Involvement of pelvic girdle and proximal leg muscles in early oculopharyngeal muscular dystrophy.

Although limb girdle weakness is not part of the major diagnostic criteria of oculopharyngeal muscular dystrophy (OPMD), it has frequently been observed in the Dutch and other OPMD cohorts. In the Dutch cohort, this might be related to the relatively old age or the severity of the genetic defect. This patient-control study (14 OPMD patients and 12 controls) investigated the involvement of limb girdle muscles with a multidimensional approach in early OPMD. We assessed functional abilities, disease impact, physical activity, muscle strength, histopathology and fatty infiltration using questionnaires, actometer, functional tests, manual and quantitative muscle testing, muscle biopsy and muscle MRI. The study showed that involvement of pelvic girdle and proximal leg can be a relatively early feature of OPMD, resulting in impaired daily life activities. The fat fraction of the hip adductors and hamstrings was significantly higher in OPMD patients than in controls. Future studies should include assessment of hip flexors, hip adductors and hamstrings (muscle strength measurements and MRI), functional tests and questionnaires. These findings are important in future diagnostics, management and for the design of outcome measures in trials.

Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.

OBJECTIVES: Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis. MATERIALS AND METHODS: Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients. INTERPRETATION: Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

The yield of diagnostic work-up of patients presenting with myalgia, exercise intolerance, or fatigue: A prospective observational study.

Myalgia, fatigue, and exercise intolerance are cause for referral to a neurologist. However, the diagnostic value of history, neurological examination, and ancillary investigations in patients with these symptoms is unknown. This study provides a sound footing for deciding which ancillary investigations should be conducted. A prospective observational study of the diagnostic approach in 187 patients with myalgia, exercise intolerance, or fatigue as their predominant symptom was performed. The primary outcomes were independent contribution of referral letter, history, examination, and ancillary investigations to a myopathy diagnosis. The secondary outcome was diagnostic value of combined ancillary investigations. 27% of patients had a myopathy. Positive family history (OR 3.2), progressive symptoms (OR 2.2), atrophy (OR 9.7), weakness (OR 10.9), and hyporeflexia (OR 4.4) were associated with a myopathy. Positive predictive values for myopathy were calculated for CK (0.32), EMG (0.66), ultrasound (0.47), and muscle biopsy (0.78). All contributed significantly in predicting myopathy. Multivariate analysis yielded a diagnostic algorithm facilitating a more efficient work-up in future patients. CK levels, EMG, ultrasound, and muscle biopsy independently contribute to predicting a myopathy. The diagnostic algorithm shows which combination of ancillary investigations should be employed in different subgroups and when to omit invasive techniques. This algorithm may drastically improve diagnostic efficiency.

No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome.

Myotonic dystrophy type 2 (DM2) is a rare, autosomal dominant, multisystem disorder with proximal weakness, myotonia, pain and cataract as important symptoms. Given the assumed underreporting of DM2 in the Netherlands combined with the predominant role of pain in DM2 as well as in fibromyalgia syndrome (FMS), we hypothesized there will be an excess prevalence of DM2 in patients with (suspected) FMS. Our objective was to determine the prevalence of DM2 in patients with suspected FMS. A prevalence of 2% was considered a relevant excess frequency. Between November 2011 and April 2014, 398 patients with suspected FMS who had been assessed by a rheumatologist participated in this cross-sectional study. 95% of the study population was female, with a mean age of 42 years. The final ICD-9 diagnoses were collected, in 96% the diagnosis was FMS. 92% met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FMS. A questionnaire including neuromuscular symptoms was completed. Creatine kinase was determined, and genetic testing for DM2 was conducted in all patients. DM2 was established in only one patient (0.25%, 95% CI 0.04-1.4%), thus disapproving our hypothesis of a relevant prevalence of 2%. Our results suggest that patients with suspected FMS should not routinely be tested for DM2.

RYR1-related myopathies: a wide spectrum of phenotypes throughout life.

BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

Strong association between myotonic dystrophy type 2 and autoimmune diseases.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is a dominantly inherited multisystem disorder, characterised by progressive proximal weakness, myotonia, cataracts and cardiac conduction abnormalities. Our clinical impression of an association between DM2 and autoimmune diseases or autoantibody formation has not been published previously. OBJECTIVE: The aim of the present study was to investigate the frequency of autoimmune diseases and serum autoantibodies in patients with DM2 compared with patients with adult onset myotonic dystrophy type 1 (DM1). METHODS: 28 genetically proven Dutch DM2 patients participated in the study and were compared with 51 age and sex matched adult onset DM1 patients. As the primary outcome measure, the presence of an autoantibody or autoreactive T cell associated autoimmune disorder was assessed. As a secondary outcome measure, the presence of autoantibodies in serum (nuclear and non-nuclear antibodies) was assessed in all patients. RESULTS: The frequency of autoimmune diseases (21% vs 2%) and the frequency of autoantibodies (25% vs 2%) were both significantly (p<0.01) higher in DM2 patients compared with DM1 patients. Data on DM1 patients were comparable with the general population. Results were not confounded by smoking, medication use, familial clustering, age or sex. CONCLUSION: The results provide new insight into the clinical picture of DM2. In addition, possible explanations for the association between DM2 and autoimmune diseases are proposed.

Dysphagia is present but mild in myotonic dystrophy type 2.

The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of 29 DM2 patients reported to have difficulty in swallowing for solid food. The aim of the study was to investigate the presence of dysphagia in patients with genetically proven DM2 who reported difficulty in swallowing for solid food at the questionnaire survey. Swallowing function and fiberoptic endoscopic evaluation of swallowing (FEES) were examined by a speech therapist and otorhinolaryngologist, respectively. In DM2 patients who reported difficulty in swallowing the presence of dysphagia could be confirmed (clinically in 100%, by FEES in 88%). A correlation exists between Dysphagia Outcome and Severity Score (DOSS) and age (p=0.05). None of the patients was underweight, and none of the patients had suffered aspiration pneumonia in the past. Dysphagia is present among DM2 patients and is more severe in older patients. However, dysphagia is generally mild, and do not lead to weight loss, or aspiration pneumonia.

Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate.

BACKGROUND/AIMS: To determine the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis and polymyositis. METHODS: A multicentre open-label controlled trial was conducted. Disease activity was assessed using patient's and physician's disease activity assessment, manual muscle testing (MMT), handheld dynamometry, and serum CK. The primary objective was to assess the efficacy using MMT after a period of 26 weeks. RESULTS: The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction. The few patients who did reach the primary endpoint showed improvement in all aspects studied. CONCLUSION: Infliximab combined with weekly methotrexate might be safe and well tolerated in a small subgroup of patients with drug-naive recent-onset myositis. At present, we do not advocate the use of this treatment because treatment response cannot be predicted beforehand.

Clinical neurophysiology of fatigue.

Fatigue is a multidimensional concept covering both physiological and psychological aspects. Chronic fatigue is a typical symptom of diseases such as cancer, multiple sclerosis (MS), Parkinson's disease (PD) and cerebrovascular disorders but is also presented by people in whom no defined somatic disease has been established. If certain criteria are met, chronic fatigue syndrome can be diagnosed. The 4-item Abbreviated Fatigue Questionnaire allows the extent of the experienced fatigue to be assessed with a high degree of reliability and validity. Physiological fatigue has been well defined and originates in both the peripheral and central nervous system. The condition can be assessed by combining force and surface-EMG measurements (including frequency analyses and muscle-fibre conduction estimations), twitch interpolation, magnetic stimulation of the motor cortex and analysis of changes in the readiness potential. Fatigue is a well-known phenomenon in both central and peripheral neurological disorders. Examples of the former conditions are multiple sclerosis, Parkinson's disease and stroke. Although it seems to be a universal symptom of many brain disorders, the unique characteristics of the concomitant fatigue also point to a specific relationship with several of these syndromes. As regards neuromuscular disorders, fatigue has been reported in patients with post-polio syndrome, myasthenia gravis, Guillain-Barré syndrome, facioscapulohumeral dystrophy, myotonic dystrophy and hereditary motor and sensory neuropathy type-I. More than 60% of all neuromuscular patients suffer from severe fatigue, a prevalence resembling that of patients with MS. Except for several rare myopathies with specific metabolic derangements leading to exercise-induced muscle fatigue, most studies have not identified a prominent peripheral cause for the fatigue in this population. In contrast, the central activation of the diseased neuromuscular system is generally found to be suboptimal. The reliability of the psychological and clinical neurophysiological assessment techniques available today allows a multidisciplinary approach to fatigue in neurological patients, which may contribute to the elucidation of the pathophysiological mechanisms of chronic fatigue, with the ultimate goal to develop tailored treatments for fatigue in neurological patients. The present report discusses the different manifestations of fatigue and the available tools to assess peripheral and central fatigue.

Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

Anti-signal recognition particle autoantibodies: marker of a necrotising myopathy.

OBJECTIVE: To elucidate the clinical importance of the anti-signal recognition particle (SRP) autoantibody in patients with myositis. METHODS: Retrospective systematic assessment of the clinical, laboratory and histological characteristics of 23 anti-SRP-positive patients from six European centres. Data were compared with a large group of anti-SRP-negative patients with myositis published previously. RESULTS: Clinically, patients with anti-SRP autoantibodies often had a severe symmetric proximal muscle weakness resulting in marked disability, dysphagia and highly elevated levels of serum creatine kinase. Three patients had typical dermatomyositis rashes. The disease was associated with the occurrence of extramuscular signs and symptoms including interstitial lung disease. No association was found with an increased risk of cardiac involvement, and the disease carried a reasonably favourable prognosis with most patients responding to treatment. None of the patients had the typical histological features of myositis. Most muscle biopsy specimens showed the presence of necrotic muscle fibres and no inflammatory infiltrates. CONCLUSIONS: Anti-SRP autoantibodies are associated with a syndrome of a necrotising myopathy in the spectrum of immune-mediated myopathies that differs from typical polymyositis. Further studies are needed to elucidate the pathogenesis and to clarify the role of the anti-SRP autoantibodies in this unique disease.

Clinical characteristics of patients with myositis and autoantibodies to different fragments of the Mi-2 beta antigen.

OBJECTIVES: To assess the clinical implications of autoantibodies directed against different parts of the Mi-2 beta autoantigen in patients with myositis. METHODS: A systematic assessment of the clinical, laboratory, and histological characteristics of 48 anti-Mi-2 positive patients from six European centres was made. Anti-Mi-2 autoantibodies were determined with an ELISA using four overlapping fragments spanning the entire amino acid sequence of the autoantigen. Data were compared with results for a large group of anti-Mi-2 negative patients with myositis published previously. RESULTS: Anti-Mi-2 autoantibodies were found in dermatomyositis, polymyositis, and inclusion body myositis. In general, myositis with anti-Mi-2 autoantibodies was characterised by relatively mild disease, sometimes accompanied by extra-muscular symptoms, including arthralgia, arthritis, Raynaud's phenomenon, and interstitial lung disease. Cardiac disease was not seen, and treatment response was fair. No differences were found between patients with autoantibodies to different fragments of the Mi-2 beta antigen, except for a potentially increased risk of cancer in patients with antibodies directed to the N-terminal fragment of the autoantigen. CONCLUSIONS: Anti-Mi-2 autoantibodies are not a marker of a specific subtype of myositis. No significant differences between patients with autoantibodies to different fragments of the Mi-2 beta autoantigen are found, with the possible exception of an increased risk of cancer in patients with antibodies to the N-terminal fragment.

Relation between muscle fiber conduction velocity and fiber size in neuromuscular disorders.

To determine the relation between muscle fiber conduction velocity (MFCV) and muscle fiber diameter (MFD) in pathological conditions, we correlated invasively measured MFCV values with MFD data obtained from muscle needle biopsies in 96 patients with various neuromuscular disorders. MFCV was significantly correlated with MFD and independent of the underlying disorder. Pathological diameter changes were fiber-type dependent, with corresponding MFCVs. A linear equation expresses the relation well: MFCV (m/s)=0.043.MFD (microm)+0.83. We conclude that fiber diameter determines MFCV largely independent of the underlying neuromuscular disorders studied.

[The practice guideline 'Dermatomyositis, polymyositis and sporadic inclusion body myositis']. / Richtlijn 'dermatomyositis, polymyositis en sporadische "inclusion body"-myositis'.

This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a skin biopsy is advisable. A muscle biopsy is indicated when other examinations are inconclusive and the musculature is involved. The working group considers screening for cancer to be required in adults with dermatomyositis and presents recommendations for the way that this should be done. At least one-third of all patients with polymyositis has, or will develop, an associated inflammatory connective tissue disease. If a patient with a connective tissue disease develops symmetrical, proximal muscle weakness in the course of weeks or months, this may be assumed to be due to polymyositis. In the absence ofpre-existing connective tissue disease, demonstration of a mononuclear cell infiltrate in muscle tissue is a prerequisite for the diagnosis ofpolymyositis. The histopathology of muscle tissue is used as the gold standard for the diagnosis of sIBM. The practice guideline presents criteria for the concept 'activity' of myositis. Disease activity serves as a guideline for the treatment of polymyositis and dermatomyositis. The treatment of choice for dermatomyositis and polymyositis is high-dose prednisone. Physical activity does not have a negative effect on the course of these diseases. The long-term prognosis ofdermatomyositis and polymyositis is not well known. The clinical course of sIBM is slowly progressive.

