Population-based incidence rates of 15 neuromuscular disorders: a nationwide capture-recapture study in the Netherlands.

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

The 2022 European postgraduate (residency) programme in neurology in a historical and international perspective.

BACKGROUND AND PURPOSE: Neurology residency programmes, which were first established at the beginning of the 20th century, have become mandatory all over Europe in the last 40-50 years. The first European Training Requirements in Neurology (ETRN) were published in 2005 and first updated in 2016. This paper reports the most recent revisions of the ETRN. METHODS: Members of the EAN board performed an in depth revision of the ETNR 2016-version, which was reviewed by members of the European Board and Section of Neurology of the UEMS, the Education and Scientific Panels, the Resident and Research Fellow Section and the Board of the EAN, as well as the presidents of the 47 European National Societies. RESULTS: The new (2022) ETRN suggest a 5-year training subdivided in three phases: a first phase (2 years) of general neurology training, a second phase (2 years) of training in neurophysiology/neurological subspecialties and a third phase (1 year) to expand clinical training (e.g., in other neurodisciplines) or for research (path for clinical neuroscientist). The necessary theoretical and clinical competences as well as learning objectives in diagnostic tests have been updated, are newly organized in four levels and include 19 neurological subspecialties. Finally, the new ETRN require, in addition to a programme director, a team of clinician-educators who regularly review the resident's progress. The 2022 update of the ETRN reflects emerging requirements for the practice of neurology and contributes to the international standardization of training necessary for the increasing needs of residents and specialists across Europe.

Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis.

The aim of this study was to investigate the surgical and long-term neurological outcomes of patients with acetylcholine-receptor-antibody-associated myasthenia gravis (AChR-MG) who underwent robotic thymectomy (RATS). We retrospectively analyzed the clinical-pathological data of all patients with AChR-MG who underwent RATS using the DaVinci® Robotic System at the MUMC+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. In total, 230 myasthenic patients including 76 patients with a thymoma (33.0%) were enrolled in this study. Mean follow-up time, procedure time and hospitalization were, respectively 65.7 ± 43.1 months, 111±52.5 min and 3.3 ± 2.2 days. Thymomatous patients had significantly more frequently and more severe complications than nonthymomatous patients (18.4% vs. 3.9%, p<0.001). Follow up data was available in 71.7% of the included patients. The Myasthenia Gravis Foundation of America postintervention score showed any kind of improvement of MG-symptoms after RATS in 82.4% of the patients. Complete stable remission (CSR) or pharmacological remission (PR) of MG was observed in 8.4% and 39.4% of the patients, respectively. Mean time till CSR/PR remission after thymectomy was 26.2 ± 29.2 months. No statistical difference was found in remission or improvement in MGFA scale between thymomatous and nonthymomatous patients. RATS is safe and feasible in patients with MG. The majority of the patients (82.4%) improved after thymectomy. CSR and PR were observed in 8.4% and 39.4% of the patients, respectively, with a mean of 26.2 months after thymectomy. Thymomatous patients had more frequently and more severe complications compared to nonthymomatous patients.

Slow Channel Syndrome Revisited: 40 Years Clinical Follow-Up and Genetic Characterization of Two Cases.

BACKGROUND: The slow channel syndrome is a rare hereditary disorder caused by a dominant gain-of-function variant in one of the subunits of the acetylcholine receptor at the neuromuscular junction. Patients typically experience axial, limb and particularly extensor finger muscle weakness. OBJECTIVE: Age at diagnosis is variable and although the long-term prognosis is important for newly diagnosed patients, extensive follow-up studies are rare. We aim to provide answers and perspective for this patient group by presenting an elaborate description of the lifetime follow-up of two slow channel syndrome patients. METHODS: We describe 40 years follow-up in two, genetically confirmed cases (CHRNA1; c.866G > T p.(Ser289Ile)(legacy Ser269Ile) and CHRNE; c.721C > T p.(Leu241Phe)(legacy Leu221Phe) variants). RESULTS: We find that the disease course has a fluctuating pattern and is only mildly progressive. However, hormonal imbalances, (psychological) stress or excessive hot or cold environments are often aggravating factors. Quinidine and fluoxetine are helpful, but ephedrine and salbutamol may also improve symptoms. CONCLUSION: Slow channel syndrome is mildly progressive with a fluctuating pattern. The observations reported here provide a lifespan perspective and answers to the most pressing questions about prognosis and treatment options for newly diagnosed patients.

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

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.

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis.

