Publications by authors named "Jan J G M Verschuuren"

91 Publications

Prevalence and associated factors of fatigue in autoimmune myasthenia gravis.

Neuromuscul Disord 2021 Apr 24. Epub 2021 Apr 24.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Fatigue is usually defined as a subjective perception of lacking energy, mentally or physically, with a difficulty sustaining voluntary activities. It is a common symptom of many diseases and most likely has a multifactorial cause. In myasthenia gravis (MG), fatigue has a high prevalence and is correlated with female sex and disease severity. However, no large scale studies have been performed. Therefore, we aimed to evaluate fatigue in the Dutch participants (n = 420) of the Dutch-Belgian Myasthenia Patient Registry using an online survey. Additional information was obtained on mood, sleep, coping, quality of life, disease severity, physical activities and medication. Severe fatigue was present in 62% with a mean score of 37.1 ± 13.2 points. Fatigue severity and prevalence increased significantly with disease severity. A positive correlation was found for female gender, BMI, disease severity and depressive symptoms. A negative correlation was found for strenuous physical activities and older age. The strong association with disease severity suggests that fatigue should be recognized as an element of the symptomatology of MG. The observed association between strenuous activity and fatigue and differences in coping style between fatigued and non-fatigued patients warrant future clinical trials on exercise and cognitive behavioral therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2021.04.002DOI Listing
April 2021

Preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients.

J Cachexia Sarcopenia Muscle 2021 May 8. Epub 2021 May 8.

Duchenne Center, Leiden, Netherlands.

Background: Clinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non-ambulant DMD patients, hand function is relatively preserved and crucial for daily-life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non-ambulant DMD patients.

Methods: Seventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (range 9.5-25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4-point Dixon, and T2 was determined using multiecho spin-echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non-parametric tests.

Results: Total volume was lower in patients compared with healthy controls (6.9 cm , 5.3-9.0 cm vs. 13.0 cm , 7.6-15.8 cm , P = 0.010). CV was also lower in patients (6.3 cm , 4.6-8.3 cm vs. 11.9 cm , 6.9-14.6 cm , P = 0.010). FF was slightly elevated (9.7%, 7.3-11.4% vs. 7.7%, 6.6-8.4%, P = 0.043), while T2 was higher (31.5 ms, 30.0-32.6 ms vs. 28.1 ms, 27.8-29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137-4.010 to 2.243 kg, 1.930-3.339 kg, and 29 points, 20-36 to 23 points, 17-30, both P < 0.001), while PROM did not (49 points, 36-57 to 44 points, 30-54, P = 0.041). All patients were able to play for 10 min at baseline or follow-up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2 (rho = 0.57, rho = 0.51, and rho = -0.59).

Conclusions: Low thenar FF, increased T2 , correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12711DOI Listing
May 2021

Clinical Management of Duchenne Muscular Dystrophy in the Netherlands: Barriers to and Proposals for the Implementation of the International Clinical Practice Guidelines.

J Neuromuscul Dis 2021 Mar 30. Epub 2021 Mar 30.

Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Department of Rehabilitation, Nijmegen, The Netherlands.

Background: In order to successfully implement the international clinical care guidelines for Duchenne muscular dystrophy (DMD) in the Netherlands, it is essential to know what barriers are experienced by healthcare practitioners regarding guideline adherence and organization of care. In the Netherlands, academic medical centers provide follow up visits and work together with peripheral hospitals, rehabilitation centers, centers for home ventilation and primary care centers for treatment.

Objective: To investigate perceived barriers to international clinical DMD guideline adherence and identify potential areas of improvement for implementation in the Dutch 'shared care' organization.

Methods: Semi-structured in-depth interviews with healthcare practitioners of academic medical hospitals and questionnaires for healthcare practitioners of rehabilitation centers, based on the framework of Cabana.

Results: The analyses identified 4 barriers for non-adherence to the DMD guideline: (i) lack of familiarity/awareness, (ii) lack of agreement with specific guideline, (iii) lack of outcome expectancy, (iv) external barriers.

Conclusions: A heterogeneous set of barriers is present. Therefore, a multifaceted intervention strategy is proposed to overcome these barriers, including a clear division of roles, allowing for local (Dutch) adaptations per specialism by local consensus groups, and the facilitation of easy communication with experts/opinion leaders as well as between care professionals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-200586DOI Listing
March 2021

Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial.

