variants in FBLN5. Symptomatic cranial nerve involvement has never been reported in patients with CMT1H. CASE REPORT: We report a 45-year-old woman with a history of long-standing diplopia. On examination, she had bilateral limitation of eye abduction, with double vision in all directions of gaze, particularly horizontally. She was unable to heel-walk, had mild lower limb distal weakness, decreased tendon reflexes with absent Achilles reflexes, reduced distal vibration sense, pes cavus, and hammertoes. A dominant family history was noted. Brain MRI revealed bilateral contrast enhancement and thickening of cranial nerves III through XII. Genetic testing with whole exome sequencing revealed a known, recurring, heterozygous, likely pathogenic missense variant in FBLN5 [c.1117C>T; p. (Arg373Cys)], consistent with a diagnosis of CMT1H. INTERPRETATION: This is the first reported case of FBLN5-related CMT1H with symptomatic cranial nerve involvement, expanding the known phenotypic spectrum of the disease.
Senanayake B, Rajaratnam A, Thennakoon T
… +2 more, Ekanayake N, Ruwanpathirana P
J Peripher Nerv Syst
· 2026 Mar · PMID 41732033
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BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is classically a monophasic illness. In resource-limited settings, patients with GBS are not routinely followed up. However, these patients may suffer from residual symp...BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is classically a monophasic illness. In resource-limited settings, patients with GBS are not routinely followed up. However, these patients may suffer from residual symptoms and disability. In this study, we assessed the trajectory of recovery and burden of residual symptoms in patients who developed GBS. METHODS: This prospective cohort study was conducted at the National Hospital of Sri Lanka from January 1, 2020 to April 1, 2025. We assessed the patients during the illness and then at 1, 3, and 6 months after discharge. The primary outcome was the GBS Disability Score (0 [no disability]-6 [death]), and the secondary outcomes were the individual residual symptoms. All patients with GBS were included. The serial improvement of the GBS Disability Score was assessed using the generalized equation estimate. The burden of residual symptoms was given as percentages. RESULTS: We included 144 patients with GBS (mean age 46.2 ± 17.3 years; male:female 0.92), and 67 completed the follow-up. There was no in-hospital mortality; one patient (1.5%) died within 6 months. The disability improved significantly, with only 5.9% unable to walk independently at 6 months. Increasing age and axonal variants (AMAN/AMSAN, 37%) were independent negative predictors of recovery. The residual symptoms at 6 months included positive sensory symptoms (42.6%), fatigue (30.9%), and subjective limb weakness (29.4%). Forty-eight percent had to make some change in their occupation. INTERPRETATION: Although many patients achieve motor recovery, there is a high burden of residual symptoms at 6 months in patients with GBS.
Rahman M, Papri N, Mohammed A
… +5 more, Hasan I, Sultana S, Jahan I, Hayat S, Islam Z
J Peripher Nerv Syst
· 2026 Mar · PMID 41732002
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BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is an acute post-infectious autoimmune neuropathy, frequently triggered by antecedent infections. While climate influences the seasonality and distribution of infections...BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is an acute post-infectious autoimmune neuropathy, frequently triggered by antecedent infections. While climate influences the seasonality and distribution of infections, its role in triggering GBS remains underexplored. We aimed to evaluate the impact of climatic and geographical variations on infections preceding GBS in Bangladesh. METHODS: Five hundred and sixty-six GBS patients were enrolled from four prospective cohorts (2010-2024). Antecedent events were recorded within 4 weeks of weakness onset. Meteorological data were retrieved from the World Bank's Climate Change Knowledge Portal (2010-2020) and Bangladesh Meteorological Department (2021-2024). Patients were categorized by regions (northern, central, southwestern, and eastern), seasons (summer, autumn, winter, spring). Analysis were performed in R using chi-square, t-tests, Kaplan-Meier, and multivariable logistic regression. RESULTS: Among 566 patients (69% male, median age: 31 years). Antecedent events were reported in 70%, predominantly GE (46%) and URTI (19%). The axonal subtype predominated (64%), with 31% receiving intravenous immunoglobulin or plasma exchange. GE was associated with higher disability (GBS-DS = 4, 61% vs. 46%, p = 0.014) and cranial nerve involvement (57% vs. 43%, p = 0.017) compared to URTI. GE peaked during spring (31%) and URTI in winter (35%, p = 0.009), with no subtype-season association after adjustment (p = 0.180). GE occurred more at higher mean temperatures (26.06°C vs. 25.05°C, p = 0.048) and at higher precipitation (162.65 mm vs. 105.04 mm, p = 0.0001). GE cases correlated positively, while URTI inversely, with temperature (r = 0.185) and precipitation (r = 0.053). INTERPRETATIONS: Warmer temperature and higher precipitation, particularly spring and summer, favor GE-related GBS. Further studies are warranted to explore climate-sensitive infectious triggers of GBS in Bangladesh.
