A wide range of established treatment options is currently available for myasthenia gravis. These include cholinesterase inhibitors for symptomatic treatment and a broad spectrum of immunosuppressive, immunomodulating or cell-depleting options to modify the underlying immunological process. Appropriate use allows the great majority of patients to lead a normal life. Specialized centers integrating outpatient and in-hospital resources as well as interdisciplinary competences offer important advantages for optimum individualized therapy. pain, hypotension, lumbar pain, anaphy lactic reactions ( Caution IgA deficiency), anemia, arthritis, failure, heart failure, arterial hypertension,
In recent years much progress has been made in the investigation of the pathophysiology, characterizing subgroups, and extension of multimodal treatment of myasthenia gravis (MG). This applies especially to the role of thymectomy (Thx). Thymectomy is always indicated for thymoma-associated myasthenia gravis. Furthermore, based on large cohort studies, during recent decades thymectomy has also become a central part of immune-modulating MG therapy in patients without thymoma. The lack of randomized studies, however, caused a certain persistent reluctance as to the significance of thymectomy. The current MGTX trial has shown the effectiveness of thymectomy. A significant improvement of myasthenic complaints and the reduction of immunosuppressive medication was primarily shown for acquired early-onset MG (EOMG) with complete resection of all thymic tissue. Because the MGTX study only included patients younger than 65 years with generalized MG and positive for acetylcholine-receptor antibodies, at present the significance of Thx for other relevant subgroups as juvenile MG, MG in older patients, ocular MG, as well as seronegative patients is under investigation. Even the prevailing opinion of no benefit of thymectomy for MuSk-positive patients probably needs reevaluation based on ambiguous findings. With respect to surgery, based on the exclusive performance of extended median sternotomy for MG in the MGTX, the value of thoracoscopic modifications for thymectomy as a minimally-invasive alternative is currently under evaluation. For clinical reasons further judgment regarding different minimally-invasive thymectomy techniques compared to the conventional open procedures in the form of randomized comparative studies would be required. Currently, however, an experience-based robotic-assisted thoracoscopic unilateral approach to thymectomy meets all requirements related to surgical, clinical-neurological and patient aspects. Ethical reasons, therefore, will lead to other strategies for comparison of different surgical techniques.
Elevated serum creatine kinase (CK) activity is usually an indicator of muscle damage. HyperCKemia is often an incidental finding and should be controlled after refraining from physical activity for some days, especially in asymptomatic patients. Furthermore, data from recent studies indicate that the upper limits of normal (ULN) need to be revised upward. This review includes an algorithm for differential diagnosis of CK elevation in patients without muscular symptoms. In the field of neurology, in particular myopathies and neuropathies with affection of the lower motoneuron, can cause symptomatic hyperCKemia, with CK values >1000U/l (16.7 mu kat/l) being indicative of a primary muscle disorder. Diseases with very high CK values include subtypes of muscular dystrophies, idiopathic inflammatory myopathies and metabolic myopathies. However, a normal or only slightly elevated CK value does not exclude the presence of a myopathy. The individual diagnostic procedure (e.g. muscle imaging, special laboratory studies, muscle biopsy and genetic testing) depends on the clinical phenotype and the results of electrophysiological studies. HyperCKemia can also be an adverse effect of several drugs including statins. In asymptomatic patients, a statin-associated CK elevation < 5-fold of ULN can be tolerated. In patients with higher CK values and/or muscle symptoms, LDL cholesterol-lowering therapy should be changed. Rhabdomyolysis is a potentially life- threatening condition and is accompanied by highly elevated CK values. Acute-phase treatment includes preserving renal function and restoring metabolic balance.
AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Most patients die within 2–5 years of symptom onset due to the lack of effective therapy options. A diagnostic delay is encountered quite often, since disease progression as well as site and speed of onset may vary significantly. Some diseases can mimic features of ALS, especially in early stages. It is very important to differentiate those mimics from ALS as potentially treatable conditions might be missed otherwise. ALS typically affects the upper as well as the lower motor neuron, which implies that diseases sharing at least one of these clinical features have to be considered in the differential diagnosis. The following conditions should be taken into account as a differential diagnosis for ALS with predominant affection of the lower motor neuron: Immune mediated neuropathies such as multifocal motor neuropathy (MMN) with pronounced distal paresis without striking atrophy signs and conduction blocks in electroneurography, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with common signs of sensibility disturbances, areflexia and cytoalbuminologic dissociation in the cerebrospinal fluid (CSF). Sporadic inclusion body myositis (sIBM) with typical biopsy findings and clinically predominant affection of the finger flexors. Spinal and bulbar muscular atrophy (SBMA), in which androgen receptor (AR-)gene testing and clinical signs of androgen insensitivity will help to differentiate the disease from ALS. Hirayama disease shows cold paresis; a cervical MRI scan and a normal neurography will help to confirm the diagnosis. In benign fasciculation syndrome, there is no muscle paresis or atrophy, and acute denervation cannot be detected in the EMG. In spinal muscular atrophy (SMA), testing for the SMN gene will help to differentiate the condition from ALS; furthermore, SMA is a very rare disease in adults. As a differential diagnosis for ALS with both clinical affection of the upper and lower motor neuron e. g. metabolic diseases such as adrenoleukodystrophy, metachromatic leukodystrophy and Tay-Sachs disease should be taken into account. Here, laboratory tests are the most important steps for a correct diagnosis. Cervical myelopathy is also capable of affecting the upper and lower motor neuron, but can easily be differentiated by a cervical MRI scan. As a differential diagnosis of ALS with predominant affection of the upper motor neuron, we discuss hereditary spastic paraparesis (HSP) which presents with a symmetric spasticity of the legs. The MRI often shows atrophy of the spinal cord, and SPG gene testing is done to differentiate HSP from ALS.
Pure ocular myasthenia has always been described as a separate entity in historical publications. More than 50% of patients develop generalized symptoms in the course of the disease. Therefore, pure ocular symptoms can be the beginning of a generalized myasthenia; nevertheless, there is a small group of patients with pure ocular symptoms lifelong. Special immunological, biochemical and pathophysiological mechanisms lead to specific local changes of the neuromuscular junction. The diagnostic procedure is hampered as antibodies against acetylcholine receptor and MuSK can be demonstrated in less than 50% of these patients. Therapy of pure ocular myasthenia does not differ fundamentally from that of other subgroups of myasthenia gravis and is implemented with cholinesterase inhibitors, steroids and common immunosuppressants. Thymomectomy is not recommended in general but randomized controlled studies are missing.
Abstract Background Stroke is a major public health problem of enormous epidemiological significance. Each year, approximately 200.000 people in Germany suffer a stroke. Stroke is the third leading cause of death and the most common cause of acquired disabilities in adults. About one fourth of stroke survivors report severe limitations in activities of daily living three months after acute stroke. The most common post-stroke conditions are motor and cognitive dysfunctions as well as affective problems. Stroke rehabilitation plays a crucial role in coping with stroke sequelae. The large number of strokes and the often debilitating consequences raise the question to what extent participation can be increased by medical rehabilitation. Methods A prospective, multicenter survey study was conducted in six neurological inpatient rehabilitation centers. Recruitment focused on patients with recent acute stroke and disease severity corresponding to BAR phase D. Patients completed questionnaires at three points of measurement: at the beginning and at the end of the inpatient rehabilitation and after four months. Primary outcome was participation, secondary outcomes included several parameters of subjective well-being. Furthermore, utilization of aftercare and satisfaction with the rehabilitation program were measured. Results At the beginning of the rehabilitation, patients experienced severe limitations in participation and reduced subjective well-being. At the end of inpatient rehabilitation, significant improvements of small effect sizes for subjective well-being and medium effect sizes for participation were achieved. After four months, effects had decreased, yet improvements compared to baseline were still noticeable. Patient ratings of the rehabilitation program and the outcomes achieved were consistently positive. Two thirds of the patients were advised to make use of aftercare offerings and most patients (83%) participated in an aftercare program of any kind. Conclusions The results of this study support the notion that stroke rehabilitation has significant and sustainable effects. Participation in particular seems to improve through medical rehabilitation. Partly decreased effects after four months raise the question of adequate aftercare.
