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Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3–5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints. [ABSTRACT FROM AUTHOR]

Background and purpose: Myasthenia gravis activities of daily living (MG‐ADL) is a commonly used questionnaire in MG trials. To investigate whether MG‐ADL is equally sensitive to oculobulbar and generalized weakness, its correlation with the oculobulbar and generalized domain of the quantitative myasthenia gravis (QMG) score was analyzed (QMGob and QMGgen, respectively). To test whether the sensitivity of MG‐ADL for generalized weakness could be improved, the additional value of ACTIVLIM on top of MG‐ADL in the prediction QMGgen in was investigated. Methods: MG‐ADL, QMG and ACTIVLIM, an ADL questionnaire focusing on generalized weakness, were analyzed in a prospective cohort of 112 MG patients. A generalized linear model was used to calculate the correlation of MG‐ADL with QMGob and QMGgen and to assess the additional value of ACTIVLIM on top of MG‐ADL for its correlation with QMGgen. Results: MG‐ADL had a higher correlation with QMGob than with QMGgen (B = 0.68, P < 0.001, and B = 0.38, P < 0.001, respectively). A similar trend was found for changes in the scores (B = 0.68, P = 0.132, and B = 0.39, P = 0.492, respectively). ACTIVLIM had a significant additional value on top of MG‐ADL in the prediction of QMGgen, both cross‐sectionally (B = −0.61, P < 0.001) and for changes within individual patients (B = −0.93, P = 0.041). Conclusion: MG‐ADL has a lower sensitivity for generalized weakness than for oculobulbar weakness. Adding questions on generalized weakness would improve the sensitivity of the MG‐ADL for generalized weakness. [ABSTRACT FROM AUTHOR]

Objectives: To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Methods: Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5–15.4 years) and 12 age-matched healthy controls (range: 5–14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. Results: PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. Discussion and conclusion: The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles ( p<0.05) and an increased mean diffusivity ( p<0.05) and λ3 ( p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient ( p<0.009) and λ3 in the TA and GCL muscles ( p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

At least 13 different disease entities affecting the central nervous system, peripheral nervous system and connective tissue of the skin or kidneys are associated with immunoglobulin G4 (IgG4) immune reactivity. IgG4 has always been considered a benign, non-inflammatory subclass of IgG, in contrast to the well-known complement-activating pro-inflammatory IgG1 subclass. A comprehensive review of these IgG4 autoimmune disorders reveals striking similarities in epitope binding and human leukocyte antigen ( HLA) associations. Mechanical interference of extracellular ligand−receptor interactions by the associated IgG4 antibodies seems to be the common/converging disease mechanism in these disorders. [ABSTRACT FROM AUTHOR]

Current available therapies control Myasthenia gravis (MG) reasonably well, but Health Related Quality of life (HRQOL) remains lower than expected. The aim was provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders and assess the impact of potential predictors for quality of life such as a) clinical characteristics b) antibodies c) thymoma and d) treatment in a population-based cohort. Methods: We designed a population-based cross-sectional study including 858 patients, 373 from Norway and 485 from the Netherlands. The Short Form Health Survey 36 (SF-36) and a cross-cultural validated questionnaire were used. Data were in addition compared to the general population, other chronic diseases and previous studies. Results: Mean physical composite score was 59.4 and mental composite score 69.0 with no differences between the countries. The mean HRQOL score was lower in patients with bulbar and generalized symptoms (p < 0.001) compared to sex and age adjusted healthy controls, but not in patients with ocular symptoms or patients in remission. Multivariate analysis revealed that female gender, generalized symptoms and use of secondary immunosuppressive drugs at the time of testing were risk factors for reduced HRQOL. Conclusions: Remission and absence of generalized symptoms were favorable factors for HRQOL in MG patients. Historically, the HRQOL levels have not changed since 2001 and no new clinical predictors could be detected in this exhaustive population-based study. Further studies should explore the impact of non clinical factors like ethnic variations, socio-economic and hormonal factors on HRQOL. [ABSTRACT FROM AUTHOR]

Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and 31P MRS. MRI and 31P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher ( P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls ( P ≤ 0.05). The Pi/ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions ( P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions ( P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls ( P < 0.05). These findings suggest that 31P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship. [ABSTRACT FROM AUTHOR]

Objective: Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45-47 deletion. Methods: Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. Results: 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%-78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45-47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45-47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients' age. Conclusions: Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45-47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced. [ABSTRACT FROM AUTHOR]

Autoantibodies against three different postsynaptic antigens and one presynaptic antigen at the neuromuscular junction are known to cause myasthenic syndromes. The mechanisms by which these antibodies cause muscle weakness vary from antigenic modulation and complement-mediated membrane damage to inhibition of endogenous ligand binding and blocking of essential protein-protein interactions. These mechanisms are related to the autoantibody titre, specific epitopes on the target proteins and IgG autoantibody subclass. We here review the role of specific autoantibody-binding epitopes in myasthenia gravis, their possible relevance to the pathophysiology of the disease and potential implications of epitope mapping knowledge for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. Methods: Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. Results: Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. Conclusions: This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to evaluate fracture risk after onset of myasthenia gravis using the UK General Practice Research Database. Overall fracture risk is not statistically increased compared with age- and gender-matched controls irrespective of glucocorticoid use, but was increased in those using antidepressants, anxiolytics or anticonvulsants. Introduction: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. The aim of this study was to evaluate the risk of fracture after onset of MG. Methods: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2009). Each MG patient was matched by age, sex, calendar time and practice to up to six patients without a history of MG and we identified all fractures and those associated with osteoporosis. Results: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure. However, fracture risk was higher in patients with MG prescribed antidepressants (AHR 3.27 [95 % CI, 1.63-6.55]), anxiolytics (AHR 2.18 [95 % CI, 1.04-4.57]) and anticonvulsants (AHR 6.88 [95 % CI, 2.91-16.27]). Conclusion: Overall risk of fracture in patients with MG is not statistically increased compared with age- and gender-matched controls irrespective of glucocorticoid use but was increased in those using antidepressants, anxiolytics or anticonvulsants. These findings have implications in strategies preserving bone health in patients with MG. [ABSTRACT FROM AUTHOR]

Helderman-van den Enden ATJM, van den Bergen JC, Breuning MH, Verschuuren JJGM, Tibben A, Bakker E, Ginjaar HB. Duchenne/Becker muscular dystrophy in the family: have potential carriers been tested at a molecular level? Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease. After identification of the mutation in the index patient, family members can be reliably investigated. Carriers should be informed about their risk of having offspring with the disease and about their own risk for cardiomyopathy for which regular cardiac surveillance is recommended. In a small country like the Netherlands with well-organized genetic services, one would expect that most DMD families are adequately informed about the above mentioned risks for carriers. We have investigated whether women at risk had been tested at a molecular level. In the national Duchenne/Becker database 311 DMD and 99 Becker muscular dystrophy (BMD) patients had been registered up to 1 July 2009. These patients were asked to give information about the number of sisters and maternal aunts of the DMD/BMD patient and anything that was known about their genetic status and that of the mother. This information was compared with the information known at the genetic laboratory. Thirty-five of 104 adult sisters/maternal aunts of DMD patients with a 50% risk of being a carrier and 45 of 148 adult women with a 4.3% risk because of germ line mosaicism for DMD had not been tested by DNA analysis. Our study indicates that about one third of the potential carriers have not been tested. Given the possible far-reaching clinical consequences of being a carrier, further studies are needed to investigate the reasons why potential female carriers have not been tested. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. An overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. Many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A-C were possible, but good practice points were agreed by consensus. The nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3-6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy. Click for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

The article focuses on the economic stimulus programs in the Netherlands. It examines the provisions of the Crisis and Recovery Act (CRA) enacted by the government to speed up the decision making processes in resolving the economic crisis in the country. It discusses the provisions and characteristics of the new law, and analyses the legal critique of the CRA to assess its ability to help the economy recover without violating the legal system. It explores the four main elements of the regulation and describes the different economic projects associated with the CRA.