Lancet Neurol 2021 04 17;20(4):275-283. Epub 2021 Mar 17.

Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.

Background: Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré 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-Barré syndrome with a predicted poor outcome.

Methods: In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré 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-Barré 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-Barré 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-Barré 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-Barré 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-Barré syndrome.

Funding: Prinses Beatrix Spierfonds and Sanquin Plasma Products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(20)30494-4DOI Listing
April 2021

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

NMR Biomed 2021 01 7;34(1):e4407. Epub 2020 Sep 7.

CJ Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2 ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2 values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2 and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm (LoA: ± 0.36 cm ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm ) and MG (0.8 ± 0.2 cm ) compared with HC (0.6 ± 0.2 cm ). The average T2 for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2 was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757175PMC
January 2021

Improved diagnosis of viral encephalitis in adult and pediatric hematological patients using viral metagenomics.

J Clin Virol 2020 09 31;130:104566. Epub 2020 Jul 31.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Metagenomic sequencing is a powerful technique that enables detection of the full spectrum of pathogens present in any specimen in a single test. Hence, metagenomics is increasingly being applied for detection of viruses in clinical cases with suspected infections of unknown etiology and a large number of relevant potential causes. This is typically the case in patients presenting with encephalitis, in particular when immunity is impaired by underlying disorders. In this study, viral metagenomics has been applied to a cohort of hematological patients with encephalitis of unknown origin. Because viral loads in cerebrospinal fluid of patients with encephalitis are generally low, the technical performance of a metagenomic sequencing protocol with viral enrichment by capture probes targeting all known vertebrate viral sequences was studied. Subsequently, the optimized viral metagenomics protocol was applied to a cohort of hematological patients with encephalitis of unknown origin. Viral enrichment by capture probes increased the viral sequence read count of metagenomics on cerebrospinal fluid samples 100 - 10.000 fold, compared to unenriched metagenomic sequencing. In five out of 41 (12%) hematological patients with encephalitis, a virus was detected by viral metagenomics which had not been detected by current routine diagnostics. BK polyomavirus, hepatitis E virus, human herpes virus-6 and Epstein Barr virus were identified by this unbiased metagenomic approach. This study demonstrated that hematological patients with encephalitis of unknown origin may benefit from early viral metagenomics testing as a single step approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2020.104566DOI Listing
September 2020

Multi-parametric MR in Becker muscular dystrophy patients.

NMR Biomed 2020 11 5;33(11):e4385. Epub 2020 Aug 5.

C.J. Gorter Center, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross-sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non-fat-replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat-replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three-point Dixon, multi-spin-echo and diffusion-weighted spin-echo echo planar imaging) and 2D chemical shift imaging P MRS data were acquired in 24 patients with BMD (age 18.8-66.2 years) and 13 healthy controls (age 21.3-63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687231PMC
November 2020

Fatigue in patients with myasthenia gravis. A systematic review of the literature.

Neuromuscul Disord 2020 08 1;30(8):631-639. Epub 2020 Jul 1.

Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

Myasthenia Gravis (MG) is a chronic autoimmune disease affecting the neuromuscular junction. Although a hallmark of MG is muscle fatigability due to dysfunction of the neuromuscular junction (peripheral fatigue), a large number of MG patients also report symptoms of central fatigue, defined as an experienced lack of energy, physically and/or mentally. We systematically reviewed the literature on all aspects of central fatigue in MG. Results were categorized in 5 domains: prevalence, diagnosis, pathophysiology, treatment or impact. The prevalence of patient-reported fatigue varies between 42 and 82%, which is significantly higher than in control subjects. Fatigue severity is usually assessed with standardized questionnaires, but the choice of questionnaire varies widely between studies. The pathophysiology of fatigue is unknown, but it is strongly associated with depressive symptoms, female gender and disease severity. Fatigue is also highly prevalent in ocular MG and patients in remission, suggesting a multifactorial origin. Fatigued MG patients have a lower quality of life. Pharmacological treatment of MG is associated with improvement of fatigue and promising results have been found with physical and psychological training programs. Fatigue is a highly prevalent symptom of MG with a severe negative impact on quality of life. Physicians treating patients with MG should be aware of this symptom, as it may be treatable with physical or psychological training programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2020.06.010DOI Listing
August 2020

The face of myasthenia gravis.