Hu N, Li J, Guan H
… +6 more, Zhao Y, Ren H, Guan Y, Liu M, Qian M, Chen L
J Peripher Nerv Syst
· 2026 Mar · PMID 41693239
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OBJECTIVE: To compare the pathological features of patients with different forms of vasculitic neuropathy (VN). METHODS: Patients with clinically probable VN were enrolled. Clinical characteristics and ancillary examinat...OBJECTIVE: To compare the pathological features of patients with different forms of vasculitic neuropathy (VN). METHODS: Patients with clinically probable VN were enrolled. Clinical characteristics and ancillary examinations were collected and evaluated. Nerve biopsies were performed. RESULTS: A total of 48 patients with VN were involved, including 20 primary systemic VN (PSVN), 17 secondary systemic VN (SSVN), and 11 non-systemic VN (NSVN). Patients that fulfilled the pathologically definite, probable, and possible VN were 20 (41.67%), 8 (16.67%), and 12 (25.00%), respectively. The frequencies of acute vascular damage showed no significant difference across three subgroups (PSVN 80.00%, SSVN 82.35%, NSVN 90.91%). Chronic vascular damage was more frequently observed in PSVN (90.00%) and SSVN (76.47%) than in NSVN (54.55%) with no significance. Perivascular inflammatory cell infiltration in the endoneurium was more common in NSVN (45.45%) than PSVN (15.00%, p = 0.004) and none with SSVN (0.00%, p = 0.002). CONCLUSION: The overall rate of pathologically definite and probable VN in nerve biopsy was 58%. Acute vascular lesion is commonly seen in all forms of VN, while chronic vascular damage is more frequently observed in SVN. Perivascular inflammatory cell infiltration in the epineurium is primarily found in NSVN. SIGNIFICANCE: The study further elucidated the clinical significance of nerve biopsy in VN.
Wang AC, Lee MC, Fan HC
… +3 more, Wang MH, Chou CH, Wu PY
J Peripher Nerv Syst
· 2026 Mar · PMID 41668414
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BACKGROUND AND AIMS: Immune cells and circulating inflammatory proteins play crucial roles in chronic inflammatory demyelinating polyneuropathy (CIDP) pathogenesis. However, the causal associations between these factors...BACKGROUND AND AIMS: Immune cells and circulating inflammatory proteins play crucial roles in chronic inflammatory demyelinating polyneuropathy (CIDP) pathogenesis. However, the causal associations between these factors and CIDP remain unclear. Herein, we aimed to explore these associations using a two-sample, two-step Mendelian randomization (MR) approach. METHODS: Two-sample MR analysis was conducted using genome-wide association studies data to assess links between immune cells, inflammatory proteins, and CIDP. Data on 731 immune cell traits were obtained from a cohort of 3757 Sardinians, 91 inflammatory proteins from 14 824 Europeans across 11 cohorts, and CIDP data from 456 348 Europeans in the UK Biobank. Fixed-effect inverse variance weighted and Bayesian-weighted MR methods were used, along with a two-step MR to assess mediation effects. Sensitivity analyses were performed to check for horizontal pleiotropy and heterogeneity. RESULTS: Twenty-five immune cell traits were found to be significantly associated with CIDP. Of these, 17 immunophenotypes increased CIDP risk, whereas 8 were protective. Among inflammatory proteins, cystatin D (CST5) and interleukin-18 (IL-18) were linked to CIDP risk. Although not statistically significant, CST5 appeared to partially mediate the association between CD8+ NKT %T cells and CIDP (OR, 1.006; 95% CI, 1.00-1.02), accounting for approximately 3% of the mediation effect. INTERPRETATION: Our findings highlight several novel immune cell and inflammatory protein interactions implicated in CIDP. These results present new immune targets for future CIDP therapies.
