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The aim of this exploratory study was to evaluate diaphragmatic function across various neuromuscular diseases using spirometry-controlled MRI. We measured motion of the diaphragm relative to that of the thoracic wall (cranial-caudal ratio vs. anterior posterior ratio; CC-AP ratio), and changes in the diaphragmatic curvature (diaphragm height and area ratio) during inspiration in 12 adults with a neuromuscular disease having signs of respiratory muscle weakness, 18 healthy controls, and 35 adult Pompe patients – a group with prominent diaphragmatic weakness. CC-AP ratio was lower in patients with myopathies (n=7, 1.25±0.30) and motor neuron diseases (n=5, 1.30±0.10) than in healthy controls (1.37±0.14; p=0.001 and p=0.008), but not as abnormal as in Pompe patients (1.12±0.18; p=0.011 and p=0.024). The mean diaphragm height ratio was 1.17±0.33 in patients with myopathies, pointing at an insufficient diaphragmatic contraction. This was also seen in patients with Pompe disease (1.28±0.36), but not in healthy controls (0.82±0.33) or patients with motor neuron disease (0.82±0.24). We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases. Whether MRI can also be used to evaluate progression of diaphragmatic dysfunction requires additional studies.

Objective To determine which compound muscle action potential (CMAP) scan-derived electrophysiological markers are most sensitive for monitoring disease progression in amyotrophic lateral sclerosis (ALS), and whether they hold value for clinical trials. Methods We used four independent patient cohorts to assess longitudinal patterns of a comprehensive set of electrophysiological markers including their association with the ALS functional rating scale (ALSFRS-R). Results were translated to trial sample size requirements. Results In 65 patients, 225 thenar CMAP scan recordings were obtained. Electrophysiological markers showed extensive variation in their longitudinal trajectories. Expressed as standard deviations per month, motor unit number estimation (MUNE) values declined by 0.09 (CI 0.07–0.12), D50, a measure that quantifies CMAP scan discontinuities, declined by 0.09 (CI 0.06–0.13) and maximum CMAP by 0.05 (CI 0.03–0.08). ALSFRS-R declined fastest (0.12, CI 0.08 – 0.15), however the between-patient variability was larger compared to electrophysiological markers, resulting in larger sample sizes. MUNE reduced the sample size by 19.1% (n = 388 vs n = 314) for a 6-month study compared to the ALSFRS-R. Conclusions CMAP scan-derived markers show promise in monitoring disease progression in ALS patients, where MUNE may be its most suitable derivate. Significance MUNE may increase clinical trial efficiency compared to clinical endpoints.

Not available. ispartof: HAEMATOLOGICA vol:107 issue:7 pages:1726-1730 ispartof: location:Italy status: published

Background and purpose: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. Methods: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6–78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. Results: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p = 1.21, 95% confidence interval [CI] = 1.05–1.39 and ORBMI, p = 1.21, 95% CI = 1.04–1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p = 0.79, 95% CI = 0.68–0.92 and ORalcohol, p = 1.17, 95% CI = 1.02–1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp and polyneuropathy. Conclusions: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.

ObjectiveTo assess and compare the diagnostic performance of qualitative and (semi-)quantitative MRI and ultrasound for distinguishing chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) from segmental spinal muscular atrophy (sSMA).MethodsPatients with CIDP (n = 13), MMN (n = 10), or sSMA (n = 12) and healthy volunteers (n = 30) were included. MRI of the brachial plexus, using short tau inversion recovery (STIR), nerve-specific T2-weighted (magnetic resonance neurography [MRN]), and diffusion tensor imaging (DTI) sequences, was evaluated. Furthermore, with ultrasound, cross-sectional areas of the nerves were evaluated. Three radiologists blinded for diagnosis qualitatively scored hypertrophy and increased signal intensity (STIR and MRN), and intraobserver and interobserver agreement was assessed. For the (semi-)quantitative modalities, group differences and receiver operator characteristics were calculated.ResultsHypertrophy and increased signal intensity were found in all groups including healthy controls. Intraobserver and interobserver agreements varied considerably (intraclass correlation coefficients 0.00–0.811 and 0.101–0.491, respectively). DTI showed significant differences (p < 0.05) among CIDP, MMN, sSMA, and controls for fractional anisotropy, axial diffusivity, and radial diffusivity in the brachial plexus. Ultrasound showed significant differences in cross-sectional area (p < 0.05) among CIDP, MMN, and sSMA in upper arm and brachial plexus. For distinguishing immune-mediated neuropathies (CIDP and MMN) from sSMA, ultrasound yielded the highest area under the curve (0.870).ConclusionQualitative assessment of hypertrophy and signal hyperintensity on STIR or MRN is of limited value. DTI measures may discriminate among CIDP, MMN, and sSMA. Currently, ultrasound may be the most appropriate diagnostic imaging aid in the clinical setting.

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Management of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is complicated by the challenging diagnosis, monitoring of disease activity, and treatment response. Real world data about the current practice of care in CIDP are rare, but important to improve clinical guidelines. In this study, we determined the current practice of diagnosis and treatment in relation to the clinical outcome of patients with CIDP in a cross-sectional study in The Netherlands. All patients registered at the Dutch neuromuscular patient organization and patients at the Erasmus Medical Center were approached. CIDP diagnosis was confirmed by using patient files and expert consensus. The response rate was 137/197 (70%) and the diagnosis CIDP was confirmed in 112 patients. The time from onset of symptoms until CIDP diagnosis was median 5 months and > 12 months in 26% of the patients. Patients with a late diagnosis (>5 months) compared to patients with an early diagnosis (≤5 months) more frequently had another initial diagnosis (P < .001), multifocal abnormalities (P = .011), final diagnosis made in university hospitals (P = .001), and more (residual) complaints, also illustrated via two patient reported, validated clinical outcome measures. Although 97% of patients received treatment, 88% reported (residual) neurological symptoms and deficits. CIDP diagnosis is often delayed, especially in patients with atypical CIDP variants. Diagnostic delay may result in delayed initiation of treatment. A more rapid and accurate diagnosis of CIDP may prevent or at least reduce residual neurological deficits and accompanying disability in CIDP.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

