Christiane Schneider-Gold

Muscle pathology in 57 patients with myotonic dystrophy type 2

We evaluated muscle biopsies from 57 patients with genetically confirmed myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM). Light microscopy showed myopathic together with “denervation‐like” changes in almost all biopsies obtained from four different muscles: increased fiber size variation, internal nuclei, small angulated fibers, pyknotic nuclear clumps, and predominant type 2 fiber atrophy. Quantitative morphometry in 18 biopsies that were immunostained for myosin heavy chain confirmed a predominance of nonselective type 2 fiber atrophy. These histological changes were similar in all patients regardless of the site of biopsy, the predominant clinical symptoms and signs, and the clinical course. It is likely that, in a number of undiagnosed patients, DM2 is the underlying disorder. With a better understanding of the histopathological pattern in DM2, biopsies from patients with undiagnosed neuromuscular disorders can now be reevaluated. Muscle Nerve 29: 275–281, 2004

Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): a quantitative 31P-MRS and MRI study.

In myotonic dystrophy type 2 (DM2/PROMM), cardiac muscle involvement is usually more benign than in DM1, but clinically severe cardiomyopathy has been reported in some patients. Using a novel method of magnetic resonance spectroscopy (MRS), we examined the left ventricular myocardium and the left gastrocnemius muscle in 11 unselected DM2/PROMM patients without overt cardiac disease. Data on cardiac morphology and function were obtained by gradient echo two‐dimensional cine magnetic resonance imaging (MRI); no significant differences were found between DM2 patients and healthy controls, but using a median split approach older patients showed mildly increased left ventricular (LV) volumes, i.e., 59% increase of end‐systolic volume index (ESVI) and 35% increase of end‐diastolic volume index (EDVI), and an increase of LV mass (26%). On cardiac MRS, DM2/PROMM patients showed a reduction of phosphocreatine (PCr) and adenosine triphosphate (ATP) by 25 and 20% compared to matched healthy controls. No significant differences were found between younger and older patients. In skeletal muscle of the DM2 patients, no significant decrease of PCr and ATP concentrations was found. However, in older patients, who commonly show overt hip flexor muscle weakness, we observed reduced values for PCr and ATP. Our MRS and MRI findings reveal evidence for subclinical cardiomyopathy in DM2/PROMM patients without overt heart disease. Future prospective studies are needed to clarify the risk of developing overt cardiac disease in DM2 and to define prognostic factors. Muscle Nerve, 2004

Successful Treatment of Anti-Caspr2 Syndrome by Interleukin 6 Receptor BlockadeThrough Tocilizumab

IMPORTANCE A patient with a Caspr2 autoantibodies-associated syndrome had an unusual clinical triad and an excellent response to B-cell-anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor. OBSERVATIONS A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months. CONCLUSIONS AND RELEVANCE In our patient, the implementation of a B-cell-anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.

Immunoadsorption versus plasma exchange versus combination for treatment of myasthenic deterioration

Objectives: The goal of this study was to analyze safety and assess the efficacy of standard plasma exchange (PE) compared with immunoadsorption (IA) alone, or an alternating combination of both in deteriorating myasthenia gravis (MG). Methods: A total of 72 patients with MG who had received PE procedures for treatment of severe deterioration were retrospectively analyzed. They received either five cycles of PE (1–1.5 plasma volumes), or five cycles of IA in line with plasma separation, or a sequential alternating procedure of one cycle of PE followed by two cycles of IA, which was repeated once or more if needed. Results: A total of 19 patients received PE, 24 patients IA, and 29 the alternating combination therapy. All groups were equally distributed by sex and mean MG score before treatment. The number of treatment cycles and days on therapy did not differ between the groups. Mean MG scores at discharge were 3.0 (PE), 1.8 (IA) and 1.6 (combination) (p = 0.028 for combination versus PE). Inpatient time was 30.7 days (PE), 22.3 days (IA) and 20.0 days in combination therapy (p < 0.05 for combination versus PE). Side effects such as allergic reactions or hypocoagulability were significantly more frequent in the PE group (37% in PE versus 4% in IA and 3.6% in the alternating combination, p < 0.05). Conclusion: Semiselective IA in combination with PE, and to a lesser extent IA alone, was associated with a shorter hospital stay and more pronounced reduction of the MG score than PE.