Neurology 2020 07 10;95(2):89-90. Epub 2020 Jun 10.

From the Department of Neurology, Leiden University Medical Center, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009782DOI Listing
July 2020

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome.

Muscle Nerve 2020 07 22;62(1):111-114. Epub 2020 Apr 22.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition of this rare disease.

Methods: We determined the sensitivity and specificity of 60% and 100% cutoff values in all consecutive patients who underwent increment testing in our hospital from 1999 to 2016.

Results: We included 156 patients, 63 with LEMS and 93 without LEMS. Sensitivity of a 60% cutoff for increment testing was 77.8% (95% confidence interval 65.5%-87.3%) and 58.7% (45.6%-71.0%) for 100%. Specificity was 98.9% (94.2%-100%) and 100% (96.1%-100%) using a threshold of 60% and 100%, respectively.

Conclusions: Lowering the cutoff value for abnormal increment to 60% greatly increases sensitivity to diagnose LEMS without an overt loss in specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318278PMC
July 2020

Myasthenia Gravis Impairment Index: Sensitivity for Change in Generalized Muscle Weakness.

J Neuromuscul Dis 2020 ;7(3):297-300

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: The recently developed Myasthenia Gravis Impairment Index (MGII) is a promising measure as it has less floor effects and a higher relative efficiency in its responsiveness to treatment effect compared to other MG measures. This study aimed at validating the MGII in a Dutch cohort of MG patients and analyzing the sensitivity of MGII compared to MG-ADL for changes in generalized weakness.

Methods: We analyzed (generalized items of; -gen) MGII, quantitative myasthenia gravis (QMG), Myasthenia Gravis Activities of Daily Living (MG-ADL), EQ-5D visual analog, Myasthenia Gravis Composite (MGC) and ACTIVLIM (an ADL questionnaire focusing on generalized weakness) scores in a prospective cohort of 99 MG patients. We investigated correlations between MGII and other outcome measures. We used a generalized linear model to assess whether MGIIgen had an additional sensitivity on top of MG-ADLgen for changes (Δ) in QMGgen in individual patients.

Results: MGII had a lower floor effect (4%) compared to QMG (6%), MG-ADL (11%) and MGC (16%). MGII correlated well with QMG (r = 0.68), MG-ADL (r = 0.83) and MGC (r = 0.74). As expected, the correlations with EQ visual analog and ACTIVLIM were lower (r = - 0.57 and - 0.48). ΔMGIIgen had an additional value on top of ΔMG-ADLgen in the prediction of ΔQMGgen (B = 0.54, p = 0.01).

Discussion: The MGII score was cross-culturally validated in a Dutch cohort of MG patients. MGII had a higher sensitivity for generalized weakness than MG-ADL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-200484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369124PMC
March 2021

Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids.

Neuromuscul Disord 2020 02 14;30(2):111-119. Epub 2019 Dec 14.

Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.

Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs and thymectomy. Corticosteroids remain the cornerstone of treatment beside symptomatic medication due to their low cost, wide availability and fast mode of action. However, long term steroid use carries substantial risks of severe adverse side effects. Therefore, non-steroidal immunosuppressive drugs are commonly added to the treatment. Unfortunately, they have a delayed-onset effect and evidence of their efficacy appears to be difficult to obtain. Several trials using drugs that have had clear positive results in other immunological disorders have failed in myasthenia. This failure may in part be related to difficulties in the design of clinical trial for myasthenia, which has a fluctuating disease course involving weakness that may be difficult to assess quantitively. This problem is exacerbated by the tendency of most clinical trials to select patients with a stable, but severe disease. Future trials should: select patients with weakness and fatigability that is completely explained by their myasthenia gravis, use a design that avoids the exclusion of patients with recent changes in medication, and explore the possibilities to completely avoid the use of corticosteroids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.12.003DOI Listing
February 2020

Long-term follow-up, quality of life, and survival of patients with Lambert-Eaton myasthenic syndrome.

Neurology 2020 02 12;94(5):e511-e520. Epub 2019 Dec 12.