Background: The most common subtypes of Guillain-Barré syndrome (GBS) are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). In the first days after the onset of weakness, standard nerve conduction studies (NCS) may not distinguish GBS subtypes. Reduced nerve excitability may be an early symptom of nerve dysfunction, which can be determined with the compound muscle action potential (CMAP) scan. The aim of this study was to explore whether early changes in motor nerve excitability in GBS patients are related to various subtypes. Methods: Prospective case–control study in 19 GBS patients from The Netherlands and 22 from Bangladesh. CMAP scans were performed within 2 days of hospital admission and NCS 7–14 days after onset of weakness. CMAP scans were also performed in age- and country-matched controls. Results: CMAP scan patterns of patients who were classified as AMAN were distinctly different compared to the CMAP scan patterns of the patients who were classified as AIDP. The most pronounced differences were found in the stimulus intensity parameters. Conclusions: CMAP scans made at hospital admission demonstrate several characteristics that can be used as an early indicator of GBS subtype.

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks. The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of ≥1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over ≤12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose-evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP.

To determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation. We used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function. Of 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250–1:31,250) in 40%, and none or low (0–1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy. In adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype. Genet Med 19 1, 90–97.

Background: Respiratory insufficiency occurs in 20 % of Guillain–Barre syndrome (GBS) patients, and the duration of mechanical ventilation (MV) ranges widely. We identified predictors of prolonged MV to guide clinical decision-making on tracheostomy. Methods: We analyzed prospectively collected data from 552 patients with GBS in the context of two clinical trials and three cohort studies in The Netherlands. Potential predictors for prolonged MV, defined as duration of ≥14 days, were considered using crosstabs. Selected predictors were analyzed using Cox regression analysis. Results: On a total of 150 (27 %) patients requiring MV, 106 (71 %) patients needed prolonged MV. The median duration of MV was 28 days (Interquartile Range [IQR] 12–60 days). The strongest observed predictors of prolonged MV were muscle weakness and axonal degeneration or unexcitable nerves on nerve conduction studies. Patients who are unable to lift the arms from the bed (bilateral Medical Research Council [MRC] of deltoid muscles of 0–2) at 1 week after intubation have an 87 % chance to require prolonged MV versus 69 % in patients who are able to lift the arms from the bed (bilateral MRC of deltoid muscles of 3–10). Patients in this last group who had axonal degeneration or unexcitable nerves on nerve conduction studies also have a 90 % chance to require prolonged MV. Conclusions: Ventilated GBS patients who are unable to lift the arms from the bed and patients who have axonal degeneration or unexcitable nerves at 1 week are at high risk of prolonged MV, and tracheostomy should be considered in these patients.

Alemtuzumab is approved for the treatment of relapsing-remitting MS and is used off-label for patients with chronic lymphocytic leukemia and as induction and antirejection therapy in kidney transplant recipients.1 Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) complicating alemtuzumab treatment was reported in 9 patients with hematologic malignancy or MS.1–3 The risk of GBS or CIDP in solid organ transplant recipients treated with alemtuzumab is unknown.

Objective To investigate the association between diet quality and chronic axonal polyneuropathy. Methods Between June 2013 and January 2017, among 1650 participants of the Rotterdam Study (median age 69.1 years, 54.2% women), diet quality was quantified based on food frequency questionnaires as a sum score of adherence (yes/no) to 14 components of the Dutch dietary guidelines. Presence of polyneuropathy was determined based on a questionnaire, neurological examination of the legs, and nerve conduction studies. We used logistic regression to associate diet quality with the presence of chronic axonal polyneuropathy and linear regression to associate with sural sensory nerve action potential (SNAP) amplitude in participants without polyneuropathy. Results were adjusted for age, sex, time between measurements, body mass index, blood pressure, diabetes mellitus, smoking, kidney function, and education. Results Overall diet quality was not associated with chronic axonal polyneuropathy (odds ratio [OR] = 0.99, 95% confidence interval [CI] 0.88; 1.12, P = 0.842), nor with sural SNAP amplitude in participants without polyneuropathy (difference = 0.01, 95% CI −0.14; 0.15, P = 0.993). Although not surviving multiple testing, a nominally significant association was found between salt intake ≤6 g/day and presence of chronic axonal polyneuropathy (OR = 0.55, 95% CI 0.35; 0.86, P = 0.008). Interpretation We did not find an association between diet quality and chronic axonal polyneuropathy.

Axonal damage in chronic inflammatory demyelinating polyneuropathy (CIDP) is the main predictor of poor outcome. We hypothesized that serum neurofilament light chain (sNfL) reflects disease activity by detecting ongoing neuro-axonal damage in CIDP. Three prospective cohorts of CIDP patients were studied: (a) patients starting induction treatment (IT cohort, N = 29) measured at baseline and 6 months after starting treatment; (b) patients on maintenance treatment (MT) starting intravenous immunoglobuline (IVIg) withdrawal (MT cohort, N = 24) measured at baseline and 6 months after IVIg withdrawal or at time of relapse; and (c) patients in long-term remission without treatment (N = 27). A single molecule array assay was used to measure sNfL. Age-matched healthy controls (N = 30) and age-specific reference values were used for comparison. At baseline, sNfL was higher in patients starting IT compared to healthy controls. Ten out of 29 IT (34%) patients have sNfL levels above the 95th percentile of age-specific cut-off values. In the MT and remission cohort, elevated sNfL levels were infrequent and not different from healthy controls. sNfL levels were correlated with electrophysiological markers of axonal damage. At follow-up assessment, patients with active disease (non-responders and patients who relapsed after IVIg withdrawal) had higher sNfL levels compared with patients with stable disease (responders and patients who were successfully withdrawn from IVIg treatment). sNfL levels were increased in a third of CIDP patients starting IT and reflected axonal damage. sNfL levels might be usable as biomarker of disease activity in a subset of CIDP patients.