Doneddu PE, Collet-Vidiella R, Gallo C
… +16 more, Cocito D, Manganelli F, Falzone Y, Bella ED, Benedetti L, Mazzeo A, Peci E, Spina E, Strano C, Germano F, Gentile L, Liberatore G, Cutellè C, Bianchi E, Querol L, Nobile-Orazio E
J Peripher Nerv Syst
· 2026 Mar · PMID 41649095
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BACKGROUND AND AIMS: Rituximab has been proposed as a potential treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but formal evidence regarding its clinical effectiveness is weak. The CIDPRIT...BACKGROUND AND AIMS: Rituximab has been proposed as a potential treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but formal evidence regarding its clinical effectiveness is weak. The CIDPRIT trial found no clinical benefit in comparison with placebo, but secondary analyses suggested some beneficial effect. Analysis of serum neurofilament light chain (sNfL) may provide evidence to support rituximab's effect on CIDP patients. METHODS: We performed a post hoc analysis of sNfL levels from the CIDPRIT trial participants. Blood samples were collected at baseline, month 6, and 12. sNfL was measured using Simoa technology. Geometric means and z-scores were compared across groups. Linear mixed-effects models and survival analyses were used to evaluate treatment effects and clinical correlations. RESULTS: 33 participants were included (18 rituximab, 15 placebo). Baseline sNfL was significantly higher in the rituximab group (11.51 vs. 6.67 pg/mL, p = 0.019). While between-group differences over time were not statistically significant, rituximab-treated patients showed stable sNfL levels at month 6 and a slight decrease at month 12, contrasting with modest increases in the placebo group. Among rituximab-treated patients who remained clinically stable at month 12, sNfL showed a non-significant decline by 31%. No significant associations were found between baseline sNfL and clinical worsening. NfL levels correlated with neurophysiological parameters of axonal damage. INTERPRETATION: The analysis did not demonstrate biomarker-based evidence of rituximab efficacy in CIDP. However, observed trends suggest a possible biological effect in reducing axonal injury in a subset of patients. Further studies are needed to clarify the role of sNfL in treatment monitoring and patient stratification.
Loser V, Benkert P, Vicino A
… +7 more, Ghika N, Ferrière PLD, Daigneault C, Kuntzer T, Maceski AM, Kuhle J, Théaudin M
J Peripher Nerv Syst
· 2026 Mar · PMID 41640232
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BACKGROUND AND AIMS: In individuals with hereditary transthyretin amyloidosis (ATTRv) polyneuropathy, monitoring of disease progression and treatment response is crucial. The objective is to determine if serum neurofilam...BACKGROUND AND AIMS: In individuals with hereditary transthyretin amyloidosis (ATTRv) polyneuropathy, monitoring of disease progression and treatment response is crucial. The objective is to determine if serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are reliable biomarkers of ATTRv polyneuropathy. METHODS: We included 48 ATTRv individuals (38 symptomatic, 10 asymptomatic). Yearly assessments (over 4 years) included a full clinical examination with disease severity and functional scores, electrochemical skin conductance, nerve conduction studies, and measurement of sNfL and sGFAP levels. Using a reference database, sNfL and sGFAP were converted to Z-scores (zNfL and zGFAP). RESULTS: Median zNfL was -0.50 in asymptomatic, 1.44 in converters, and 2.46 in symptomatic subjects. zNfL > 1.42 discriminated symptomatic from asymptomatic subjects (AUC 0.936), not zGFAP (AUC 0.588). zNfL, not zGFAP, correlated with most clinical and electrophysiological neuropathy severity scales. Two asymptomatic carriers became symptomatic during follow-up. In one of them, a significant rise in zNfL occurred 1 year before symptomatic transition. INTERPRETATION: In ATTRv, zNfL correlates with neuropathy severity and symptomatic transition. A zNfL > 1.42 may discriminate symptomatic from asymptomatic subjects. zGFAP is not a reliable biomarker of polyneuropathy in ATTRv. Routine use of NfL should be based on deviation measure such as Z-score.