Background: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs’ syndrome). Methods: To prepare consensus guidelines for the treatment of the autoimmune NMT disorders, references retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts. Conclusions: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point). Plasma exchange is recommended in severe cases to induce remission and in preparation for surgery (recommendation level B). IvIg and plasma exchange are effective for the treatment of MG exacerbations (recommendation level A). For patients with non-thymomatous MG, thymectomy is recommended as an option to increase the probability of remission or improvement (recommendation level B). Once thymoma is diagnosed, thymectomy is indicated irrespective of MG severity (recommendation level A). Oral corticosteroids are first choice drugs when immunosuppressive drugs are necessary (good practice point). When long-term immunosuppression is necessary, azathioprine is recommended to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (recommendation level A). 3,4-Diaminopyridine is recommended as symptomatic treatment and IvIG has a positive short-term effect in LEMS (good practice point). Neuromyotonia patients should be treated with an antiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point). For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlying tumour is essential (good practice point). Immunosuppressive treatment of LEMS and neuromyotonia should be similar to MG (good practice point). [ABSTRACT FROM AUTHOR]

Dysphagia is an important yet inconsistently recognized symptom of inclusion body myositis (IBM). It can be disabling and potentially life-threatening. We studied the prevalence and symptom-sign correlation of dysphagia. Fifty-seven IBM patients were interviewed using a standard questionnaire for dysphagia and 43 of these underwent swallowing videofluoroscopy (VFS). Symptoms of dysphagia were present in 37 of 57 patients (65%). Nevertheless, only 17 of these patients (46%) had previously and spontaneously complained about swallowing to their physicians. Both symptoms of impaired propulsion (IP) (59%) and aspiration-related symptoms (52%) were frequently mentioned. Swallowing abnormalities on VFS were present in 34 of 43 patients (79%) with IP of the bolus in 77% of this group. The reported feeling of IP was confirmed by VFS in 92% of these patients. Dysphagia in IBM is common but underreported by the vast majority of patients if not specifically asked for. In practice, two questions reliably predict the presence of IP on VFS: ‘Does food get stuck in your throat’ and ‘Do you have to swallow repeatedly in order to get rid of food’. These questions are an appropriate means in selecting IBM patients for further investigation through VFS and eventual treatment. [ABSTRACT FROM AUTHOR]

3,4-Diaminopyridine and pyridostigmine are widely used to treat Lambert–Eaton myasthenic syndrome (LEMS), either alone or in combination. 3,4-Diaminopyridine enhances the release of acetylcholine at the neuromuscular synapse, and pyridostigmine inhibits the degradation of this neurotransmitter. Although this could lead to a synergistic effect on neuromuscular transmission, no studies have compared the effects of these drugs in patients with LEMS. Therefore, we performed a placebo-controlled, double-dummy, double-blind, randomized, crossover study in nine patients with LEMS.Clinical Pharmacology & Therapeutics (2009); 86, 1, 44–48 doi:10.1038/clpt.2009.35 [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert–Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS. [ABSTRACT FROM AUTHOR]

Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short-term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non-thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long-term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti-epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point). [ABSTRACT FROM AUTHOR]

A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer. [ABSTRACT FROM AUTHOR]

Background: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate "true" PNS from neurological syndromes that are coincidental with a cancer. Objective: To provide more rigorous diagnostic criteria for PNS. Methods: An international panel of neurologists interested in PNS identified those defined as "classical" in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as "well characterised". The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. Results: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: "definite" and "possible". Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of "classical" syndrome and "well characterised" onconeural antibody. Conclusions: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases. [ABSTRACT FROM AUTHOR]