Objective: To determine the prevalence of chronic polyneuropathy in an unselected community-dwelling population of middle-aged and elderly people. Methods: The current study was embedded in the prospective, population-based Rotterdam Study. Between June 2013 and October 2015, 1,310 participants (mean age 70 years, 55% female) were screened for the presence of polyneuropathy. This screening consisted of a questionnaire, neurologic examination, and nerve conduction studies. Polyneuropathy was diagnosed by a consensus panel that categorized participants into no, possible, probable, or definite polyneuropathy, depending on the level of abnormality of the screening. Medical records were scrutinized to evaluate whether the disorder was diagnosed before and laboratory investigations were performed to determine the presence of associated risk factors. Results: Prevalence of definite polyneuropathy was 5.5% (95% confidence interval 4.4–6.9), age-standardized to the population of the Netherlands 4.0% (3.1–5.3). Prevalence was higher in male participants (6.7% compared to 4.5%) and increased with age. When combining probable and definite polyneuropathy, age-standardized prevalence was 9.4% (7.9–11.1). Almost half of the polyneuropathies (49%) were newly diagnosed. The majority of polyneuropathies were idiopathic (46%). Diabetes, present in 31% of participants with polyneuropathy, was the most commonly found risk factor. Conclusions: Prevalence of polyneuropathy in the general middle-aged and elderly population is at least 4%, and increases with age. Almost half of the cases were newly diagnosed, indicating that the presence of polyneuropathy is underreported or underdiagnosed. Currently, almost half of the polyneuropathies are idiopathic. Future prospective cohort studies should focus on identifying new determinants of polyneuropathy.

Objective Diabetes mellitus is a known risk factor for polyneuropathy, but the role of pre-diabetes and metabolic syndrome remains unclear. We aimed to investigate the role of these factors in a community-dwelling middle-aged and elderly population. Methods 1256 participants of the population-based Rotterdam Study (mean age 70.0, 54.5% females) were screened for polyneuropathy with a questionnaire, neurological examination and nerve conduction studies. Data on type 2 diabetes and components of metabolic syndrome were also collected. Logistic regression was used to investigate associations of diabetes, pre-diabetes and metabolic syndrome and its separate components with polyneuropathy. Linear regression was used to investigate associations with nerve conduction parameters in participants without polyneuropathy. Findings Diabetes was associated with polyneuropathy (OR 3.01, 95% CI 1.60 to 5.65), while impaired fasting glucose was not (OR 1.55, 95% CI 0.70 to 3.44). Metabolic syndrome was associated with polyneuropathy (OR 1.92, 95% CI 1.09 to 3.38), with a stronger association when more components of the syndrome were present. Analysing separate components of metabolic syndrome revealed associations for elevated waist circumference (OR 2.84, 95% CI 1.35 to 5.99) and elevated triglycerides (OR 2.01, 95% CI 1.11 to 3.62). Similar associations were found after excluding participants with diabetes. In participants without polyneuropathy, metabolic syndrome associated with lower sural sensory nerve action potential amplitudes. Conclusions Metabolic syndrome, abdominal obesity and dyslipidaemia, are strongly associated with polyneuropathy, irrespective of the presence of diabetes. Metabolic syndrome also associates with impaired nerve function in people without polyneuropathy. Our study therefore suggests that cardiometabolic disturbances have an impact on peripheral nerve function that extends beyond clinically manifest disease.

Aims To investigate the association of diabetes mellitus and impaired fasting glucose with gait in the general middle-aged and elderly population. Methods We performed a cross-sectional study on 3019 participants from the population-based Rotterdam Study (aged >45years, 54% women). The presence of diabetes mellitus and impaired fasting glucose was evaluated by measuring serum glucose levels and by documenting anti-diabetic treatment. Participants underwent gait analysis using an electronic walkway. Thirty gait variables were summarized into five independent gait domains for normal walking ( Rhythm , Variability , Phases , Pace and Base of Support ), one for turning ( Turning ) and one for walking heel to toe ( Tandem ), which were averaged into Global Gait . Linear regression analyses were performed to determine the association of diabetes, impaired fasting glucose and continuous glucose levels within the normal range with gait. Results Diabetes mellitus was associated with worse Global Gait (Z-score difference −0.19, 95% confidence interval (CI) −0.30; −0.07), worse Pace (−0.20, 95% CI −0.30; −0.10) and worse Tandem (−0.21, 95% CI −0.33; −0.09), after adjusting for age, sex, height and weight. The association with Tandem remained significant after additional adjustment for cardiovascular risk factors. Impaired fasting glucose and continuous glucose levels within the normal range were not associated with any of the gait domains. Conclusion In our population-based study diabetes mellitus was associated with worse Global Gait , which was mostly reflected in Pace and Tandem . These associations were partly driven by other cardiovascular risk factors, emphasizing the importance of optimal control of cardiovascular risk factor profiles in patients with diabetes.

Background— Elevated plasma cardiac troponin T (cTnT) levels in patients with neuromuscular disorders may erroneously lead to the diagnosis of acute myocardial infarction or myocardial injury. Methods and Results— In 122 patients with Pompe disease, the relationship between cTnT, cardiac troponin I, creatine kinase (CK), CK-myocardial band levels, and skeletal muscle damage was assessed. ECG and echocardiography were used to evaluate possible cardiac disease. Patients were divided into classic infantile, childhood-onset, and adult-onset patients. cTnT levels were elevated in 82% of patients (median 27 ng/L, normal values P Conclusions— Elevated plasma cTnT levels in patients with Pompe disease are associated with skeletal muscle damage, rather than acute myocardial injury. Increased cTnT levels in Pompe disease and likely other neuromuscular disorders should be interpreted with caution to avoid unnecessary cardiac interventions.