OBJECTIVE: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. METHODS: sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNP+ and AL/PNP-, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNP+), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age- and sex-matched to both AL/PNP- (HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. RESULTS: sNfL levels were increased both in 10 AL/PNP+ patients (p < .001) and in 10 AL/PNP- patients (p < .005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNP+ patients than in AL/PNP- patients (p < .005). sNfL levels were also increased in 15 ATTRv/PNP+ patients, compared to both 15 HC/TTRv (p < .0001) and 15 TTRv carriers (p < .0001). ATTRv/PNP+ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p = .05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. CONCLUSION: sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis.

Vibration threshold in non-diabetic subjects.

Measuring vibration perception threshold (VPT) accurately classifies and quantifies the severity of loss of vibration perception. A biothesiometer (Bio-thesiometer®; Bio Medical Instrument Co, Ohio, USA) appears to be the most suitable tool to determine VPT due to its low inter-rater variability and low occurence of adaption to the sensation. Different VPT values for a biothesiometer have been described, however, specification on age, height and different measurement locations is currently lacking. The objective of our study was to identify determinants of vibration perception in non-diabetic subjects, in order to provide individualized normal values of VPTs for clinical practice. Measurements of the vibration perception were performed on the big toes, insteps, lateral malleoli, and wrists. A total of 205 healthy subjects were included (108 (52.7%) males) with a median [interquartile range] age of 59 [51;64] (range 21-80) years. Mean height was 174.45 ± 9.20 cm and mean weight was 82.94 ± 14.84 kg, resulting in a mean BMI of 27.19 ± 4.00 kg/m2. In stepwise forward linear regression analyses, age (st. ß = 0.51, p < 0.001) and height (st. ß = 0.43, p < 0.001) were found to be the independent unmodifiable determinants of the VPT at the big toe. Regression coefficients for quantiles of the determinants age and height were incorporated in the corresponding regression equations. This study provides equations to calculate age- and height-specific normal values for VPT that can be used in clinical practice and in large research studies.

How students and specialists appreciate the mini-clinical evaluation exercise (mini-CEX) in Indonesian clerkships.

BACKGROUND: Cultural differences might challenge the acceptance of the implementation of assessment formats that are developed in other countries. Acceptance of assessment formats is essential for its effectiveness; therefore, we explored the views of students and specialists on the practicality and impact on learning of these formats. This study was conducted to explore Indonesian students' and specialists' appreciation of the implementation of the Mini-Clinical Evaluation Exercise (Mini-CEX) in Indonesian clerkships. METHODS: This study was conducted at the Universitas Gadjah Mada, Indonesia. Participants were 52 students and 21 specialists in neurology and 78 students and 50 specialists in internal medicine. They were asked to complete a 19-item questionnaire that covered the characteristics of the mini-CEX such as its practicality, and the impact on learning and professional development. We used a Mann-Whitney U test to analyse the data. RESULTS: In total, 124 students (46 from neurology and 78 from internal medicine) and 38 specialists (13 from neurology and 25 from internal medicine) participated in this study. Students and specialists were positive about the practicality of the mini-CEX and the impact of this assessment format on learning and on professional development. The Mann-Whitney U test showed that there were no significant differences between students' and specialists' opinions on the mini-CEX, except for 2 items: specialists' appreciation of direct observation (mean rank = 93.16) was statistically significantly higher than students' appreciation of it (mean rank = 77.93; z = 2.065; p < 0.05), but students' appreciation of the item that students' past mini-CEX results affected their recent mini-CEX outcomes (mean rank = 85.29) was significantly higher than specialists' appreciation of it (mean rank = 69.12; z = 2140; p < 0.05). CONCLUSION: Students and specialists were positive about the mini-CEX in Indonesian clerkships, although it was developed and validated in another culture. We found only small differences between their appreciations, which could be explained by the patterns of specialist-student interaction in Indonesian culture as large power distance and low individualism country.

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

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, p < 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, p < 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, p = 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.

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10-6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.

The prevalence and severity of disease-related disabilities and their impact on quality of life in neuromuscular diseases.

PURPOSE: People with neuromuscular disease experience lower quality of life levels than people from the general population. We examined the prevalence and severity of a broad range of neuromuscular disease-related disabilities and their impact on health-related quality of life. MATERIALS AND METHODS: A cross-sectional postal survey study was conducted among patients diagnosed with neuromuscular disease. Patients completed the Neuromuscular Disease Impact Profile, a disease-related disability impact questionnaire, and two generic health-related quality of life questionnaires: the medical outcome study Short Form Questionnaire and the World Health Organization Quality of Life-bref. The impact of disabilities on quality of life was estimated using multiple regression analyses. RESULTS: Six hundred sixty two patients (68% response rate) completed the questionnaires. There were no differences in quality of life between diagnosis-based subgroups. 'Impairments in muscle functions' had the highest prevalence and severity scores in the total sample and diagnosis-based subgroups. Neuromuscular disease-related disabilities showed strong and independent associations with all aspects of health-related quality of life. 'Impairments in mental functions and pain' was the most important predictor of health-related quality of life followed by 'restrictions in participation in life situations'. CONCLUSIONS: Although 'impairment in muscle functions' is the most prevalent and severe disability, the 'impairments in mental functions and pain' have a strong association with health-related quality of life in patients with a neuromuscular disease. Implications for rehabilitation Disease-related disabilities have a strong and independent associations with all aspects of health-related quality of life. Although health-related domains of quality of life are affected by the neuromuscular disease, the general quality of life is quite good. The most prevalent and severe disability in total group and diagnosis-based subgroups is 'impairments in muscle functions'. The most significant predictor in health-related quality of life is 'impairments in mental functions and pain'.