From the Departments of Neurology (A.F.L., J.J.G.M.V.) and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Department of Neurology (A.F.L.), Groene Hart Hospital, Gouda, the Netherlands; Department of Neurology (M.I.B., C.M.T.), Oslo University Hospital, Norway; Departments of Immunology (M.W.J.S.) and Neurology (M.J.T.), Erasmus University Medical Center, Rotterdam; Department of Neurology (J.B.M.K.), University Medical Center Groningen, the Netherlands; and Faculty of Medicine (C.M.T.), University of Oslo, Norway.

Objective: To study survival and to characterize long-term functional impairments and health-related quality of life (HRQOL) of patients with Lambert-Eaton myasthenic syndrome (LEMS).

Methods: In this observational study, survival of patients with LEMS, separately for nontumor (NT) and small cell lung cancer (SCLC), was compared to that of the Dutch general population and patients with SCLC. Disease course in patients with LEMS was recorded retrospectively. Several scales for functional impairments and health-related quality of life were assessed.

Results: We included 150 patients with LEMS. Survival was similar to that of the general population in 65 patients with NT-LEMS. Tumor survival was significantly longer in 81 patients with SCLC-LEMS compared to patients with non-LEMS SCLC (overall median survival 17 vs 7.0 months, < 0.0001). At diagnosis, 39 (62%) of 63 patients with complete follow-up data were independent for activities of daily living, improving to 85% at the 1-year follow-up. The physical HRQOL composite score (55.9) was significantly lower than in the general population (76.3, < 0.0001) and comparable to that of patients with myasthenia gravis (60.5). The mental HRQOL composite score was 71.8 in patients with LEMS, comparable to that of the general population (77.9, = 0.19) and patients with myasthenia gravis (70.3).

Conclusions: This study shows that patients with NT-LEMS have normal survival. Patients with SCLC-LEMS have an improved tumor survival, even after correction for tumor stage. A majority of patients with LEMS report a stable disease course and remain or become independent for self-care after treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080283PMC
February 2020

Treating muscle-specific kinase myasthenia gravis from the inside out.

Neurol Neuroimmunol Neuroinflamm 2020 01 12;7(1). Epub 2019 Dec 12.

From the Department of Neurology (M.G.H., J.J.G.M.V.) and Department of Human Genetics (M.G.H.), Leiden University Medical Center, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935833PMC
January 2020

Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis.

Neuromuscul Disord 2019 09 26;29(9):664-670. Epub 2019 Jul 26.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond differently to therapeutic interventions, it is important to acknowledge this variability. We analysed the distribution of muscle weakness in 225 AChR MG patients over time. On the basis of combinations of muscle weakness, seven phenotypes were defined: 'ocular' (O), 'bulbar' (B), 'neck/limbs/respiratory' (NLR), or a combination (O+B, O+NLR, B+NLR and O+B+NLR). MG remained restricted to ocular weakness in 5%, whereas 7% never had ocular weakness. At last follow-up, ocular or bulbar weakness had resolved more frequently than NLR weakness (40%, 38% and 25%; p = 0.003, respectively). Patients with O, B or OB phenotype at baseline had a higher age at onset and were more frequently male than patients with NLR, ONLR, BNLR or OBNLR phenotype (52.7 ± 17.5 vs. 44.0 ± 18.9; p = 0.007 and 64% vs. 37%; p = 0.002, respectively). MG patients have heterogeneous distributions of muscle weakness and frequently shift between phenotypes. The phenotypic variations found in AChR MG suggest that also other factors aside from the AChR antibody mediated immune response are of importance in determining the disease expression in MG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.07.006DOI Listing
September 2019

Ocular Weakness in Myasthenia Gravis: Changes in Affected Muscles are a Distinct Clinical Feature.

J Neuromuscul Dis 2019 ;6(3):369-376

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: In this study we quantitatively describe ocular weakness patterns in myasthenia gravis (MG) to help neurologists in making the clinical diagnosis and to investigate how the current outcome measures reflect ocular weakness in MG.

Methods: We investigated ptosis and diplopia patterns in a retro- and prospective cohort of 306 MG patients. Diplopia was systematically examined by testing extra-ocular muscle (EOM) fatigability in two horizontal and four oblique directions for 60 seconds.