Bortezomib in severe MuSK-antibody positive myasthenia gravis: first clinical experience

Background Myasthenia gravis (MG) is an autoimmune disease caused by antibodies to different antigens of the neuromuscular junction, in particular to acetylcholine receptor (AChR) and muscle tyrosine kinase (MuSK).1 Standard therapies comprise pyridostigmine, glucocorticosteroids, azathioprine or alternatively mycophenolate mofetil, cyclosporine A and tacrolimus. In severe MG, escalating immunotherapy by application of plasma exchange (PE), immunoadsorption (IA), intravenous immunoglobulins (IVIGs), rituximab or cyclophosphamide has to be initiated.2 For those patients who do not respond to these strategies, novel therapeutic options are critically needed. Such ‘cutting edge’ treatments may be recruited from the therapeutic arsenal used in other autoimmune or neoplastic diseases (e.g. rituximab, an established compound in lymphoma therapy was recently transferred to MG therapy). The whole spectrum of upcoming and in part very specific and sophisticated new immunotherapies includes a variety of T-cell directed monoclonal antibodies that block the intracellular cascade associated with T-cell activation, monoclonal antibodies directed against key B-cell molecules, and inhibitors of complement, cytokines and transmigration molecules (reviewed by Dalakas3).

Myotonic dystrophy: present management, future therapy (2004)

This recently published book edited by P.S. Harper, B. van Engelen, B, Eymard and D. E. Wilcox presents a detailed overview of the clinical picture and pathogenesis of type 1 and type 2 myotonic dystrophy (DM1 and DM2), strategies of disease management and future therapeutic options. The content of the book is divided into six sections. In the first part of the introductory section, the spectrum of clinical manifestations of myotonic dystrophies is described. In the second part, the molecular genetic aspects of the disease are reviewed. The authors provide a thorough discussion of the pathomechanisms in myotonic dystrophies, referring to all relevant studies published throughout the last few years. The authors show that myotonic dystrophy research has made considerable progress, opening a new dimension of basic research studies and nourishing hope that future effective therapeutic approaches may arise. The second section of the book deals with the management of neuromuscular manifestations of myotonic dystrophy. It starts with the difficulties of making the diagnosis and the implications of missing the diagnosis. As a guideline for clinicians who are involved in managing patients with myotonic dystrophy, various useful assessment protocols for follow-up studies are presented. In a special chapter, the management of neuromuscular symptoms and signs, with special emphasis on physical disability and help for the individual patient, is addressed. The third section of the book examines the main systemic problems of the disease, such as cardiac and endocrinological disturbances and gastrointestinal and respiratory dysfunction. Possible therapeutic strategies and strategies for anaesthesia are presented. The fourth section focuses on special aspects of myotonic dystrophy: pregnancy and perinatal complications are reviewed in a separate chapter, as is the congenital form of myotonic dystrophy, which requires special management strategies. Genetic counselling and the possibilities and problems of genetic testing are covered as a special scientific and ethical area of disease management. In the fifth section, the book provides information regarding how to build a scientific team to help patients with myotonic dystrophy, including the role of support groups. In the last section of the book, all relevant former trials in myotonic dystrophy are reviewed and future therapeutic options are discussed. In summary, the book illustrates all the various clinical aspects of this complex disease and gives insight into the pathogenesis and possibilities of the management of each complication at the different stages of myotonic dystrophy. The completeness of the data presented in each chapter is impressive. The chapters are well structured and the illustrations are clear and informative. The flow charts are adequately structured and easy to understand. The references are well selected and up-to-date. All chapters are written by renowned experts in the field of the myotonic dystrophies and neuromuscular diseases. It is a most educative book for clinicians working in the field of neuromuscular diseases and for geneticists responsible for the genetic counselling of patients with myotonic dystrophy. The book encourages the optimisation of the management of patients with myotonic dystrophy in an interdisciplinary setting and in cooperation with the patients and their families.

Two years’ long-term follow up in chronic inflammatory demyelinating polyradiculoneuropathy: efficacy of intravenous immunoglobulin treatment

Background: Administration of intravenous immunoglobulins (IVIgs) is established for long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Prevention of secondary axonal loss going along with permanent clinical disability and muscular atrophy is a major aim in CIDP therapy. To assess long-term clinical efficacy of IVIg treatment despite heterogenous disease course and variable complaints reported by the patients, long-term electrophysiological monitoring was performed for systematic evaluation of therapeutic efficacy of IVIg. Methods: A total of 21 patients with CIDP treated with IVIg 1 g/kg bodyweight every 3–6 weeks were examined electrophysiologically every 12 months over a period of 2 years. Results: Assessment of clinical symptoms, using the Inflammatory Neuropathy Cause and Treatment (INCAT) and Hughes functional grading score (F-score) revealed improvement of motor and sensory symptoms over a period of 2 years. As electrophysiological results remained stable, IVIg treatment seems to be suitable to prevent axonal loss in CIDP. Conclusions: This study confirms efficacy of IVIg as firstline therapy in CIDP. Doses and frequency of IVIg application should be adapted based on clinical evaluation and analysis of long-term electrophysiological findings.