Journal of the Peripheral Nervous System最新文献

Objectives

There are currently no FDA-approved disease-modifying therapies for diabetic peripheral neuropathy (DPN). We evaluated the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in Type 2 diabetes mellitus (T2DM) with DPN.

Research Design and Methods

In this prospective, open-label, randomised, controlled study, 40 participants with DPN were randomised to receive add-on 10 mg dapagliflozin OD (Group A) to existing oral antidiabetic drugs (OAD) (n = 22) or continue OADs as a standard of care (Group B) (n = 18). Participants underwent assessment of neuropathic symptoms and signs (MNSI), vibration perception threshold (VPT), corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL) and skin biopsy to assess intraepidermal nerve fibre density (IENFD) and plasma markers of oxidative stress at randomisation and after 6 months.

Results

HbA1c decreased in Group A (p = 0.002) and Group B (p = 0.003), with no change in weight, body mass index (BMI) or lipids. Total MNSI increased in Group A (p = 0.01) with no change in Group B (p = 0.06). IENFD increased significantly in Group A (p = 0.01) and Group B (p = 0.01), while CNFD (p = 0.002), CNBD (p < 0.001) and CNFL (p = 0.025) increased in Group A with no change in Group B. There was a significant increase in glutathione peroxidase (p = 0.02) in Group A with no change in Group B, and a decrease in malondialdehyde in both groups (p < 0.001).

Conclusions

In participants with T2DM and DPN, dapagliflozin was associated with small nerve fibre regeneration and improvement in markers of oxidative stress.

Trial Registration: Clinical Trial Registry India, CRTI Reg. No (CTRI/2022/06/043236); ClinicalTrials.gov Identifier: NCT05162690

Background and Aims

Immune-mediated sensory neuronopathies (SNN) can occur alongside autoimmune disorders (e.g., Sjögren syndrome), involve autoantibodies (such as anti-FGFR3 or anti-AGO antibodies), or present in isolation. The underlying mechanisms remain unclear. This study aimed to investigate the role of proinflammatory cytokines in these conditions.

Methods

Blood levels of IL-1β, IL-6, IL-17, TNF-α, INF α-2, and INF-γ were measured using a Bioplex T200 platform and the Bio-Plex Pro Reagent Kit III in 113 patients with SNN between 2.4 and 464.4 months after symptom onset, categorized based on disease course (acute, subacute, chronic). Eighteen patients had anti-AGO antibodies, 48 had anti-FGFR3 antibodies, and 14 had an autoimmune disease without detectable anti-AGO or FGFR3 antibodies. Disease extent was measured by the SNN score, while the disease severity was evaluated using the modified Rankin score. Immunoreactivity against IL-6 and INF-γ was measured via ELISA.

Results

Multicomponent analysis utilizing cytokines levels identified four distinct patient subgroups characterized by differences in age at onset and SNN score. No significant differences were observed among the subgroups regarding disease course and severity, presence of anti-AGO or anti-FGFR3 antibodies, or association with an autoimmune disease. A small subgroup of three younger patients exhibited the highest levels of TNF-α, IL-6, and IL-1β. Another subgroup of seven patients displayed elevated INF α-2 levels and tended towards highest SNN scores. The largest group (95 subjects) comprised older individuals with relatively lower cytokine levels and decreased anti-IL-6 immunoreactivity.

Interpretation

These cytokine profiles suggest diverse underlying mechanisms within immune-mediated SNN. Further investigation is warranted to determine whether certain profiles, particularly those involving young patients with elevated proinflammatory cytokines, might benefit from targeted treatments.

Background and Aims

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disorder; about 20%–30% of patients do not adequately respond to first-line treatments (immunoglobulins, therapeutic plasmapheresis, and corticosteroids) posing diagnostic and therapeutic challenges.

Case Report

We report the case of a 58-year-old man diagnosed with CIDP. During follow-up, he progressively became refractory to all first-line treatments. Therefore, 20 months after the diagnosis, an add-on therapy with Rituximab was tried. Despite previous works supporting the use of Rituximab in refractory CIDP, in our case, the patient experienced relapses and progressive increases in disability. After the exclusion of potential CIDP mimics and considering the histological findings that showed complement activation, we opted for an innovative therapeutic approach with Eculizumab that granted a significant clinical and neurophysiological benefit that persists after 7 months of follow-up.

Interpretation

CIDP pathogenesis is characterized by a complex interplay of different immunopathological mechanisms, and the complement system may play a major role. The present case supports the role of complement-dependent toxicity in CIDP and suggests that complement-targeted therapies may represent a well-tolerated and effective alternative for CIDP treatment.

Background and Aims

Guillain–Barré syndrome (GBS) is an acute autoimmune peripheral neuropathy driven by autoantibodies and classical complement pathway activation. Despite treatments with intravenous immunoglobulin or plasma exchange, GBS remains characterized by variability in recovery and high incidence of residual disabilities. This randomized, double-blind, placebo-controlled Phase 1 trial evaluated the safety, tolerability, and pharmacokinetics of ANX005, a novel therapeutic targeting the classical complement cascade.