Triggering of balance corrections may depend on both leg and trunk proprioceptive inputs. To study this issue and to determine how a total proprioceptive loss in the legs (ToLPL) would affect postural reactions in different directions, we investigated the postural control of a patient with a long-standing dorsal root ganglionopathy. This patient had absent stretch reflexes at the ankle and knee joints, delayed reflexes at the hips, but normal muscle strength. Postural control was probed with support-surface movements driven by two different experimental protocols. The first protocol concentrated on leg muscle responses by varying ankle inputs during pitch plane perturbations. The second protocol focussed on the directional sensitivity of upper body responses using combined roll and pitch tilt perturbations. For both protocols, identical techniques were used to record ankle torques, angular velocities of the upper legs and trunk, and surface EMG from leg, hip and trunk muscles. For the first protocol, pitch plane stance perturbations with three different ankle inputs were imposed by a movable support surface. A simultaneous 4-cm rearward translation and 4-deg toe-up rotation produced an 80-deg/s "enhanced ankle input", a simple toe-up rotation gave a 40-deg/s "normal" ankle input and a simultaneous 4-cm rearward translation and 4-deg "toe-down" rotation yielding a 0-deg/s "nulled ankle input". Responses in the ToLPL patient were compared to those of healthy controls and those of patients with lower-leg proprioceptive loss (LLPL). Following normal and enhanced ankle input perturbations, stretch reflexes were absent in ankle and knee joint muscles of the ToLPL patient. Balance correcting responses in the lower legs were diminished and delayed by some 45 ms. In quadriceps, balance-correcting responses were larger than normal, peaked earlier and were not delayed. During the nulled ankle input condition, the ankle muscle responses in the ToLPL patient were again diminished and delayed by 40 ms with respect to both normal subjects and LLPL patients. However, the ToLPL patient again generated an earlier, larger, balance correcting response in quadriceps. For the second protocol, combinations of roll and pitch perturbations were also delivered by a moving support surface. The amplitude was 7.5 deg at 50 deg/s. Eight different directions were applied randomly (pure "toes down", pure "toes up" and directions at 45-deg intervals of roll). As with the first protocol pre-stimulus background muscle activity was excessive in all trunk and most leg muscles. Responses to roll tilt produced several striking changes from normal in the ToLPL patient. First reflexes in gluteus medius were delayed. Second, the trunk roll which commences around 30 ms in normals was in the opposite direction. This roll was accompanied by oppositely directed stretch reflexes in paraspinal muscles. Third, directional sensitivity of balance corrections was far more roll oriented in leg and trunk muscles. Fourth, some tilt directions caused a deactivation response of background activity. This "deactivation strategy" strongly contrasted with the strategy of controls who had low pre-stimulus background activity and activated responses around 100 ms to correct postural instability. These findings provide new insights into the generation of pitch and roll plane directed balance corrections based on the interaction of proprioceptive trigger signals from the ankles, knees and hips. Without proprioceptive input from the ankle and knee, ankle muscle responses are delayed but not absent. Upper leg and trunk responses are not delayed. This suggests that most, if not all, lower leg balance correcting responses are triggered by hip and, possibly, trunk proprioceptive inputs. When leg proprioceptive input is absent, balance correcting responses lose pitch plane sensitivity. The solution used by the patient to overcome these deficits was to markedly raise background muscle activity levels, presumably to provide a stiffer body structure. The lack of trunk flexibility and lateral instability this produced for roll tilts was offset by the ability to compensate by using a hitherto not described "deactivation response" strategy. The patient had a clinical picture usually described as "deafferented"; yet our roll tilt perturbations revealed delayed reflex responses in hip muscles. With vestibulospinal and neck-proprioceptive inputs, these responses may have helped with the development of compensation processes for the total leg proprioceptive deficit. [ABSTRACT FROM AUTHOR]