Results: Of patients with initial symmetric ptosis, 40% developed asymmetric ptosis at the second visit. Changes in form of ptosis occurred less often in seronegative MG patients (50%) than in patients with acetylcholine receptor (AChR) antibodies (70%) or muscle-specific kinase (MuSK) antibodies (69%) (p = 0.038). Of patients with diplopia on the first visit, double vision contained both a vertical and horizontal component in 95%. At the second visit, 83% manifested diplopia in other gaze directions. The mean time (in seconds) to diplopia was 11.6±14.0 and the mean time to ptosis was 27.6±19.8. Diplopia or ptosis manifested within 30 seconds in 87% and 58%, respectively. Patients who manifested diplopia after 30 seconds, reported no limitations due to diplopia.

Discussion: Changes in the gaze directions in which diplopia occurs or ptosis side occur frequently in MG. In diagnostically challenging cases, we recommend testing ptosis and diplopia in multiple gaze directions for 30-60 seconds during at least two follow-up visits to maximize the chance of observing changes in ocular weakness patterns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-190407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839603PMC
February 2020

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis.

Neurology 2019 06 22;92(23):e2661-e2673. Epub 2019 May 22.

From the Department of Neurology (J.F.H.), University of North Carolina, Chapel Hill; Krembil Neuroscience Centre (V.B.), University Health Network, Toronto, Canada; Department of Neurology (T.M.B.), University of Virginia, Charlottesville; Department of Neuroimmunology and Neuromuscular Diseases (R.M.), Fondazione Istituto Neurologico Carlo Besta, Milan, Italy; Department of Neurology (B.M.), Wroclaw Medical University; Department of Neurology (A.S.), Jagiellonian University Medical College, Cracow, Poland; Department of Neurology (S.B.), University of Southern California, Keck School of Medicine, Los Angeles County Medical Center; Department of Neurology (F.J.R.D.R.G.), La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Spain; Neuroimmunology Unit, Department Clinical Neuroscience (F.P.), Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden; USC Neurologia (M.R.), USS Malattie Autoimmuni-Centro Sclerosi Multipla, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy; Neurology Department (P.V.D.), University Hospitals Leuven; Laboratory of Neurobiology (P.V.D.), Department of Neuroscience, KU Leuven and Center for Brain & Disease Research, VIB, Leuven, Belgium; Department of Neurology (T.V.), University of South Florida, Morsani College of Medicine, Tampa; Institute of Neurology (A.E.), Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy; Neurology Department (M.F.), The Ohio State University, Columbus; Department of Neurology (T.M.), University of California, Irvine; Department of Molecular and Cellular Medicine (E.S.W.), Texas A&M University Health Science Center, College Station; argenx BVBA (T.D., P.U., K.V., A.G., H.d.H., N.L.), Zwijnaarde, Belgium; and Department of Neurology (J.J.G.M.V.), Leiden University Medical Center (LUMC), the Netherlands.

Objective: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.

Methods: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.

Results: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.

Conclusions: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.

Classification Of Evidence: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556100PMC
June 2019

Myasthenia gravis.

Nat Rev Dis Primers 2019 05 2;5(1):30. Epub 2019 May 2.

Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41572-019-0079-yDOI Listing
May 2019

The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies.

Brain 2019 06;142(6):1631-1643

Department of Neurology, Erasmus Medical Center, Dr. Molewaterplein 40, GD, Rotterdam, The Netherlands.

In this study we report the clinical features of 32 patients with gamma aminobutyric acid B receptor (GABABR) antibodies, identify additional autoantibodies in patients with anti-GABABR encephalitis that mark the presence of an underlying small cell lung carcinoma and optimize laboratory methods for the detection of GABABR antibodies. Patients (n = 3225) were tested for the presence of GABABR antibodies using cell-based assay, immunohistochemistry and live hippocampal neurons. Clinical data were obtained retrospectively. Potassium channel tetramerization domain-containing (KCTD)16 antibodies were identified by immunoprecipitation, mass spectrometry analysis and cell-based assays. KCTD16 antibodies were identified in 23/32 patients with anti-GABABR encephalitis, and in 1/26 patients with small cell lung carcinoma and Hu antibodies, but not in 329 healthy subjects and disease controls. Of the anti-GABABR encephalitis patients that were screened sufficiently, 18/19 (95%) patients with KCTD16 antibodies had a tumour versus 3/9 (33%) anti-GABABR encephalitis patients without KCTD16 antibodies (P = 0.001). In most cases this was a small cell lung carcinoma. Patients had cognitive or behavioural changes (97%) and prominent seizures (90%). Thirteen patients developed a refractory status epilepticus with intensive care unit admittance (42%). Strikingly, 4/32 patients had a rapidly progressive dementia. The addition of KCTD16 to the GABABR cell-based assay improved sensitivity of the in-house fixed cell-based assay, without loss of specificity. Twenty-two of 26 patients improved (partially) to immunotherapy or chemotherapy. Anti-GABABR encephalitis is a limbic encephalitis with prominent, severe seizures, but patients can also present with rapidly progressive dementia. The co-occurrence of KCTD16 antibodies points towards a paraneoplastic origin. The addition of KCTD16 improves the sensitivity of the cell-based assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536844PMC
June 2019

Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial.

Lancet Neurol 2019 03 25;18(3):259-268. Epub 2019 Jan 25.

Department of Neurology, University of Florida, Jacksonville, FL, USA.

Background: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.

Methods: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.

Findings: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.

Interpretation: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.

Funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(18)30392-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774753PMC
March 2019

A prospective, double-blind, randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis.

Vaccine 2019 02 16;37(7):919-925. Epub 2019 Jan 16.

Department of Neurology, Leiden University Medical Center, the Netherlands.

Objective: To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG).

Methods: An influenza vaccination or placebo was administered to 47 AChR MG patients. Before and 4 weeks after administration blood samples and clinical outcome scores were obtained. Antibodies to the vaccine strains A/California/7/2009 (H1N1)pdm09, A/Hong Kong/4801/14 (H3N2) and B/Brisbane/060/08 were measured using the hemagglutination-inhibition (HI) assay and disease-specific AChR antibody titers were measured with a radio-immunoprecipitation assay. Forty-seven healthy controls (HC) were vaccinated with the same influenza vaccine to compare antibody titers.

Results: A post-vaccination, seroprotective titer (HI ≥ 1:40) was achieved in 89.4% of MG patients vs. 93.6% in healthy controls for the H3N2 strain, 95.7% vs 97.9% for the H1N1 strain and 46.8 vs 51% for the B-strain. A seroprotective titer for all three strains of the seasonal influenza vaccine was reached in 40.4% (19/47) of the MG group and in 51% (24/47) of the HC group. Immunosuppressive medication did not significantly influence post geomean titers (GMT). The titers of disease-specific AChR antibodies were unchanged 4 weeks after vaccination. The clinical outcome scores showed no exacerbation of MG symptoms.

Conclusion: The antibody response to an influenza vaccination in patients with AChR MG was not different from that in healthy subjects, even in AChR MG patients using immunosuppressive medication. Influenza vaccination does not induce an immunological or clinical exacerbation of AChR MG.

Clinical Trial Registry: The influenza trial is listed on clinicaltrialsregister.eu under 2016-003138-26.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2019.01.007DOI Listing
February 2019

Serum Acetylcholine Receptor Antibodies Before the Clinical Onset of Myasthenia Gravis.

J Neuromuscul Dis 2018 ;5(2):261-264

Department of Neurology, University Medical Centre of Groningen, The Netherlands.

A patient with autoimmune myasthenia gravis and a clinical and serological follow-up of 13 years is described. In this unique case, serum samples were available up to two years before the clinical onset of the myasthenia gravis and showed gradual increase of acetylcholine receptor antibodies, starting two years before onset of the clinical symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-180313DOI Listing
November 2018

Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice.

Neuromuscul Disord 2018 05 6;28(5):427-442. Epub 2018 Mar 6.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Dystrophin is a sub-sarcolemmal component of skeletal muscle fibres and is enriched at the postsynaptic membrane of the neuromuscular junction (NMJ). In the mdx mouse, dystrophin absence not only causes muscle damage but also mild synaptic dysfunctions and clear morphological aberrations at NMJs. In particular, reduction of postsynaptic sensitivity for the neurotransmitter acetylcholine and extra exhaustion of presynaptic acetylcholine release during intense synaptic activity exists. Current experimental therapeutic approaches in Duchenne muscular dystrophy aim to restore dystrophin expression. An important question is what dystrophin levels are needed to improve muscle function. Recent experimental and clinical studies suggested that levels as low as a few percent of normal can be beneficial. Similarly, it is of interest to know how dystrophin levels relate to NMJ function and morphology. We investigated NMJs of a series of mdx-Xist mice, which expressed dystrophin between ~2% and 19% of normal. Most functional and morphological NMJ parameters of these mice remained comparable to mdx. On the other hand, mdx mice (expressing ~50% dystrophin) showed normal NMJ features. Thus, the minimal dystrophin level required for normal NMJ function and morphology lies between 19% and 50% of normal when expression of dystrophin is not uniform.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2018.02.013DOI Listing
May 2018