Song J, Kokubun N, Qiao B
… +2 more, Wang Y, Yuki N
J Peripher Nerv Syst
· 2026 Mar · PMID 41631567
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BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is categorized into acute inflammatory demyelinating polyneuropathy (AIDP) and axonal GBS. Bifacial weakness with paresthesias (BFP) is regarded as a rare regional varia...BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is categorized into acute inflammatory demyelinating polyneuropathy (AIDP) and axonal GBS. Bifacial weakness with paresthesias (BFP) is regarded as a rare regional variant of AIDP, yet its electrophysiological characteristics remain inadequately defined. This study aimed to clarify the pathophysiological basis of BFP and its classification under AIDP through serial nerve conduction study (NCS) analysis. METHODS: NCS data of six patients diagnosed with BFP were retrospectively analyzed. Four patients underwent serial NCSs, while two received a single NCSs. The electrophysiological criterion for AIDP diagnosis was applied to data from both single and serial studies. RESULTS: Five of the six patients were classified with AIDP. Among the two with a single NCS, one was classified with AIDP and another with equivocal. All four patients with serial NCSs ultimately met AIDP criteria, with three showing demyelination initially and one progressing from equivocal. Three showed temporal evolution of demyelinating features. INTERPRETATION: Our study demonstrates a demyelinating nature of BFP. Repeated NCS over time enhance the probability of identifying de- and re-myelination process, characterizing the underlying pathophysiology of BFP patients.
Cebulla N, Schirmer D, Runau E
… +16 more, Flamm L, Terhorst C, Jähnel L, Güse J, Giordani N, Wieser A, Schoch F, Reinle ML, Gommersbach S, Papagianni A, Zhou X, Einsele H, Reinhold AK, Rittner H, Kortüm KM, Sommer C
J Peripher Nerv Syst
· 2026 Mar · PMID 41578688
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BACKGROUND AND AIMS: Bortezomib-induced peripheral neuropathy (BIPN) remains a common treatment side effect in patients with multiple myeloma (MM). Data from rodent models indicate a role of proinflammatory cytokines in...BACKGROUND AND AIMS: Bortezomib-induced peripheral neuropathy (BIPN) remains a common treatment side effect in patients with multiple myeloma (MM). Data from rodent models indicate a role of proinflammatory cytokines in BIPN pathophysiology, making them potential therapeutic targets. We therefore tested cytokine levels throughout the course of BIPN in a cohort of MM patients. METHODS: We performed an interim analysis of a monocentric, non-randomized, observational study including 113 patients with MM. Three groups of patients-within their first cycle of BTZ treatment (FC), with ongoing BTZ treatment at the time of recruiting (OT), and with BTZ treatment in the past (PT)-were compared to controls. Sixteen FC patients were followed up for a median of 6 months. Serum TNF-α, IL-6, and CCL2, the cytokines most often implied in the animal models, were analyzed via the ELLA device. RESULTS: CCL2 levels were not different among our patient groups or in comparison with healthy controls. Compared to healthy controls, the FC group had the highest IL-6 levels, followed by the PT and then the OT group. The FC group also had higher TNF-α levels compared to all other groups. Six months after inclusion, patients showed a decrease in TNF-α levels compared to their baseline. There was no correlation between TNF-α levels and neuropathy severity or impairment in daily life. INTERPRETATION: Factors related to MM may influence systemic cytokine levels in BIPN patients, limiting conclusions on their role in BIPN pathophysiology and their utility as drug targets.