Background Pompe disease is a rare metabolic myopathy. In adult patients, progressive weakness of limb-girdle and respiratory muscles often leads to wheelchair and respirator dependency. Clinical studies have shown enzyme replacement therapy (ERT) to positively affect motor and respiratory outcomes. Here we investigate whether ERT reduces patients’ risk of needing a wheelchair or respirator. Methods Data were collected as part of a prospective international survey, the IPA/Erasmus MC Pompe survey, which was conducted annually between 2002 and 2016. We excluded patients who were already using a wheelchair or respirator, those under 18 at survey entry, and those who had missing information. Time-dependent Cox proportional hazard models were used. Results The inclusion criteria for analyzing the risk of wheelchair use were met by 189 patients (median age 47 years; range 18–75). During follow-up, 126 (67%) started ERT. Over 1120 person-years of follow-up (median 5 years), 46 became wheelchair dependent, 16 of whom used ERT. After adjustment for disease duration, sex and country, ERT reduced the risk for wheelchair use (HR 0.36; 95% CI 0.17–0.75). For analyses of respirator use, 177 patients met the inclusion criteria (median age 46 years; range 18–73). Over 1190 person-years of follow-up (median 6 years), 125 patients (71%) were treated and 48 started respiratory support, 28 of whom received ERT. We found no association between ERT and the risk for respirator use (HR 1.23; 95% CI 0.61–2.47). Conclusions Our study found that ERT reduced the risk for wheelchair dependency. We could not demonstrate an effect on respiratory support.

The majority of children and adults with Pompe disease in the population of European descent carry the leaky splicing GAA variant c.-32-13T>G (IVS1) in combination with a fully deleterious GAA variant on the second allele. The phenotypic spectrum of this patient group is exceptionally broad, with symptom onset ranging from early infancy to late adulthood. In addition, the response to enzyme replacement therapy (ERT) varies between patients. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been suggested to be a modifier of disease onset and/or response to ERT. Here, we have investigated the effect of the ACE I/D polymorphism in a relatively large cohort of 131 children and adults with Pompe disease, of whom 112 were followed during treatment with ERT for 5 years. We assessed the use of wheelchair and mechanical ventilation, muscle strength assessed via manual muscle testing and hand-held dynamometry (HHD), distance walked on the six-minute walk test (6MWT), forced vital capacity (FVC) in sitting and supine position and daily-life activities assessed by R-PAct. Cross sectional analysis at first visit showed no differences between the genotypes with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use. Also response to ERT over 5 years assessed by linear mixed model analyses showed no significant differences between ACE groups for any of the outcome measures. The patient cohort contained 24 families with 54 siblings. Differences in ACE genotype could neither explain inter nor intra familial differences. We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant.

Summary Background Pompe disease is an inheritable metabolic disorder for which enzyme replacement therapy (ERT) has been available since 2006. Effects of ERT have been shown on distance walked, pulmonary function and survival. We investigated whether it also improves quality of life and participation in daily life in adult patients with the disease. Methods In an international survey, we assessed quality of life (Short Form 36, SF-36) and participation (Rotterdam Handicap Scale, RHS) annually between 2002 and 2012. Repeated measurements mixed effects models were used to describe the data over time. Results Responses were available for 174 adult patients. In the periods before and after start of ERT, the median follow-up times were 4 years each (range 0.5-8). The SF-36 Physical Component Summary measure (PCS) deteriorated before ERT (-0.73 score points per year (sp/y); CI 95 % -1.07 to -0.39), while it improved in the first 2 years of ERT (1.49 sp/y; CI 0.76 to 2.21), and remained stable thereafter. The Mental Component Summary measure (MCS) remained stable before and during ERT. After declining beforehand (-0.49 sp/year; CI -0.64 to-0.34), the RHS stabilized under ERT. Conclusion In adult patients with Pompe disease, ERT positively affects quality of life and participation in daily life. Our results reinforce previous findings regarding the effect of ERT on muscle strength, pulmonary function and survival.

Objective: To determine whether there is a relation between electrically evoked multiplet discharges (MDs) and motor axonal excitability properties. We hypothesized that electrically evoked MDs share their underlying pathophysiological mechanism with fasciculations. Methods: High-density surface EMG and motor nerve excitability recordings of the thenar muscles were performed in 22 patients with motor neuron disease (MND) in their differential diagnosis and who were referred for EMG examination. Results: Supernormality (hyperexcitable phase following the refractory period) was significantly increased in patients with MDs (n = 10) compared to patients without MDs (n = 12) (25.5% vs 17.0%; p = 0.02). Depolarizing threshold electrotonus differed significantly between both groups as well (TEd-peak, 76.6% vs 66.6%, p < 0.01; TEd90-100 ms, 51.7% vs 44.3%, p < 0.01) Conclusions: Our findings imply that the same pathophysiological excitability changes are involved in generating MDs and fasciculations. Yet, MDs may be quantified more easily, and may be more specific for abnormal distal excitability than fasciculations, because fasciculations may originate along the motor axon as well as in the neuron cell body. Significance: MDs are potentially useful as objective measure of increased distal axonal excitability at individual motor unit level and might complement clinical studies in MND. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Objective: To investigate whether restless legs syndrome (RLS) is associated with impaired physical functioning using subjective and objective assessments. Methods: From 2006-2013, 5,960 participants (mean age 67.2; 57.5% females) of the prospective population-based Rotterdam Study, aged 45 years and over, were cross-sectionally investigated for presence of restless legs syndrome using a questionnaire. Physical functioning was assessed subjectively with the Stanford Health Assessment Questionnaire (basic activities of daily living) and the Instrumental Activities of Daily living scale (instrumental activities of daily living). Additionally, physical functioning was assessed objectively by quantifying fine motor performance with the Purdue Pegboard Test and by quantifying gait with an electronic walkway. Results: Restless legs syndrome was present in 13.7% of the participants. Persons with restless legs had more impairment in basic (difference in score 0.65, 95% CI 0.41; 0.90) and instrumental activities of daily living (difference in score 0.28, 95% CI 0.09; 0.48) than persons without restless legs. This association was strongest when symptoms were present two or more times a week (basic activities of daily living score difference 1.69, 95% CI 1.28; 2.09). The association between restless legs syndrome and activities of daily living attenuated after adjusting for sleep quality or depressive symptoms. There was no association with the Purdue Pegboard Test score nor with gait. Conclusions: Individuals with restless legs syndrome experienced significantly more impairment in activities of daily function than persons without restless legs. This seemed to be (partly) mediated by poor sleep quality and depressive symptoms. No association was found with objectively assessed physical functioning. (C) 2014 Elsevier B.V. All rights reserved.