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

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.

Clinical workplace learning: perceived learning value of individual and group feedback in a collectivistic culture.

BACKGROUND: Feedback is essential for workplace learning. Most papers in this field concern individual feedback. In collectivistic cultures, however, group feedback is common educational practice. This study was conducted to investigate the perceived learning value and characteristics of individual and group feedback in a collectivistic culture. METHODS: During two weeks, on a daily basis, clerkship students (n = 215) from 12 clinical departments at Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia, recorded individual and group feedback moments by using a structured form: the providers, focus and perceived learning value of feedback. Data were analysed with logistic regression and multilevel techniques. RESULTS: Students reported 2687 group and 1535 individual feedback moments. Group feedback more often focused on history taking, clinical judgment, patient management, patient counselling, and professional behaviour (OR ranging from 1.232, p < .01, to 2.152, p < .001), but less often on physical examination (OR = .836, p < .01). Group feedback less often aimed at correcting performance deficiencies (OR = .523, p < .001) and more often at comparing performance to the standard (OR = 2.447, p < .001) and planning action to improve performance (OR = 1.759, p < .001). Group feedback was perceived as more valuable than individual feedback (M = 4.08 and 3.96, respectively, ß group = .065, SE = .026, p < .01). CONCLUSION: In collectivistic cultures, group feedback may add to the array of educational measures that optimize student learning. Congruence between culture and type of feedback may be important for the effectiveness of feedback.

The extremity function index (EFI), a disability severity measure for neuromuscular diseases: psychometric evaluation.

OBJECTIVE: To adapt and to combine the self-report Upper Extremity Functional Index and Lower Extremity Function Scale, for the assessment of disability severity in patients with a neuromuscular disease and to examine its psychometric properties in order to make it suitable for indicating disease severity in neuromuscular diseases. DESIGN: A cross-sectional postal survey study was performed among patients diagnosed with a neuromuscular disease. METHODS: Patients completed both adapted extremity function scales, questionnaires for psychometric evaluation, and disease-specific questions. Confirmatory factor analysis was performed, and reliability and validity were examined. RESULTS: Response rate was 70% (n = 702). The Extremity Function Index model with a two-factor structure - for upper and lower extremities - showed an acceptable fit. The Extremity Function Index scales showed good internal consistency (alphas: 0.97-0.98). The known-groups validity test confirmed that Extremity Function Index scales discriminate between categories of "Extent of limitations" and "Quality of Life." Convergent and divergent validity tests confirmed that Extremity Function Index scales measure the physical impact of neuromuscular diseases. Relative validity tests showed that the Extremity Function Index scales performed well in discriminating between subgroups of patients with increasing "Extent of limitations" compared to concurrent measurement instruments. CONCLUSION: The Extremity Function Index proved to be a sound and easy to apply self-report disability severity measurement instrument in neuromuscular diseases. Implications for rehabilitation The Extremity Function Index reflects the functioning of all muscles in the upper and lower extremities involved in activities of daily living. The Extremity Function Index is an easy to administer and patient-friendly disability severity measurement instrument that has the ability to evaluate differences in disability severity between relevant neuromuscular disease subgroups. The Extremity Function Index is a valid and reliable disability severity measurement instrument for neuromuscular diseases.

Stability and relative validity of the Neuromuscular Disease Impact Profile (NMDIP).