Galiá-Llaña R, Ronda-Rojas D, Del Solar-Benavides A
… +5 more, Otto-Yáñez M, Torres-Castro R, Vera-Uribe R, Fregonezi G, Rivera-Lillo G
J Peripher Nerv Syst
· 2026 Mar · PMID 41578680
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BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. A Chilean study for 2001-2012 reported an age-standardized incidence of 2.10 per 100 000. We updated nationwide GBS inci...BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. A Chilean study for 2001-2012 reported an age-standardized incidence of 2.10 per 100 000. We updated nationwide GBS incidence for 2013-2022 by sex, age, and macrozone. METHODS: We conducted a retrospective, population-based analysis of the Chilean Department of Statistics and Health Information (DEIS) hospital-discharge database. Cases were identified with the ICD-10 code G61.0 and deduplicated. Incidence rates (IRs) per 100 000, using official mid-year populations, were age-standardized to the World Health Organization standard and stratified by sex, 10-year age groups, and five macrozones. RESULTS: We identified 5096 discharges. The period crude IR was 2.73, and the age-standardized IR was 2.60 per 100 000. Annual standardized IRs ranged from 3.15 (2013) to 2.03 (2020). Men comprised 58.6% of cases; period IRs were 3.25 in males versus 2.34 in females. Age-specific IRs rose from 2.47 at 0-9 years to 5.76 at 70-79, then declined (3.63 at 80-89; 1.04 at ≥ 90). Regionally, IRs were lowest in the Far North (1.86) and North (2.26), intermediate in the Central zone (2.51), and highest in the South (4.55) and Far South (4.86). INTERPRETATION: In 2013-2022, Chile's GBS incidence remained high by international standards and higher than in 2001-2012, with persistent male predominance, a peak among older adults, and a southward gradient. These updated background rates inform service planning, surveillance, and vaccine-safety assessment, and support integrated epidemiologic-microbiologic studies across macrozones.
Briani C, Massarotti L, Branca A
… +16 more, Rossato M, Berno T, Visentin A, Castellani F, Dalla Torre C, Lucchetta M, Rosso T, Burlina A, Librizzi G, Pagano C, Marasca M, Vianello F, Zambello R, Trentin L, Salvalaggio A, Manara R
J Peripher Nerv Syst
· 2026 Mar · PMID 41578669
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BACKGROUND AND AIMS: Brain pachymeningeal thickening (PT) is common in POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome. Objective of our study was to assess PT changes i...BACKGROUND AND AIMS: Brain pachymeningeal thickening (PT) is common in POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome. Objective of our study was to assess PT changes in POEMS and correlation with hematologic and neurological response. METHODS: We performed a longitudinal brain MRI study on 18 POEMS patients. Inflammatory Neuropathy Cause and Treatment (INCAT) disability score assessed neurological impairment. Hematologic response was defined based on accepted criteria. Neurological and hematologic evaluations were performed the same week as brain MRI. RESULTS: Median disease duration at first MRI was 2 months (range 0-42). Median follow-up between first and last MRI was 44 months (range 3-167). At first MRI, 17/18 patients displayed PT. Twelve patients received bortezomib, 10 lenalidomide, 6 autologous stem-cell transplantation, 3 had ≥ 3 lines of therapy. The overall hematologic response was 72% with 44% achieving complete response. PT remained stable in 10 patients while decreased in 7 patients: all hematologically improved, 83% also neurologically improved. Among the 13 patients with hematologic improvement, 61% showed PT reduction. Among the 8 patients with neurological improvement, 63% displayed PT decrease. INTERPRETATION: PT is a common feature in POEMS syndrome and may support diagnosis. However, its evolution does not reliably reflect treatment response, limiting its use as a monitoring biomarker.
Vidon RO, Tomaselli PJ, Bittar-Braune C
… +3 more, Pitta IJ, de Lacerda GCB, Jardim M
J Peripher Nerv Syst
· 2026 Mar · PMID 41562385
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BACKGROUND AND AIMS: Biallelic pathogenic variants in PLEKHG5 are associated with two distinct recessive phenotypes, including distal hereditary motor neuropathy AR type 4 and intermediate Charcot-Marie-Tooth disease typ...BACKGROUND AND AIMS: Biallelic pathogenic variants in PLEKHG5 are associated with two distinct recessive phenotypes, including distal hereditary motor neuropathy AR type 4 and intermediate Charcot-Marie-Tooth disease type C (CMT). No South American cases have been previously reported. METHODS: We evaluated a male patient with suspected hereditary neuropathy using clinical, electrophysiological, and genetic studies. RESULTS: Symptoms began at 12 years with progressive distal weakness. At 40 years, he had foot drop, pes cavus, distal atrophy, areflexia, and sensory loss to the knees. Disability scales indicated moderate impairment. Electroneuromyography revealed abolished responses in the lower limbs and motor conduction velocities in the intermediate range (35-40 m/s). Genetic analysis identified the homozygous variant c.59G>A (p.Arg20Gln) in PLEKHG5, currently classified as VUS. INTERPRETATION: This reports presents a case from South American linking a homozygous PLEKHG5 variant to recessive intermediate CMT, expanding the geographic and phenotypic spectrum of PLEKHG5-related neuropathies.