Patients with Miller Fisher syndrome (MFS) may have a relatively mild clinical course or progress to Guillain-Barré syndrome (GBS) with limb weakness (MFS-GBS overlap syndrome). Other variants in this spectrum are GBS with ophthalmoparesis and Bickerstaff's Brainstem encephalitis (BBE). To compare the clinical course of MFS and overlap syndromes and to identify predictors of disease progression. In a prospective study of 170 patients with GBS and variant forms, 37 (22%) had a MFS, MFS-GBS overlap syndrome, ophthalmoplegic GBS or BBE. The clinical, serological, and electrophysiological features were compared. Twenty-three patients presented with MFS, of which 10 (43%) developed limb weakness (MFS-GBS overlap syndrome). All these transitions occurred in the first week after onset of symptoms. There were no differences in the clinical, electrophysiological and serological features at entry between MFS and MFS-GBS. Twelve patients had ophthalmoplegic GBS and the disease severity at nadir and outcome was worse than in the patients with a MFS-GBS overlap syndrome. No early predictors for progression from MFS to MFS-GBS overlap syndrome were found. All transitions occurred in the first week. This finding implicates that all patients with MFS need careful monitoring for at least 1 week.

Objective:To determine the effect of enzyme replacement therapy (ERT) after 5 years and to identify predictors for a favorable response because few data are available on the long-term efficacy of ERT in Pompe disease.Methods:We included 102 adult patients with Pompe disease in a nationwide, prospective cohort study. We assessed muscle strength (manual muscle testing with Medical Research Council [MRC] grading, handheld dynamometry [HHD]), muscle function (6-minute walk test, Quick Motor Function Test), daily life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale), and pulmonary function (forced vital capacity [FVC] in upright and supine positions, maximum inspiratory and expiratory pressures) at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements.Results:Median follow-up duration was 6.1 years (range 0.4–7.9 years), of which 5.0 years (range 0.2–7.3 years) were during ERT. Treated patients had better muscle strength (MRC sum score +6.6 percentage points [pp]; HHD sum score +9.6 pp, both p < 0.0001), activity levels (R-PAct +10.8 pp, p < 0.002), and pulmonary function (FVC upright +7.3 pp, FVC supine +7.6 pp, both p < 0.0003) than expected for their untreated disease course. Walking distance improved (416 vs 376 m at baseline, p = 0.03). The largest increase was seen during the first 2 to 3 years of treatment. Response to treatment was similar between groups regardless of sex, age, or disease duration.Conclusions:Long-term ERT positively affects muscle strength, pulmonary function, and daily life activities in adult patients with Pompe disease, with a peak effect at ≈2 to 3 years of treatment.Classification of evidence:This study provides Class IV evidence that for patients with Pompe disease, long-term ERT positively affects muscle strength, pulmonary function, and daily life activities.

Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm

ObjectiveTo determine and compare the diagnostic accuracy of electrically elicited multiplet discharges (MDs) and fasciculation potentials (FPs) in motor neuron disease (MND).MethodsPatients were eligible when they had MND in their differential diagnosis and were referred for electromyogram (EMG). Stimulated high-density surface EMG of the thenar muscles was performed on the same day as standard EMG examination. High-density recordings were analysed for presence of MDs and needle EMG of any muscle investigated in the cervical region for presence of FPs.ResultsOf the 61 patients enrolled in this diagnostic study, 24 patients were clinically diagnosed with amyotrophic lateral sclerosis (ALS) and 11 patients with progressive muscular atrophy (PMA). Another diagnosis was made in 26 patients. Sixteen patients in whom MDs were detected were diagnosed with either ALS (n=11) or PMA (n=5; sensitivity=47.1%, PPV=94.1%). MDs were detected in only one patient initially diagnosed with PMA, but in whom later on, multifocal motor neuropathy could not be excluded (specificity=96.2%). Electrically elicited MDs had a higher specificity than FPs (96.2% vs 53.9%, pConclusionsElectrically evoked MDs are highly specific for ALS and PMA and are an early sign of lower motor neuron dysfunction.

Objectives: We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP). Methods: One hundred thirty-seven patients (GBS: 55, CIDP: 59, IgM-MGUSP: 23) with a new diagnosis or clinical relapse assessed both scales. Patients with GBS/CIDP were examined at 0, 1, 3, 6, and 12 months; patients with IgM-MGUSP at 0, 3, and 12. We subjected all data to Rasch analyses, and calculated for each patient the magnitude of change on both scales using the minimal clinically important difference (MCID) related to the individual standard errors (SEs). A responder was defined as having anMCID-SE >= 1.96. Individual scores on both measures were correlated with the EuroQoL thermometer (heuristic responsiveness). Results: The I-RODS showed a significantly higher proportion of meaningful improvement compared with the INCAT-ONLS findings in GBS/CIDP. For IgM-MGUSP, the lack of responsiveness during the 1-year study did not allow a clear separation. Heuristic responsiveness was consistently higher with the I-RODS. Conclusion: The I-RODS more often captures clinically meaningful changes over time, with a greater magnitude of change, compared with the INCAT-ONLS disability scale in patients with GBS and CIDP. The I-RODS offers promise for being a more sensitive measure and its use is therefore suggested in future trials involving patients with GBS and CIDP.

Guillain-Barre syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-Barre syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with Guillain-Barre syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53 years (interquartile range 36-66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients during follow-up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in 95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/mu l) was found in 15%, and none had more than 50 cells/mu l. An increased cerebrospinal fluid protein concentration was found only in 64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88% after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59% fulfilled the current criteria for a distinct subtype of Guillain-Barre syndrome. Patients with a complete data set (335) were classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2 in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key diagnostic features of Guillain-Barre syndrome in the current cohort study, can be used to improve the sensitivity of the diagnostic criteria.