Myasthenia gravis affects women younger than 40 about three times more frequently than men. Therefore, questions about family planning, pregnancy and delivery are common for these patients and their treating physicians. The outcome for mother and child depends a good deal on knowledge of the influence of pregnancy on myasthenia, therapy options, the relationship between the disease and delivery and the newborn. This paper provides an overview of these situations to support women with myasthenia gravis and their physicians in their decision-making regarding desire for children, the course of pregnancy and delivery and neonatal considerations. With thorough advice, good preparation and support of partners and families, the wish for child can come true for patients with myasthenia gravis. Taking special precautions and with interdisciplinary treatment, the risks for mother and child can be minimized.
ZusammenfassungDie moderne Radioonkologie verfügt über eine Reihe hochmoderner Techniken, sodass die Therapiekonzepte und Entscheidungen individualisiert vorgenommen werden. Moderne Techniken ermöglichen eine hohe lokale Dosisdeposition bei optimaler Schonung von gesundem Normalgewebe. Diese Entwicklungen haben die therapeutische Breite der Strahlentherapie entscheidend verbessert. Molekulare Eigenschaften von Tumoren bestimmen heute die Therapieentscheidung im interdisziplinären Kontext sowohl für primäre als auch für sekundäre Hirntumoren. Vor allem Patienten mit Tumoren an der Schädelbasis profitieren von einer hochpräzisen Strahlentherapie, hier kann die Bestrahlung oft auch als Alternative zu Resektion gesehen werden.
AbstractSeveral neuroimmunological registries have been established in Germany during the last 10 years. The common aim is to investigate the course of different diseases, mainly under various therapeutic conditions, to identify predictive factors as well as the side effects of immunomodulating therapies. Six nationwide neuroimmunological registries will be presented in this article. The German Network for Research on Autoimmune Encephalitis (GENERATE) with more than 40 participating clinical centers and 570 documented patients (September 2016) collects data and biomaterials of autoimmune encephalitis with known and unknown antibodies. The registry coordinates and mediates between scientists and clinicians and acts as a platform for the development of guidelines and procedures. The neuromyelitis optica study group (NEMOS) has established a national registry for patients with neuromyelitis optica and neuromyelitis optica spectrum disorders. In addition to 22 academic hospitals, 17 regional hospitals and several practices are participating. Currently, 250 patients are enrolled. Moreover, NEMOS is now establishing a prospective patient cohort (NationNMO) within the competence network multiple sclerosis. Current research focuses on treatment strategies for relapses and interval therapy of neuromyelitis optica. The competence network multiple sclerosis has initiated a multi-center, prospective cohort study of patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (MS) (NationMS), with the aim of long-term follow-up and clinical and paraclinical characterization of the patients. Between August 2010 and December 2014, 1,212 patients in 22 university und non-university centers were enrolled in the NationMS cohort. Standardized clinical data as well as biomaterial and MRI images were collected and stored. The German MS Society (DMSG, Bundesverband e.V.) established in 2001 a long-term project to obtain a consistent and reliable overview of MS patients in Germany. Since 2014 the registry has been revised comprehensively, with the main purpose of establishing a permanent data repository for healthcare research while ensuring the collection, storage and provision of data over decades and enabling the description of long-term outcomes. Currently, more than 170 German centers are participating and over 48,000 patients are enrolled in the registry. Since 2013, the competence network multiple sclerosis has established the immunotherapy registry REGIMS with the objective to obtain information on incidence, type and characteristics of adverse events of new immunomodulating therapies for patients with multiple sclerosis or clinical isolated syndrome. As of January 2017 more than 700 patients have been recruited from 36 active centers. The German Multiple Sclerosis and Pregnancy Registry aims to obtain safety information of disease modifying drug exposure during pregnancy. In addition to safety aspects, disease course during pregnancy and postpartum and the identification of predictors of disease activity are investigated. During the last ten years 1,500 pregnant MS patients were prospectively enrolled in the registry and at least 250 new pregnancies are followed every year. These six registries make an important epidemiological and scientific contribution. Numerous colleagues from clinics and practice support these registries. The objective is the closer understanding of the disease course, the influence of therapeutic decisions and thus the improvement of counseling and care.