BACKGROUND: The aim of this study was to examine the stability and relative validity (RV) of the Neuromuscular Disease Impact Profile (NMDIP) using criterion-related groups. In a previous study the NMDIP-scales showed good internal consistency, convergent and discriminant validity. Known-groups analysis showed that the NMDIP discriminates between categories of extent of limitations. METHODS: A cross-sectional postal survey study was performed on patients diagnosed with a NMD and registered at the Department of Neurology, University Medical Center Groningen, the Netherlands. Participants were asked to complete the preliminary NMDIP, the Medical Outcome study Short Form Questionnaire (SF-36), the World Health Organization Quality Of Life-abbreviation version (WHOQOL-bref), and two generic domain specific measures: the Groningen Activity Restriction Scale (GARS) and the Impact on Participation and Autonomy Questionnaire (IPAQ). The variables 'Extent of Limitations' and 'Quality of Life' were used to create criterion-related groups. Stability over time was tested using the Wilcoxon Signed Rank Test for paired samples and the intraclass correlation coefficients for repeated measures. RV was examined by comparing the ability of NMDIP with generic multidimensional health impact measures, and domain specific measures in discriminating between criterion-related subgroups using the Kruskal-Wallis H-test. RESULTS: Response rate was 70% (n = 702). The NMDIP-scales showed sufficient stability over time, and satisfactory or strong RV. In general, the NMDIP scales performed as well as or better than the concurrent measurement instruments. CONCLUSIONS: The NMDIP proved to be a valid and reliable disease-targeted measure with a broad scope on physical, psychological and social functioning.

Influence of feedback characteristics on perceived learning value of feedback in clerkships: does culture matter?

BACKGROUND: Various feedback characteristics have been suggested to positively influence student learning. It is not clear how these feedback characteristics contribute to students' perceived learning value of feedback in cultures classified low on the cultural dimension of individualism and high on power distance. This study was conducted to validate the influence of five feedback characteristics on students' perceived learning value of feedback in an Indonesian clerkship context. METHODS: We asked clerks in Neurology (n = 169) and Internal Medicine (n = 132) to assess on a 5-point Likert scale the learning value of the feedback they received. We asked them to record whether the feedback provider (1) informed the student what went well, (2) mentioned which aspects of performance needed improvement, (3) compared the student's performance to a standard, (4) further explained or demonstrated the correct performance, and (5) prepared an action plan with the student to improve performance. Data were analyzed using multilevel regression. RESULTS: A total of 250 students participated in this study, 131 from Internal Medicine (response rate 99%) and 119 from Neurology (response rate 70%). Of these participants, 225 respondents (44% males, 56% females) completed the form and reported 889 feedback moments. Students perceived feedback as more valuable when the feedback provider mentioned their weaknesses (ß = 0.153, p < 0.01), compared their performance to a standard (ß = 0.159, p < 0.01), explained or demonstrated the correct performance (ß = 0.324, p < 0.001) and prepared an action plan with the student (ß =0.496, p < 0.001). Appraisal of good performance did not influence the perceived learning value of feedback. No gender differences were found for perceived learning value. CONCLUSIONS: In Indonesia, we could validate four out of the five characteristics for effective feedback. We argue that our findings relate to culture, in particular to the levels of individualism and power distance. The recognized characteristics of what constitutes effective feedback should be validated across cultures.

Myasthenia gravis with muscle specific kinase antibodies mimicking amyotrophic lateral sclerosis.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is hallmarked by the predominant involvement of bulbar muscles and muscle atrophy. This might mimic amyotrophic lateral sclerosis (ALS) presenting with bulbar weakness. We encountered four cases of MuSK MG patients with an initial misdiagnosis of ALS. We analyzed the clinical data of the four misdiagnosed MuSK MG patients, and investigated the presence of MuSK autoantibodies in a group of 256 Dutch bulbar-onset ALS patients using a recombinant MuSK ELISA and a standard MuSK radioimmunorecipitation assay. Clues for changing the diagnosis were slow progression, clinical improvement, development of diplopia and absence of signs of upper motor neuron involvement. No cases of MuSK MG were identified among a group of 256 bulbar ALS patients diagnosed according to the revised El Escorial criteria. A misdiagnosis of ALS in patients with MuSK MG is rare. We recommend to carefully consider the diagnosis of MuSK MG in patients presenting with bulbar weakness without clear signs of upper motor neuron dysfunction.

The epidemiology of neuromuscular disorders: Age at onset and gender in the Netherlands.

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.

Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity.

Muscle weakness in MuSK myasthenia gravis (MG) is caused predominantly by IgG4 antibodies which block MuSK signalling and destabilize neuromuscular junctions. We determined whether the binding pattern of MuSK IgG4 antibodies change throughout the disease course ("epitope spreading"), and affect disease severity or treatment responsiveness. We mapped the MuSK epitopes of 255 longitudinal serum samples of 53 unique MuSK MG patients from three independent cohorts with ELISA. Antibodies against the MuSK Iglike-1 domain determine disease severity. Epitope spreading outside this domain did not contribute to disease severity nor to pyridostigmine responsiveness. This provides a rationale for epitope specific treatment strategies.

Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis.

PURPOSE OF REVIEW: These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. RECENT FINDINGS: The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. SUMMARY: Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.