Objective: To define the clinical and diagnostic characteristics of paraparetic Guillain-Barre syndrome (GBS) with weakness restricted to the legs, compared with the classic quadriparetic GBS. Methods: Prospectively collected data from a cohort of 490 patients with GBS, previously involved in therapeutic or clinical studies, were used to define the demography, clinical presentation, diagnostic investigations, and clinical course in patients with paraparesis during a 6-month follow-up. Results: Forty patients (8%) presented with a paraparesis without weakness of arms and hands. In 29 patients (73%), normal strength of upper extremities persisted during the follow-up period. Patients with paraparesis compared to patients with quadriparesis had a milder form of GBS, with less frequent cranial nerve involvement and less severe leg weakness, despite the fact that the majority of these patients were unable to walk unaided. Median time between onset of weakness and study entry was 6 days (interquartile range 4–11 days) for patients with paraparesis compared with 5 days (interquartile range 3–8 days) for patients with quadriparesis ( p = 0.031). Fifty percent of patients with paraparesis presented with arm sensory deficits and 73% had reduced or absent arm reflexes. Nerve conduction studies demonstrated arm nerve involvement in 89% of these patients. At 6 months of follow-up, 98% of patients with paraparesis were able to walk unaided compared with 81% of the patients with quadriparesis ( p = 0.008). There was no association between paraparesis and age, sex, or preceding infections. Conclusions: Paraparesis is an atypical clinical presentation or subform of GBS in which the diagnosis is usually supported by the presence of sensory deficits, reduced reflexes, or abnormal nerve conduction of the arms.

Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease.In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale.We followed 163 patients for a median period of 4 years before ERT and for 3 years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function.Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect.

A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening. (C) 2013 Elsevier B.V. All rights reserved.

Amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA) are characterized by a loss of motor units (MUs), reinnervation and, eventually, muscle fibre loss. These three aspects are all reflected in the compound muscle action potential scan (CMAP scan, a high-detail stimulus response curve), which visualizes large MU potentials as 'steps'. We explored changes in the CMAP scan over time, combined the information on steps and CMAP amplitude into a CMAP scan-based progression score (CSPS), and correlated this score with motor unit number estimates (MUNE). Ten patients (three PMA, seven ALS; age 37-77 years) were included. CMAP scan and MUNE measurements were performed five times during a three-month period. Nine patients had additional measurements. The follow-up period was 3-24 months. Results demonstrated that abnormalities in steps preceded a decline in maximum CMAP amplitude during follow-up. Usually, both steps and maximum CMAP amplitude changed between recordings. The correlation between the CSPS and MUNE was -0.80 (p < 0.01). In conclusion, the CMAP scan can be used to visualize and quantify disease progression in a muscle affected by MND. The CSPS is a measure of MU loss that is quick and easy to obtain and that, in contrast to MUNE, has no sample bias.

Polyneuropathy is a prevalent and disabling disorder. Despite extensive evaluation, the cause often remains unknown. Factors that predispose for the development of polyneuropathy need to be identified. We investigated the effect of anthropometric and metabolic factors on peripheral nerve function in 908 participants of the population-based Rotterdam Study without any symptoms or signs of polyneuropathy. Participants underwent nerve conduction studies of the sural and peroneal nerve. Data on age, height, weight, waist circumference, diabetes, lipid levels, hypertension, and kidney function were collected. Regression analyses were used to investigate determinants of nerve action potential amplitudes. The frequency of abnormal sural sensory nerve action potential (SNAP) amplitudes increased with age from 1% under 60 years to 23% over 80 years. Similarly, the frequency of abnormal peroneal nerve compound motor action potential (CMAP) amplitudes increased from 4% to 13%. High weight and body mass index were independently associated with reduced sural SNAP amplitudes and peroneal CMAP amplitudes. Participants with hypertension and kidney dysfunction were more likely to have abnormal sural SNAP amplitudes. Older age, high weight, hypertension, and moderate kidney dysfunction might thus lead to peripheral nerve dysfunction in persons yet without symptoms or signs of polyneuropathy.

Objective:To extensively investigate the association of chronic polyneuropathy with basic and instrumental activities of daily living (BADL and IADL), falls, and gait.Methods:A total of 1,445 participants of the population-based Rotterdam Study (mean age 71 years, 54% women) underwent a polyneuropathy screening involving a symptom questionnaire, neurologic examination, and nerve conduction studies. Screening yielded 4 groups: no, possible, probable, and definite polyneuropathy. Participants were interviewed about BADL (Stanford Health Assessment questionnaire), IADL (Instrumental Activities of Daily Living scale), and frequency of falling in the previous year. In a random subset of 977 participants, gait was assessed with an electronic walkway. Associations of polyneuropathy with BADL and IADL were analyzed continuously with linear regression and dichotomously with logistic regression. History of falling was evaluated with logistic regression, and gait changes were evaluated with linear regression.Results:Participants with definite polyneuropathy had more difficulty in performing BADL and IADL than participants without polyneuropathy. Polyneuropathy related to worse scores of all BADL components (especially walking) and 3 IADL components (housekeeping, traveling, and shopping). Participants with definite polyneuropathy were more likely to fall, and these falls more often resulted in injury. Participants with polyneuropathy had worse gait parameters on the walkway, including lower walking speed and cadence, and more errors in tandem walking.Conclusions:Chronic polyneuropathy strongly associates with impairment in the ability to perform daily activities and relates to worse gait and an increased history of falling.

The outcome of Guillain-Barré syndrome remains unchanged since plasma exchange and intravenous immunoglobulin were introduced over 20 years ago. Pathogenesis studies on GBS have identified the terminal component of complement cascade as a key disease mediator and therapeutic target. We report the first use of terminal complement pathway inhibition with eculizumab in humans with GBS. In a randomised, double-blind, placebo-controlled trial, 28 subjects eligible on the basis of GBS disability grade of at least 3 were screened, of whom 8 (29%) were randomised. Five received eculizumab for four weeks, alongside standard intravenous immunoglobulin treatment. The safety outcomes, monitored via adverse events capture, showed eculizumab to be well tolerated and safe when administered in conjunction with IVIg. Primary and secondary efficacy outcomes in the form of GBS disability scores, MRC sum scores, Rasch Overall Disability Scores and Overall Neuropathy Limitation Scores are reported descriptively. For the primary efficacy outcome at 4 weeks after recruitment, 2 of 2 placebo and 2 of 5 eculizumab-treated subjects had improved by 1 or more grades on the GBS disability score. Although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in GBS are warranted.