Methods

Patients with recent-onset GBS, who had no access to intravenous immunoglobulin or plasma exchange, received escalating doses of ANX005 or placebo as a single IV infusion. Primary objectives included assessments of safety. Secondary objectives included determination of pharmacokinetic and pharmacodynamic profiles and clinical outcomes through Week 8. Exploratory objectives included an evaluation of serum and cerebrospinal fluid (CSF) complement and tissue damage biomarkers.

Results

Fifty patients were randomized to receive either ANX005 (n = 38) or placebo (n = 12). ANX005 was well-tolerated across all doses with no dose-limiting toxicities, suggesting an acceptable safety profile. Pharmacodynamic data showed effective C1q inhibition and a reduction in neurofilament light chain levels, suggesting nerve damage mitigation. Exploratory endpoints evaluating clinical outcomes included improvements in Medical Research Council sum scores, GBS-Disability Score, and Overall Neuropathy Limitations Scale with ANX005 compared to placebo, particularly in patients receiving doses that inhibited serum C1q for ≥ 1 week and provided C1q blockade in the CSF.

Interpretation

These results support ANX005 as a targeted therapy for GBS that modulates the classical complement pathway. Further investigation in a larger Phase 3 trial is warranted to confirm these results and assess the long-term benefits of complement inhibition in patients with GBS.

Background and Aims

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic autoimmune neuropathy worldwide. A significant proportion of CIDP patients enter spontaneous or medication-related remission, remaining stable without immunotherapy. Overtreatment of CIDP has clinical and financial implications. We examined performance of IVIg cessation trials in our CIDP cohort and report safety and cost analysis outcomes.

Methods

In individuals with CIDP on maintenance IVIg treatment, a cessation trial was proposed in clinically stable patients with a static IVIg regimen over a 12-month period. We explored the proportion who were stable off treatment for 12 or more months and the time to recovery in those who declined and were re-treated. We examined cost implications of this approach.

Results

45/125 individuals met criteria for clinical stability, with median age 58 years, I-RODS 37/48, MRC-SS 69/70 and annual treatment costs £107 000/person. Nine individuals had cessation trials resulting in decline within 2 years prior and were not re-challenged, leaving 36 eligible individuals. 12 of 36 (33.3%) consented to cessation trial and eight of those (66.7%) remained stable off treatment for ≥ 12 months. The successful cessation trials resulted in a cost saving of £855 000/year, with a potential further saving of £1.7 million/year if all the eligible individuals had consented. All patients who deteriorated were rescued to previous baseline on retreatment.

Interpretation

Individuals with CIDP should be counselled about the natural history of the disease and future scheduled, targeted cessation trials. A dedicated clinical infrastructure is vital to safely perform cessation trials.

Background and Aims

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disorder characterized by peripheral nerve damage. Although T lymphocytes (T-cells) are implicated in the pathogenesis of CIDP, we previously observed that the frequency of highly expanded T-cell clones (HECs) in peripheral blood of CIDP patients was not different from healthy controls. To investigate if local T-cells might be pathogenic, we employed next-generation sequencing to compare the TCRβ repertoire between peripheral blood and nerve tissue of CIDP patients.

Methods

Adaptive immune receptor repertoire sequencing (AIRR-Seq) of the TCRβ chain was conducted on peripheral blood and nerve tissue obtained from three newly diagnosed CIDP patients.

Results

All patients showed high numbers of highly expanded TCRβ clones in nerve tissue that were not detected or detected only in very low frequencies in blood, whereas in blood other HECs were found. Clustering analysis based on CDR3-similarity showed that these nerve tissue-restricted TCRβ clones were distinct from blood clones, as evidenced by the absence of prominent clusters.

Interpretation

Unique nerve tissue-restricted TCRβ clones may indicate a highly localized immune response with localized expansion and/or retention of T-cells that could contribute to the pathomechanism of CIDP.

Further characterization of the phenotype, antigen target and functionality of these T-cells is essential to determine their pathogenic role.

Objective

This study aimed to assess the impact of metabolic factors and comorbidities on peripheral neuropathy.

Methods

Qatari nationals and long-term residents from the Qatar Biobank underwent clinical/metabolic assessments, including iDXA to measure visceral adipose tissue (VAT) and subcutaneous (SAT) volumes, inflammation, thyroid function, carotid intima media thickness (CIMT), corneal confocal microscopy (CCM), vibration perception threshold (VPT), and DN4 questionnaire.

Results

In 332 adults aged 43.4 ± 12.7 years, the prevalence of neuropathy was 3.9%. The prevalence of T2D was 16.6%, and the prevalence of neuropathy was significantly higher in T2D (14.5% vs. 1.8%, p < 0.0001). A higher HbA1c (p = 0.05) and lower eGFR (p < 0.01) were associated with reduced inferior whorl length (IWL) and lower FT3 was associated with reduced corneal nerve fiber length (CNFL) (p < 0.01). Triglycerides were associated with increased neuropathic symptoms (p = 0.05). All the risk factors in this study contributed to 39% of neuropathy in T2D but had a minimal impact in those without T2D.