Author Correction: Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Sci Rep 2018 Mar 1;8(1):4058. Epub 2018 Mar 1.

Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-22154-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832820PMC
March 2018

Distinct representation of muscle weakness in QMG and MG-ADL.

Lancet Neurol 2018 03;17(3):204-205

Department of Neurology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(18)30037-1DOI Listing
March 2018

Passive transfer models of myasthenia gravis with muscle-specific kinase antibodies.

Ann N Y Acad Sci 2018 02 21;1413(1):111-118. Epub 2018 Jan 21.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is characterized by fluctuating fatigable weakness. In MuSK MG, involvement of bulbar muscles, neck, and shoulder and respiratory weakness are more prominent than in acetylcholine receptor (AChR) MG. MuSK autoantibodies are mainly of the IgG4 subclass, and as such are unable to activate complement, have low affinity for Fc receptors, and are functionally monovalent. Therefore, the pathogenicity of IgG4 MuSK autoantibodies was initially questioned. A broad collection of in vitro active immunization and passive transfer models has been developed that have shed light on the pathogenicity of MuSK autoantibodies. Passive transfer studies with purified IgG4 from MuSK MG patients confirmed that IgG4 is sufficient to reproduce clear clinical, electrophysiological, and histological signs of myasthenia. In vitro experiments revealed that MuSK IgG4 autoantibodies preferably bind the first Ig-like domain of MuSK, correlate with disease severity, and interfere with the association between MuSK and low-density lipoprotein receptor-related protein 4 and collagen Q. Some patients have additional IgG1 MuSK autoantibodies, but their role in the disease is unclear. Altogether, this provides a rationale for epitope-specific or IgG4-specific treatment strategies for MuSK MG and emphasizes the importance of the development of different experimental models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.13543DOI Listing
February 2018

Neuromuscular synapse electrophysiology in myasthenia gravis animal models.

Ann N Y Acad Sci 2018 01 25;1412(1):146-153. Epub 2017 Oct 25.

Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.

The neuromuscular junction (NMJ) forms the synaptic connection between a motor neuron and a skeletal muscle fiber. In order to achieve a sustained muscle contraction, this synapse has to reliably transmit motor neuronal action potentials onto the muscle fiber. To guarantee successful transmission even during intense activation of the NMJ, a safety factor of neuromuscular transmission exists. In the neuromuscular disorder myasthenia gravis (MG), autoantibodies are directed against acetylcholine receptors or, in the rarer variants, against other postsynaptic NMJ proteins. This causes loss of functional acetylcholine receptors, which compromises the safety factor of neuromuscular transmission, leading to the typical fatigable muscle weakness of MG. With intracellular microelectrode measurement of (miniature) endplate potentials at NMJs in ex vivo nerve-muscle preparations from MG animal models, these functional synaptic defects have been determined in much detail. Here, we describe the electrophysiological events at the normal NMJ and the pathoelectrophysiology at NMJs of animal models for MG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.13507DOI Listing
January 2018

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Sci Rep 2017 10 3;7(1):12575. Epub 2017 Oct 3.

Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-12981-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626779PMC
October 2017

Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes.

Ann Clin Transl Neurol 2017 09 28;4(9):680-686. Epub 2017 Jul 28.

Cell Biology Department of Biology Faculty of Science Utrecht University Padualaan 83584 CH Utrecht The Netherlands.

Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590547PMC
September 2017

Aggregated N-of-1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis.

Orphanet J Rare Dis 2017 05 12;12(1):88. Epub 2017 May 12.

Department of Clinical Genetics, Amsterdam Public Health research institute, VU University Medical Center, Amsterdam, The Netherlands.

Background: Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results.

Results: The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug.

Conclusions: In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-017-0636-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427624PMC
May 2017