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations ε1369delG and εR311Q were found to be common; ε1369delG was present on at least one allele in seven of the nine patients, and εR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of εR311Q and ε1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for εR311Q and ε1369delG. Electronic supplementary material The online version of this article (doi:10.1007/s00415-009-5190-7) contains supplementary material, which is available to authorized users.

BACKGROUND: Diaphragm weakness is the main reason for respiratory dysfunction in patients with Pompe disease, a progressive metabolic myopathy affecting respiratory and limb-girdle muscles. Since respiratory failure is the major cause of death among adult patients, early identification of respiratory muscle involvement is necessary to initiate treatment in time and possibly prevent irreversible damage. In this paper we investigate the suitability of dynamic MR imaging in combination with state-of-the-art image analysis methods to assess respiratory muscle weakness.METHODS: The proposed methodology relies on image registration and lung surface extraction to quantify lung kinematics during breathing. This allows for the extraction of geometry and motion features of the lung that characterize the independent contribution of the diaphragm and the thoracic muscles to the respiratory cycle.RESULTS: Results in 16 3D+t MRI scans (10 Pompe patients and 6 controls) of a slow expiratory maneuver show that kinematic analysis from dynamic 3D images reveals important additional information about diaphragm mechanics and respiratory muscle involvement when compared to conventional pulmonary function tests. Pompe patients with severely reduced pulmonary function showed severe diaphragm weakness presented by minimal motion of the diaphragm. In patients with moderately reduced pulmonary function, cranial displacement of posterior diaphragm parts was reduced and the diaphragm dome was oriented more horizontally at full inspiration compared to healthy controls.CONCLUSION: Dynamic 3D MRI provides data for analyzing the contribution of both diaphragm and thoracic muscles independently. The proposed image analysis method has the potential to detect less severe diaphragm weakness and could thus be used to determine the optimal start of treatment in adult patients with Pompe disease in prospect of increased treatment response.

Based on approximately eight years of data collection with the nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) in the Netherlands, recent epidemiologic information for thirty neuromuscular disorders is presented. This overview includes age and gender data for a number of neuromuscular disorders that are either relatively frequently seen in the neuromuscular clinic, or have a particular phenotype. Since 2004, over 20,000 individuals with a neuromuscular disorder were registered in CRAMP; 56% men and 44% women. The number per diagnosis varied from nine persons with Emery Dreifuss muscular dystrophy to 2057 persons with amyotrophic lateral sclerosis. Proportions of men ranged from 38% with post-polio syndrome to 68% with progressive spinal muscular atrophy, excluding X-chromosome linked disorders. Inclusion body myositis showed the highest median age at diagnosis of 70 years. These data may be helpful in the diagnostic process in clinical practice and trial readiness. (C) 2016 Elsevier B.V. All rights reserved.

textabstractBackground Guillain-Barre syndrome (GBS) has a highly variable clinical course, leading to frequent transfers within and between hospitals and high associated costs. We defined the current admissions, transfers and costs in relation to disease severity of GBS. Methods Dutch neurologists were requested to report patients diagnosed with GBS between November 2009 and November 2010. Information regarding clinical course and transfers was obtained via neurologists and general practitioners. Results 87 GBS patients were included with maximal GBS disability score of 1 or 2 (28%), 3 or 4 (53%), 5 (18%) and 6 (1%). Four mildly affected GBS patients were not hospital admitted. Of the 83 hospitalized patients 68 (82%) were initially admitted at a neurology department, 4 (5%) at an ICU, 4 (5%) at pediatrics, 4 (5%) at pediatrics neurology and 3 (4%) at internal medicine. Median hospital stay was 17 days (IQR 11-26 days, absolute range 1-133 days). Transfers between departments or hospitals occurred in 33 (40%) patients and 25 (30%) were transferred 2 times or more. From a cost-effectiveness perspective 21 (25%) of the admissions was suboptimal. Median costs for hospital admission of GBS patients were 15,060 Euro (IQR 11,226-23,683). Maximal GBS disability score was significantly correlated with total length of stay, number of transfers, ICU admission and costs. Conclusions Hospital admissions for GBS patients are highly heterogeneous, with frequent transfers and higher costs for those with more severe disease. Future research should aim to develop prediction models to early identify the most cost-effective allocation in individual patients.

We performed a prospective study in 32 patients with Guillain-Barre syndrome (GBS) or its variants to correlate intraepidermal nerve fiber density (IENFD) at the distal leg and lumbar region with pain, autonomic dysfunction, and outcome. In the acute phase, IENFD was reduced in 60% and 61.9% of patients at the distal leg and lumbar region, respectively. In the acute phase, 43.7% of patients complained of neuropathic pain. Their IENFD at the distal leg was significantly lower than in patients without pain (P < .001) and correlated with pain intensity (r(s) = -0.51; P = .003). Intriguingly, also patients with the pure motor variant of GBS and pain had low IENFD. At 6-month follow-up, only 3 patients complained of persisting neuropathic pain, whereas 3 patients reported late-onset pain symptoms. IENFD in the acute phase did not predict presence or intensity of pain at 6-month follow-up. IENFD in the acute phase did not correlate with clinical dysautonomia or GBS severity at nadir. However, it correlated with poorer GBS disability score at 6 months (P = .04), GBS score at nadir (P = .03), and clinically probable dysautonomia (P = .004). At 6-month follow-up, median IENFD remained significantly low both at the distal leg (P = .024) and lumbar region (P = .005). Double and triple staining confocal microscope studies showed diffuse damage of myelinated dermal nerves along with axonal degeneration, and mononuclear cell infiltration. Unmyelinated and myelinated skin nerves are diffusely affected in GBS and its variants, including the pure motor form. IENFD declines early, remains low over time, correlates with pain severity in the acute phase, and may predict long-term disability. (C) 2011 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients’ clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease. Electronic supplementary material The online version of this article (doi:10.1007/s10545-011-9388-3) contains supplementary material, which is available to authorized users.