Conclusions

This study highlights the importance of additional risk factors beyond traditional risk factors associated with peripheral neuropathy in T2D.

Background and Aims

Despite the known association of hip dysplasia and Charcot Marie Tooth disease (CMT), evidence is limited regarding its exact prevalence. Available studies pre-date genetic confirmation of CMT subtypes and current hip reconstruction surgical options. This study examined the prevalence of hip dysplasia in CMT in a tertiary neuromuscular center.

Methods

This was a retrospective study of children with CMT who had at least one pelvic radiograph between 2000 and 2020. Reimer's migration percentage, acetabular index and lateral center edge angle were used to identify hip dysplasia.

Results

A total of 178 children were included with a median age of 6.4 (IQR 3.4–11.3) years at CMT diagnosis. First pelvic radiographs were performed at a median age of 8.0 (IQR 4.6–12.2) years and 64 (35.8%) had hip dysplasia, of which 20 normalized over time. Repeat radiographs were done in 96/178 children (53.9%), and six children with originally normal radiographs developed later radiographic hip dysplasia. At the time of last follow up, 50/178 children (28.1%) had hip dysplasia and 17/178 children (9.6%) required surgical intervention. The frequency of hip dysplasia in specific CMT subtypes was: 28/100 in CMT1A, 5/7 in Dejerine-Sottas disease, 3/10 in CMT2A, and 4/4 in TRPV4-related CMT.

Interpretation

The prevalence of hip dysplasia in children with CMT in this cohort was estimated to be between 9.6% and 28.1%. Serial imaging is important to monitor outcomes into adulthood. Specific CMT subtypes were more likely to be associated with hip dysplasia.

Background and Aims

Loss of motor units in chronic inflammatory demyelinating polyneuropathy is difficult to assess by conventional nerve conduction due to collateral innervation. We aimed to assess the association between a motor unit number estimate (MUNE) derived from the compound muscle action potential (CMAP) scan using MScanFit and hand function and the clinical response to intravenous immunoglobulin (IVIG).

Methods

Forty-nine CIDP patients and 52 control subjects were included. CMAP scan recordings were obtained from the right abductor pollicis brevis muscle. The primary outcome was the correlation between MUNE and the duration of the nine-hole-peg test (9-HPT) at baseline and the change in the duration of the 9-HPT following treatment with IVIG. Secondary outcomes were grip strength, 10-m-walk test, six-spot-step test, medical research council sum score, inflammatory neuropathy cause and treatment sensory sum score, overall neuropathy limitations scale, and the Rasch-built overall disability scale (R-ODS).

Results

MScanFit analysis suggested both loss of motor units (reduced MUNE (p = 0.022) and N50 (p < 0.0001)) and collateral reinnervation (increased median amplitude (p < 0.0001) and size of the largest unit (p < 0.0001)) in CIDP patients compared to controls. In CIDP patients, there was a statistically significant correlation between MUNE and the duration of the 9-HPT (Spearman's r = −0.342; p = 0.016). Further, patients with a low MUNE had the largest reduction in the duration of the 9-HPT following IVIG treatment (r = −0.577; p = 0.043). MUNE also correlated significantly with R-ODS (r = −0.722; p = 0.007).

Interpretation

MScanFit MUNE could be a useful method for assessing motor axonal loss in CIDP, which correlates with the clinical function and treatment response.

Background and Aims

Reliable detection of antibodies against nodal targets is vital for the diagnosis of autoimmune nodopathies. The performance characteristics of recently developed in-house assays are unknown. We compared testing at four centres.

Methods

Each submitted 29–40 serum samples to a coordinating centre from one of three groups: (1) autoimmune nodopathy patients, with positive nodal/paranodal antibodies; (2) seronegative patients with other inflammatory neuropathies, and (3) healthy individuals or those with other neurological diseases. The coordinating centre recoded all samples and returned 160 identical aliquots to each testing centre for blinded testing. Once data from all centres had been received by the coordinating centre, unblinded results were returned for analysis. Sensitivity was defined by the proportion of group 1 samples returned as positive. Accuracy was defined as 0.075(sensitivity) + 0.925(specificity).

Results

Centres performed various combinations of ELISA, cell-based (CBAs) and teased-nerve fibre assays. All labs produced highly accurate results (96%–100%) and concordance for the overall result across at least 3 or all 4 test centres was observed for 98% and 89% of the samples respectively. However, 10/30 individual assays (6/14 CBAs and 4/16 ELISAs) were less than 90% sensitive. Only 3 assays had more than 1 false positive result (2 ELISAs and 1 CBA). Combining different assay modalities to produce an overall result did not improve accuracy. Inter-laboratory consistency in the determination of antibody subclasses was poor.

Interpretation

Although most samples were correctly categorised in all 4 centres, the use of a specific test modality or multiple tests did not guarantee accuracy. Early and repeated interlaboratory testing with sharing of samples is important to understand test performance and reproducibility, identify areas for improvement and maintain consistency. To aid this, we provide detailed methods for the best performing tests. Further standardisation of antibody subclass determination is required.