Neuromuscular disorders are a very heterogeneous group of diseases and comprise a large number of patients. Epidemiological key figures on incidence, prevalence and mortality serve as basic information for individualised and public health care and researchers. Geographical mapping of the specific disorders is expected to provide valuable insights into clustering of the conditions, which points to possible environmental and genetical determinants. So far, mostly geographical maps of motor neuron diseases have been reported. By using record information from the Dutch nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) we aimed to generate geographical maps for eight disorders predominantly diagnosed in adults.We investigated the geographical distribution of newly diagnosed patients in the Netherlands from 2004-2011. The variables used were diagnosis, date of diagnosis, and the first two digits of the postal code for geographical location from CRAMP. The number of incident cases was divided by the total number of people populating the postal code area.Nationwide incidence maps were constructed for myotonic dystrophy, progressive (spinal) muscular atrophy, chronic inflammatory demyelinating polyneuropathy, facioscapulohumeral muscular dystrophy, inclusion body myositis, hereditary motor and sensory neuropathy, Pompe disease and oculopharyngeal muscular dystrophy. Considerable regional variation between disorders was observed, particularly for myotonic dystrophy and facioscapulohumeral muscular dystrophy.We provided the first neuromuscular atlas of the Netherlands with maps for eight disorders commonly seen in the neuromuscular practice. To address possible outliers due to low population numbers, Bayesian smoothing techniques should be considered in future research.

BACKGROUND AND OBJECTIVES:Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity. METHODS:We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics. RESULTS:IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation. DISCUSSION:Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

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.

Background Brachial plexopathies, including backpack palsy (BPP) and neuralgic amyotrophy (NA), are not uncommon in military populations. BPP is caused by compression or stretching of the brachial plexus, while NA is an inflammatory neuropathy potentially triggered by physical strain or infection. Previous studies suggest these conditions have significant incidence rates in military personnel, but further data are limited.Methods This prospective observational study tracked the incidence of BPP and NA among Dutch military personnel from 1 June 2022 to 1 January 2025. All patients with new symptoms of brachial plexopathy were included. Incidence was calculated using the total number of active military personnel during the study period. The incidence was calculated for different age categories.Results A total of 68 cases of BPP and NA were identified over the 31-month period. The calculated incidence of BPP and NA was 28.2 and 35.7 per 100 000 person-years, respectively. BPP was most common in soldiers under 25 (89.6 per 100 000 person-years), while NA was more evenly distributed across age groups.Conclusions This study confirms a high incidence of plexopathies in the Dutch military population, particularly BPP in younger soldiers. These findings underscore the need for targeted prevention strategies to maintain operational readiness.

Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands.The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals.This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders.

The prevalence of chronic polyneuropathy will increase due to the aging population, and therefore, it becomes ever so important to optimize the diagnostic process. However, it is uncertain which blood tests are required and when nerve conduction studies (NCS) should be done in the workup of chronic polyneuropathy. We aimed to investigate the methodology used to develop national polyneuropathy guidelines and to provide an overview and strength of evidence of the recommendations. We searched PubMed and websites of national neurological associations as listed on the website of the World Federation of Neurology to identify national guidelines pertaining to the workup of chronic polyneuropathy by neurologists in an outpatient clinic setting. We identified three national guidelines in the United States and seven national guidelines in Denmark, France, Germany, the Netherlands, Norway, Spain, and Turkey. The methodology used to develop the guidelines differed greatly. All guidelines recommend a series of blood tests. Some guidelines advise to conduct NCS in all patients, while other guidelines advise to conduct NCS when certain symptoms are present. There is variation in recommendations about the extensiveness of NCS, but all mention measuring the sural nerve and the motor peroneal nerve. The evidence for the recommendations is graded as low. Despite some overlap, there are disparities between guidelines regarding the workup that is advised to do in patients with chronic polyneuropathy. It remains unclear which combination of blood tests are to be strongly recommended. Furthermore, it is undetermined whether NCS are always necessary.

Background: Knowledge gaps exist about the usefulness and extent of blood tests and nerve conduction studies in the workup of polyneuropathy. We hypothesize that a limited workup improves costs spent on diagnostics without loss of diagnostic reliability or disadvantageous effect on treatment choice in many patients with a clinical diagnosis of chronic polyneuropathy. We aim to determine which investigations are necessary in the workup of patients with suspected chronic polyneuropathy clinically diagnosed by neurologists in an outpatient clinic and will perform an early health technology assessment. Methods: This is a prospective multicenter quality in healthcare evaluation. We compare two diagnostic strategies, both performed on all participants: the standard care by each patient’s neurologist and the proposed (limited) workup by the study panel members consisting of neurologists with experience in neuromuscular diseases. Results: The primary outcome is the effectiveness of a limited workup expressed as concordance between the patient’s neurologist diagnosis and the panel diagnosis. This will be related to differences in costs and impact on treatment or patient management otherwise. Other outcomes are burden/gain for the patient in terms of number of investigations, time to diagnosis, hospital visits, sick leave, loss of productivity, expenses, experienced quality of care. Conclusion: This multicenter prospective observational study on quality in health care will provide improved evidence about the components of a cost-effective workup for patients with chronic polyneuropathy.