Bjelica B, Hendrich C, von Hardenberg S
… +6 more, Vukojevic M, Körner S, Gschwendtberger T, Haghikia A, Peric S, Petri S
J Peripher Nerv Syst
· 2026 Mar · PMID 41549766
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BACKGROUND AND AIMS: Differentiating hereditary axonal polyneuropathies caused by distinct gene variants remains a clinical challenge. This comparative case study of DNAJB2- and HINT1-related neuropathies aimed to broade...BACKGROUND AND AIMS: Differentiating hereditary axonal polyneuropathies caused by distinct gene variants remains a clinical challenge. This comparative case study of DNAJB2- and HINT1-related neuropathies aimed to broaden the phenotypic spectrum associated with these genes and to explore non-motor symptoms and quality of life (QoL) in affected individuals. METHODS: Six patients carrying two novel DNAJB2 variants and six age-matched patients with HINT1 variants underwent detailed clinical and electrophysiological characterization. Motor function was assessed longitudinally using the Medical Research Council (MRC) scale. Non-motor symptoms (neuropathic pain, autonomic dysfunction, depression, fatigue, restless legs syndrome) and QoL were evaluated with patient-reported outcomes and compared to four healthy controls (HC). RESULTS: Both patient groups exhibited a CMT2 phenotype. Nerve conduction studies revealed a length-dependent axonal predominantly motor but not pure motor neuropathy in most of the patients. Disease onset tended to occur later in patients with DNAJB2 variants, who yet developed more severe neuropathy. The spectrum of additional clinical features differed between the two groups. All patients with DNAJB2 variants fulfilled criteria for depression, compared with one with a HINT1 variant. Significant fatigue was present in the majority of both groups, while restless legs syndrome was observed in four patients with a DNAJB2 variant but in none with a HINT1. QoL was significantly reduced in DNAJB2 versus HC, with no difference in QoL between patients with DNAJB2 and HINT1 variants. INTERPRETATION: This study expands the clinical spectrum of DNAJB2- and HINT1-related neuropathies, highlighting distinct non-motor features and their impact on QoL, and providing the first direct comparison of these two rare axonal disorders.
Vatavu O, Ciletti S, Innocenti N
… +4 more, Cojazzi VML, Devigili G, Moscatelli M, Nazzi V
J Peripher Nerv Syst
· 2026 Mar · PMID 41549412
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BACKGROUND: Persistent Sciatic Artery (PSA) is a rare congenital vascular anomaly, affecting 0.05% of the population. It arises from the failure of regression of the embryonic sciatic artery, which normally recedes as th...BACKGROUND: Persistent Sciatic Artery (PSA) is a rare congenital vascular anomaly, affecting 0.05% of the population. It arises from the failure of regression of the embryonic sciatic artery, which normally recedes as the superficial femoral artery (SFA) becomes dominant in lower limb perfusion. In cases of persistence, the sciatic artery remains as a continuation of the internal iliac artery. PSA is classified based on its persistence and anatomical relationship with the SFA and is associated with complications such as limb ischemia, aneurysmal degeneration, and thromboembolism, which may clinically manifest as gluteal pain, claudication, or acute ischemia. RESULTS: We describe the case of a 50-year-old woman with a longstanding history of left-sided sciatica and paresthesia, refractory to medical therapy. Neurological examination revealed a positive Tinel's sign along the course of the sciatic nerve, and imaging studies confirmed a Pillet-Gauffre type 1 PSA, in close anatomical contiguity with the nerve. Angio-CT excluded associated aneurysmal changes. In the absence of motor involvement, a conservative management strategy was adopted, with referral for vascular surgical evaluation. INTERPRETATION: Sciatic nerve compression secondary to PSA is exceedingly rare, with most documented cases attributed to aneurysmal dilation exerting mass effect. Electrophysiological features of PSA-related sciatic neuropathy are unreported. This case emphasizes the possibility of including PSA within the differential diagnosis of sciatic pain, particularly when conventional aetiologies have been excluded. Recognition of this vascular anomaly is essential for accurate diagnosis and appropriate management, as surgical intervention does not uniformly result in symptoms resolution.