Histology of hereditary neuralgic amyotrophy.

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.

Diminished central activation during maximal voluntary contraction in chronic fatigue syndrome.

OBJECTIVE: We have investigated whether central activation failure (CAF) is increased during local muscle fatigue in chronic fatigue syndrome (CFS). METHODS: Fourteen female CFS patients and 14 age-matched healthy female controls made a 2 min sustained maximal voluntary contraction (MVC) of the biceps brachii muscle. Before, during, and after sustained MVC, electrical endplate stimulation was applied. Force and 5 channel surface EMG (sEMG) were registered. RESULTS: Although force responses upon stimulation during rest did not differ between patients and controls, MVC was significantly lower in patients. Already at the beginning of sustained MVC, CFS patients showed significantly larger CAF than controls (36.5+/-17.0% and 12.9+/-13.3%, respectively). For all individual patients mean CAF over the first 45 s was higher than 30%, while it was below 30% for all controls. Less peripheral fatigue in patients was demonstrated by the changes in muscle fibre conduction velocity and the differences between force responses before and after contraction. CONCLUSIONS: Central activation is diminished in CFS patients. Possible causes include changed perception, impaired concentration, reduced effort and physiologically defined changes, e.g. in the corticospinal excitability or the concentration of neurotransmitters. As a consequence, demands on the muscle are lower, resulting in less peripheral fatigue. SIGNIFICANCE: CFS patients show reduced central activation during MVC. The underlying pathophysiological processes remain still to be determined.

[Fatigue in neuromuscular disease]. / Moeheid bij neuromusculaire aandoeningen.

Chronic fatigue is a symptom of diseases such as cancer, multiple sclerosis, Parkinson's and cerebrovascular disease. Fatigue can also be present in people with no demonstrable somatic disease. If certain criteria are met, chronic-fatigue syndrome may be diagnosed in these cases. Fatigue is a multi-dimensional concept with physiological and psychological dimensions. The 'Short Fatigue Questionnaire' consisting of 4 questions is a tool to measure fatigue with a high degree of reliability and validity. Within the group of neuromuscular disorders, fatigue has been reported by patients with post-polio syndrome, myasthenia gravis, and Guillain-Barré syndrome. The percentage of neuromuscular patients suffering from severe fatigue (64%) is comparable with that of patients with multiple sclerosis, a disease in which fatigue is an acknowledged symptom. Now that reliable psychological and clinical neurophysiological techniques are available, a multidisciplinary approach to fatigue in patients with well-defined neuromuscular disorders may contribute towards the elucidation of the pathophysiological mechanisms of chronic fatigue, with the ultimate goal being to develop methods of treatment for fatigue in neuromuscular patients.

Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies.

BACKGROUND: Identification of mononuclear cellular infiltrates in skeletal muscle tissue is the histological cornerstone of the diagnosis of idiopathic inflammatory myopathy (IIM). However, these infiltrates are not always present. OBJECTIVE: To determine whether MHC class I antigen expression on the sarcolemma, which is absent in normal muscle tissue, is upregulated in IIM and could serve as an additional diagnostic test. METHODS: Expression of MHC class I antigens was studied in 224 muscle samples of 61 adult patients with IIM (9 dermatomyositis, 23 polymyositis, 29 inclusion body myositis) and 163 controls (normal subjects and patients with various neuromuscular disorders) in a prospective blinded manner. RESULTS: The sensitivity of the test for diagnosing IIM was 78% (95% confidence interval (CI), 66% to 88%), with a specificity of 95% (91% to 98%). The sensitivity before the start of immunosuppressive treatment was 89% (76% to 96%). The sensitivity was not changed by including all patients who had been on immunosuppressive treatment for less than four weeks before muscle biopsy (sensitivity 90% (79% to 97%)). False positive results were found in only seven controls (4%), six of whom had a muscular dystrophy. CONCLUSIONS: Detection of sarcolemmal MHC class I is a valid test for IIM. It is not affected by the short term use of immunosuppressive agents (less than four weeks) and it should be incorporated in the histological evaluation when the diagnosis of IIM is under consideration or needs to be excluded.