BACKGROUND AND PURPOSE:Complement factor C2 is a potential therapeutic target in immune-mediated neuropathies. However, literature suggests that classical complement pathway activation may proceed to C3 in the absence of C2, a so-called "C2 bypass." Here, we evaluated a C2 bypass mechanism during complement activation by pathogenic human IgM from patients with immune-mediated neuropathies. METHODS:IgM autoantibodies from 51 patients with multifocal motor neuropathy (MMN) or anti-myelin-associated glycoprotein (MAG) neuropathy (AMN) were used to activate complement in ex vivo disease models. C2 bypass was evaluated using C2-depleted (C2D) serum and a therapeutic anti-C2 antibody. RESULTS:In two different disease models of MMN, IgM anti-GM1 and IgM anti-GM2 autoantibodies from MMN patients were bound to induced pluripotent stem cell-derived motor neurons and Schwann cells, respectively, and fixed C3 upon incubation with fresh serum. C3 fixation was inhibited by anti-C2 and did not occur with C2D serum. Similarly, in an AMN model, IgM anti-MAG antibodies were incubated with fresh serum fixed C3, which in all cases was abrogated in the absence of C2 or in the presence of anti-C2. CONCLUSIONS:In ex vivo disease models of MMN and AMN, complement activation by IgM autoantibodies from 51 patients was in all cases dependent on C2 and was inhibited by an antihuman C2 antibody. No evidence of a C2 bypass mechanism was found.

International consensus on IgM ± anti‐MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease‐specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti‐myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti‐MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol.

BackgroundEarly diagnosis of hereditary ATTR polyneuropathy (ATTRv-PN) is important since treatment options have become available, which are most effective early in the disease course. ATTRv-PN is likely underdiagnosed as patients might be misdiagnosed with idiopathic polyneuropathy. It is uncertain if it is useful to test for TTR gene mutations in patients with a typical presentation for chronic idiopathic axonal polyneuropathy (CIAP) and which are the distinguishing clinical features.MethodsWe carried out a retrospective cohort study to assess the yield of TTR gene sequencing in patients with polyneuropathy and assessed if the identified patients with ATTRv-PN had a clinical presentation typical of CIAP. Additionally, we assessed which clinical features, including previously defined red flag symptoms, can differentiate between patients with CIAP and ATTRv-PN and assessed the performance of the TTR suspicion index.ResultsOut of 338 patients with polyneuropathy, 10 patients had a pathogenic TTR gene mutation (all p.Val50Met) and none had a clinical presentation typical of CIAP. Patients with ATTRv-PN more often had bilateral CTS, motor involvement of arms, cardiac involvement, family history suggestive of hATTRv, and autonomic symptoms than patients with CIAP. All patients with ATTRv-PN as well as 70% of patients with CIAP fulfilled the suspicion index.ConclusionRoutine TTR gene sequencing in patients with a typical presentation for CIAP is not useful. However, red flag symptoms can differentiate patients with ATTRv-PN from patients with CIAP. We propose an adjusted version of the TTR suspicion index to increase diagnostic yield.

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698) . Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an openlabel extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

Background Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations. The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream. Methods This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included. An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety. The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS. The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants. Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events. Discussion This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream. Trial registration ClinicalTrials.gov NCT04647877 . Registered on 1 December 2020.

BACKGROUND:In recent years, an increasing number of people adapt to a vegetarian, pescatarian or flexitarian dietary pattern that reduces the consumption of meat and fish. Although these dietary patterns have a risk for developing vitamin B12 deficiency associated polyneuropathy, it is unknown whether this risk is still increased when vitamin B12 levels are adequate.OBJECTIVE:To examine whether a vegetarian, pescatarian or flexitarian dietary pattern is associated with an increased risk for idiopathic axonal polyneuropathy.METHODS:We conducted a case-control study that included 256 idiopathic axonal polyneuropathy patients with adequate vitamin B12 blood levels and 630 controls. We used questionnaire data to determine the frequency of meat and fish consumption and defined dietary patterns.RESULTS:The vegetarian (no meat or fish consumption) and the pescatarian (fish consumption, no meat consumption) dietary patterns showed no increased risk of axonal polyneuropathy. Frequency-effect analysis and quantity-effect analysis also did not show that a reduction of meat or fish consumption (flexitarian dietary pattern), either small or large, changed the risk of axonal polyneuropathy.CONCLUSIONS:We did not find an increased risk for axonal polyneuropathy among people with a vegetarian, pescatarian or flexitarian diet and an adequate vitamin B12 level.

ABSTRACT Objective Determine vitamin B12 threshold levels below which additional testing of methylmalonic acid (MMA) and/or homocysteine (Hcy) is useful to diagnose metabolic vitamin B12 deficiency in patients with polyneuropathy, and how vitamin B12, MMA and Hcy levels relate to the effect of supplementation therapy. Methods In a retrospective cohort study of 331 patients with polyneuropathy, vitamin B12, MMA and Hcy were measured. Linear regression models with vitamin B12 as dependent and Hcy or MMA as covariate were compared, to assess which was best related to vitamin B12. Threshold vitamin B12 levels for metabolic deficiency (defined as elevatede metabolites) were determined using logistic regression with elevated metabolites as dependent and vitamin B12 as covariate. A structured interview was conducted in 42 patients to evaluate response to vitamin B12 supplementation. Results MMA was best related to vitamin B12. Using elevated MMA for metabolic deficiency, we found 90% sensitivity at a vitamin B12 threshold level <264 pmol/L (358 pg/mL) and 95% sensitivity at <304 pmol/L (412 pg/mL). Improvement after supplementation was reported by 19% patients and stabilization by 24%. 88% of patients with improvement and 90% with stabilization either had absolute deficiency (Vitamin B12 < 148 pmol/L) or metabolic deficiency (elevated MMA and vitamin B12 ≥ 148 pmol/L). There were no additional patients with improvement or stabilization with isolated elevated Hcy. Conclusion Testing of MMA has additional value in identifying patients with clinically relevant metabolic deficiency when vitamin B12 is below 304 pmol/L (412 pg/mL). Supplementation can be effective in patients with absolute and metabolic deficiency.