Activity-induced weakness was reported in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). This was attributed to activity-dependent conduction block (CB) arising in demyelinated axons. It is not known if activity-induced weakness is common, nor if it is specific for MMN and CIDP. We, therefore, carried out an investigation by questionnaire in 64 MMN patients, 52 CIDP patients, 48 progressive spinal muscular atrophy (PSMA) patients, and 30 normal subjects. Subjects were asked if they experienced an increase in weakness when performing 10 common tasks. The percentage of tasks causing activity-induced weakness was higher in the patient groups than in the normal subjects (p < 0.001). The risk of activity-induced weakness exceeding that in normal subjects was sixfold higher for each patient group when adjusted for sex, age, and a fatigue score. With further adjustment for scores of weakness and axon loss, no significant differences were found between the patient groups. In conclusion, activity-induced weakness is frequently reported in MMN and CIDP. It is, however, not specific for these neuropathies as PSMA patients reported it to the same extent.

Defining long-term outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) has been complicated by varying definitions of treatment response and differing scales measuring impairment or disability. An expert panel was convened to devise a CIDP Disease Activity Status (CDAS) and to classify long-term outcome by applying it to 106 patients with a consensus diagnosis of CIDP. Sixty of these cases were graded blindly by three independent reviewers to assess inter-rater reliability. The mean duration of follow-up was 6.4 years (range, 3 months-23 years). Eleven percent of patients were classified as cured (stable examination and off treatment for >= 5 years), 20% were in remission (stable and off treatment for < 5 years), 44% had stable active disease but required ongoing therapy for at least 1 year, 7% were improving after recent initiation of therapy, and 18% had unstable active disease (treatment naive or treatment refractory). Excellent inter-rater reliability was observed (kappa scores: 0.93-0.97; p < 0.0001). The CDAS is considered a simple and reproducible tool to classify patients with CIDP according to disease activity and treatment status that can be applied easily in practice and potentially to select patients for clinical trials.

Objective Intravenous immunoglobulin (IVIg) is the first choice treatment for Guillain-Barre syndrome (GBS). All patients initially receive the same arbitrary dose of 2g per kg body weight. Not all patients, however, show a good recovery after this standard dose. IVIg clearance may depend on disease severity and vary between individuals, implying that this dose is suboptimal for some patients. In this study, we determined whether the pharmacokinetics of IVIg is related to outcome in GBS. Methods We included 174 GBS patients who had previously participated in 2 randomized clinical trials. At entry, all patients were unable to walk unaided and received a standard dose of IVIg. Total IgG levels in serum samples obtained immediately before and 2 weeks after the start of IVIg administration were determined by turbidimetry and related to clinical outcome at 6 months. Results The increase in serum IgG (ΔIgG) 2 weeks after IVIg treatment varied considerably between patients (mean, 7.8g/L; standard deviation, 5.6g/L). Patients with a low ΔIgG recovered significantly more slowly, and fewer reached the ability to walk unaided at 6 months (log-rank p < 0.001). In multivariate analysis adjusted for other known prognostic factors, a low ΔIgG was independently associated with poor outcome (p = 0.022). Interpretation After a standard dose of IVIg treatment, GBS patients show a large variation in pharmacokinetics, which is related to clinical outcome. This may indicate that patients with a small increase in serum IgG level may benefit from a higher dosage or second course of IVIg. Ann Neurol 2009;66:597–603

The origin of antibodies to ganglioside complexes, as new immunotargets for Guillain-Barré syndrome (GBS), is unknown. This was investigated in 21 GBS patients from which Campylobacter jejuni was isolated. Two of these patients had serum IgG to the GM1/GD1a complex and two other patients had IgG to the GQ1b/GD1a complex. These pairs of patients were clinically distinct. These antibodies all cross-reacted to lipo-oligosaccharides (LOS) from the autologous C. jejuni strain. Previous mass spectrometry studies on these LOS showed the presence of oligosaccharides with a similar structure, further supporting the hypothesis that in these patients LOS induced the ganglioside complex antibodies.

Objective: To elucidate the effects of physical exercise in severely fatigued patients with Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, and to clarify the mutual relationships between 5 domains studied in these patients: physical fitness, fatigue, objectively mea sured actual mobility, perceived physical functioning, and perceived mental functioning. Design: Case series. Subjects/patients: Twenty patients with Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuro pathy. Methods: The patients undertook a 12-week physical exercise program. Relationships between domains were studied in the change scores, and additionally in the baseline data of patients. The percentage of significant relationships between each pair of domains was determined. Results: In the change scores, a small percentage of significant relationships was found between the physical fitness domain and the other 4 domains (2/30, 7%). A higher percentage of significant relationships was found between the domains perceived mental functioning and actual mobility (44%), perceived mental functioning and perceived physical functioning (44%), and between fatigue and perceived physical functioning (33%). Generally, similar patterns were found in the baseline data. Conclusion: Changes in fatigue, actual mobility and perceived functioning seem not to be influenced by changes in phy sical fitness. This study stresses the presence and importance of additional effects of a physical training program, not directly related to increasing fitness.

Summary Background Guillain-Barre syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a highly variable clinical course and outcome. We aimed to develop and validate a scoring system based on clinical characteristics in the acute phase of GBS to predict outcome at 6 months. Methods We studied patients with GBS who were unable to walk independently. A derivation set included 388 patients from two randomised controlled trials and one pilot study. Potential predictors were assessed for their association with the inability to walk independently at 6 months. A simple clinical scoring system was developed on the basis of regression coefficients of predictors in a multivariable logistic regression model. Model performance was quantified with respect to discrimination (area under receiver operating characteristics curve, AUC) and calibration (graphically). We validated our scoring system in a set of 374 patients from another randomised trial. Findings We included three variables that were predictive of poor outcome at 6 months in our model: age, preceding diarrhoea, and GBS disability score at 2 weeks after entry. Scores ranged from 1 to 7, with three categories for age, two for diarrhoea, and five for GBS disability score at 2 weeks. Predictions corresponding to these prognostic scores ranged from 1% to 83% for the inability to walk independently at 6 months. Predictions agreed well with observed outcome frequencies (adequate calibration) and showed a very good discriminative ability (AUC 0·85) in both data sets. Interpretation A simple scoring system for patients with GBS, based on three clinical characteristics, accurately predicts outcome at 6 months. The system could be used to counsel individual patients and identify high-risk groups to guide future trials.