Objectives: To follow up the level of anti-Hu antibody titres during chemotherapy and to compare the pattern of metastases and other neurological complications before and after chemotherapy in patients with small cell lung cancer (SCLC) with and without low titre anti-Hu antibodies. Seventeen per cent of patients with SCLC without paraneoplastic syndromes have a low titre of anti-Hu antibodies in their serum. Previous studies suggested that these antibodies correlate with a more indolent tumour growth.Methods: The serum of 52 consecutive patients with SCLC were studied before and during chemotherapy, and the correlation with stage of disease and pattern of metastases was examined. All serum samples were investigated using western blot and enzyme linked immunosorbent assay (ELISA) with HuD recombinant protein. All patients with SCLC were investigated using MRI of the brain, CSF, bone marrow aspiration, ultrasound of the abdomen, and radionuclide bone scan.Results: Nine (17%) of 52 SCLC serum samples were positive by western blot. At the time of diagnosis none of the anti-Hu positive patients had either CNS (brain or leptomeningeal), epidural, adrenal, or bone marrow metastases and 56% had limited disease. In eight of 43 anti-Hu negative patients CNS metastases were found at the time of diagnosis, and only 30% had limited disease. The prevalence of bone and liver metastases was similar in both groups. Survival was 11 (SD ) months for the 43 anti-Hu negative and 10 (SD 6) months for the nine anti-Hu positive patients. Male:female ratio in the anti-Hu negative group was 4.4:1, and in the anti-Hu positive group 2:1.Conclusions: No anti-Hu antibody positive serum, as tested by western blot, became negative during chemotherapy. Anti-Hu positive and anti-Hu negative patients had similar survival, but anti-Hu positive patients tended to be women, had limited disease at the time of tumour diagnosis, and initially metastases seemed to spare the nervous system. [ABSTRACT FROM AUTHOR]

Background: Myasthenia gravis and the Lambert-Eaton myasthenic syndrome (LEMS) may have a similar distribution of muscle weakness. Deciding on a diagnosis of myasthenia gravis or LEMS on clinical grounds may therefore be difficult.Objective: To compare the localisation of initial muscle weakness and the distribution of weakness at the time of maximum severity in patients with myasthenia gravis and LEMS.Subjects: 101 patients with myasthenia gravis and 38 patients with LEMS.Results: In myasthenia gravis, initial weakness involved extraocular muscles in 59%, bulbar muscles in 29%, and limb muscles in 12% of the patients. In LEMS no patient had ocular weakness, 5% had bulbar weakness, and 95% had weakness of the limbs as the first symptom (p < 0.001). At the point of maximum severity, weakness in myasthenia gravis was purely ocular in 25%, oculobulbar in 5%, restricted to the limbs in 2%, and present in both oculobulbar muscles and limbs in 68%. At this point, none of the LEMS patients had weakness restricted to extraocular or bulbar muscles (p = 0.002). The legs were affected in all LEMS patients, whereas in 12 patients with generalised myasthenia gravis limb weakness was restricted to the arms (p = 0.024).Conclusions: In a patient suspected to have a myasthenic syndrome whose first symptom is ocular weakness, LEMS is virtually excluded. Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. Muscle weakness in myasthenia gravis tends to develop in a craniocaudal direction, and in the opposite direction in LEMS. [ABSTRACT FROM AUTHOR]

Background: Sporadic inclusion body myositis (sIBM) is the most frequent acquired myopathy above the age of fifty. The exact mechanism causing this disease is not known, but immune-mediated features are prominent and are probably to play a role in its pathogenesis. TREX1 gene mutations are associated with a large range of autoimmune diseases, such as systemic lupus erythematosus. We investigated whether mutations in the TREX1 gene were associated with sIBM. Methods: Fifty-four patients with sIBM were tested for TREX1 mutations by direct sequencing. Results: All 54 patients tested negative for pathogenic mutations in the TREX1 gene. One presumed non-pathogenic polymorphism was found in 42 out of 54 patients. Conclusion: TREX1 mutations do not play a role in the pathogenesis of sIBM. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the case of a patient with narcolepsy with cataplexy who has undergone intravenous immunoglobulins therapy.

Presents a letter to the editor regarding the involvement of CNS in primary sjorgren's syndrome.