Thomas S, Ben-Davies R, Cetinkaya-Fisgin A
… +9 more, Hu X, Li X, Stewart S, Pan B, Twiss JL, Ratan RR, Willis D, Polydefkis M, Höke A
J Peripher Nerv Syst
· 2026 Mar · PMID 41502156
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BACKGROUND AND AIMS: Recent preclinical studies have shown that nicotinamide adenine dinucleotide (NAD) plays a critical role in molecular mechanisms of axon degeneration, and reductions in NAD levels are associated with...BACKGROUND AND AIMS: Recent preclinical studies have shown that nicotinamide adenine dinucleotide (NAD) plays a critical role in molecular mechanisms of axon degeneration, and reductions in NAD levels are associated with axonal degeneration. Nicotinamide riboside (NR) is a safe and widely available pyridine-nucleoside form of vitamin B3 and is an NAD precursor. METHODS: To investigate if oral supplementation of synthetic NR can act as a therapeutic agent to prevent degeneration of small somatic sensory axons innervating the skin or promote regeneration of these same fibers in humans, we utilized a validated experimental model of cutaneous nerve degeneration and regeneration and conducted a placebo-controlled, double-blinded Phase 2 study. RESULTS: NR supplementation did not result in elevation of plasma NAD levels but resulted in a small increase in NAD in the skin samples. NR supplementation did not prevent capsaicin-induced degeneration of the epidermal sensory nerve fibers, and there was no difference in the amount of epidermal reinnervation at the 90-day visit. Although there was a small but statistically significant increase in the number of epidermal sensory nerve fibers at the 60-day visit, these results are preliminary and will need to be validated in larger studies. INTERPRETATION: At present oral NR supplementation, at the doses used in this study, cannot be recommended to prevent neuropathy or to improve nerve regeneration.
Maximiano-Alves G, Lavigne-Moreira C, Simões MV
… +8 more, Galvão AJP, Valicelli FH, Coneglian FS, Vegezzi E, Garibaldi PMM, Tomaselli PJ, Cortese A, Marques W
J Peripher Nerv Syst
· 2026 Mar · PMID 41498649
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BACKGROUND: Transthyretin hereditary amyloidosis (ATTRv) clinical variability has been widely reported, not only across countries and variants but also among families and distinct regions within a single nation. One of t...BACKGROUND: Transthyretin hereditary amyloidosis (ATTRv) clinical variability has been widely reported, not only across countries and variants but also among families and distinct regions within a single nation. One of the principal challenges in disease management is the accurate determination of age of onset (AOO), which is heterogeneous and has therapeutic implications given the availability of disease-modifying treatments. METHODS: This study characterizes the genetic landscape and clinical onset spectrum of ATTRv in an admixed Brazilian cohort of 175 patients. RESULTS: Seven TTR pathogenic variants (p.Val50Met, p.Val142Ile, p.Ile127Val, p.Ile88Leu, p.Ala39Asp, p.Phe84Leu, p.Tyr98Phe) were identified. The most common was p.Val50Met (58.8%), followed by p.Val142Ile (29.7%) and p.Ile127Val (7.4%). Notably, 44% of V122I had a neurological onset. Close clinical monitoring of presymptomatic carriers reduced age at diagnosis by 10.5 years. The median AOO was 50 years, with V30M patients presenting earlier (38.5 years) than V122I (p.Val142Ile) (60y) and I107V (p.Ile127Val) (60 years). Familial cases showed a 20.5-year earlier AOO than sporadic cases. In Brazil, late-onset (> 50 years) V30M is more common than previously reported (37.5%); ethnicity can influence AOO within the same variant, and for the first time, we show a distinct geographic pattern: early-onset V30M is more frequent in São Paulo/South, whereas late-onset V30M predominates in the central region. INTERPRETATION: This study emphasizes the heterogeneity of ATTRv presentation in admixed populations and underscores the need for expanded screening and multicenter studies to refine genotype-phenotypic correlations.
Sekiguchi Y, Misawa S, Morooka M
… +4 more, Suichi T, Shiko Y, Takahashi K, Kuwabara S
J Peripher Nerv Syst
· 2026 Mar · PMID 41492176
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BACKGROUND: The modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) has been proposed to be a useful tool for predicting the risk of mechanical ventilation (MV) in Guillain-Barré syndrome (GBS), whereas most of...BACKGROUND: The modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) has been proposed to be a useful tool for predicting the risk of mechanical ventilation (MV) in Guillain-Barré syndrome (GBS), whereas most of the patients included in previous studies had classical demyelinating GBS. This study validated the utility of the mEGRIS in axonal, as well as demyelinating GBS, defined by electrophysiologic criteria in Japan. METHODS: Data from 214 consecutive patients diagnosed with GBS at our institution within 28 days from disease onset between 1998 and 2023 were reviewed and 200 patients with adequate data were analyzed. Acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) were diagnosed by sequential nerve conduction studies and mEGRIS was applied to each group. RESULTS: A total of 200 GBS patients were classified as AMAN (n = 73 [37%]), AIDP (n = 72 [36%]), or unclassified (n = 55 [28%]) and 27 (14%) patients required MV (18% of AMAN, 15% of AIDP). Patients with MV had a significantly higher mEGRIS than those without MV (17 [median range: 5-29] vs. 6 [0-22]). Approximately 81% of the patients in the moderate- or high-risk group (mEGRIS ≧ 18) required MV. Area under the curves (AUCs) of the mEGRIS prediction formulas was 0.89 (95% CI, 0.82-0.96) for total GBS group and 0.92 (95% CI, 0.85-1.00) for the AMAN group. INTERPRETATION: The mEGRIS is useful for predicting MV risk in patients with AMAN, as well as AIDP. Close monitoring was required for patients who were classified as moderate or high-risk by mEGRIS, irrespective of GBS subtypes.
Wright B, Eiffert SR, Cirincione A
… +3 more, Nardin J, Howard JF, Traub RE
J Peripher Nerv Syst
· 2026 Mar · PMID 41466101
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BACKGROUND AND AIMS: Understanding of population-level outcomes for patients with Guillain-Barré syndrome (GBS) remains limited. We identified which GBS patients are most likely to experience worse outcomes using the lar...BACKGROUND AND AIMS: Understanding of population-level outcomes for patients with Guillain-Barré syndrome (GBS) remains limited. We identified which GBS patients are most likely to experience worse outcomes using the largest and most current GBS cohort in the United States. METHODS: This retrospective cohort study used 2005-2020 fee-for-service Medicare claims to identify individuals newly diagnosed with GBS (N = 16 280). We used three person-level modified Poisson regressions to estimate hospital and intensive care unit (ICU) lengths of stay and GBS episode length as a function of sociodemographic characteristics, comorbid conditions, and year of diagnosis. We also documented hospital-acquired pressure ulcers and deep vein thromboses as quality indicators. RESULTS: Median hospital length of stay was 9 days [IQR: 6-18 days] and median GBS episode length was 26 days [IQR: 10-60 days]. Approximately 43% of patients spent time in the ICU, with most of those stays (57%) lasting ≤ 1 week. On average, stays and episodes were significantly longer for men, those with a disability, and those diagnosed with an impulse control disorder, other nervous system diagnoses, or certain cancers, but significantly shorter for Black individuals and those dually eligible for Medicare and Medicaid. Most patients avoided developing pressure ulcers (96%) or deep vein thromboses (91%). INTERPRETATION: The GBS disease course varies significantly among Medicare enrollees. We identified some factors associated with worse GBS outcomes and others suggesting structural barriers to care. Our findings can improve care delivery by helping clinicians identify high-risk patients, facilitate early interventions, and reduce morbidity and mortality.