Abstract Objectives The majority of epidemiological studies show that there is an increased burden of somatic comorbidities among people with epilepsy (PWE) compared with the general population. We sought that in the subgroup of patients with satisfactory and stable seizure situation and healthy style of living, the general health and quality of life might be similar to people without epilepsy and investigated the long-term outcome and the prevalence of comorbidities and the social outcome of adult patients who had been continuously treated at our center for at least 25 years. Material and methods We consecutively collected our adult out-patients for 10 months and identified those patients who had been treated at our center for at least 25 years. Among this group we assessed demographic data, epilepsy syndrome, seizure situation, antiepileptic therapy, the number of previous AEDs, the socioeconomic situation and co-morbidities. Results Out of a total of 1672 patients, 14.4 % (n = 241) patients fulfilled our inclusion criterion. In 200 the files allowed an appropriate analysis of the data. Mean treatment duration in Kork was 36 years (25 – 52). 60% of patients were seizure-free for more than one year. 80% of the seizure-free patients did not complain of adverse events. Adverse events were more often among patients with ongoing seizures. Somnolence, gait disturbances and tremor were the leading symptoms. Better seizure outcome correlated with higher education, better professional education and lower unemployment rates. Diseases such as cardiovascular diseases or diabetes mellitus were not more frequent than in the general population. PWE do not have necessarily an impaired prognosis of their general health.
AbstractThe off-label use of licensed drugs is widespread, and the risk of adverse events is elevated, especially if the scientific evidence is low. The treatment of rare diseases (<5/10,000) therefore may increase the risk of off-label use. The optimized standard treatment is primarily based on the regulatory decisions of the German Federal Joint Committee. The valid guidelines and the regulations of the German health system are discussed in this article. The criteria for indication and monitoring of off-label use are shown, especially focused on the problem of refractory myasthenia gravis. Escalation of treatment results regularly in off-label use. The arguments within the applicable guidelines should be followed. Some new aspects of the European regulations are likewise discussed.
AbstractMyasthenia gravis is an autoimmune disorder of the neuromuscular junction. The diagnosis of myasthenia gravis (MG) is based on clinical features, combined with neurophysiological and immunological parameters. Autoantibodies against the nicotinic acetylcholine receptor are the main finding in about 80% of the patients. More recently, autoantibodies against muscle-specific kinase (MuSK) and lipoprotein receptor-associated protein 4 (LRP4) have been identified in a subset of MG patients. Additionally, anti-titin autoantibodies can point to an underlying thymoma in younger MG patients. Neurophysiological examination includes a repetitive stimulation to detect a possible decrement as the electrical correlate of pathological muscle fatigability. Single-fiber electromyography can identify neuromuscular transmission disturbances in otherwise unclear cases.
AbstractMyasthenic exacerbation and crisis are most critical incidences in myasthenia gravis. Even nowadays myasthenic crisis is a life-threatening condition, with a lethality of 2–3%. We review means of avoiding myasthenic exacerbation and crisis, elaborate on red flags and how to establish highly-active therapy in a timely manner. This includes the reasonable use of cholinesterase inhibitors, immunoadsorption or plasma exchange, as well as immunoglobulins and steroids. Immunosuppressive agents and monoclonal antibody therapy add to the therapeutic options.Intensive care of myasthenic patients includes the management of dysphagia and delirium. Importantly, the perioperative management of patients undergoing thymectomy and weaning are specific challenges in the treatment of myasthenic patients in the ICU.Establishing timely consequent immunosuppression and treatment of myasthenic patients in specialized outpatient centres help to avoid repetitive exacerbations and crises.
ZusammenfassungTherapierefraktäre Verläufe der Myasthenia gravis (MG) mit Versagen auf oder Kontraindikationen für die (erweiterte) Standardtherapie sind mit 10 – 15 % aller Myasthenie-Patienten selten. Die aktuellen internationalen Konsens-Leitlinien für die Behandlung der MG empfehlen die Zuweisung von therapierefraktären Patienten an ein Zentrum mit Erfahrung in der Behandlung der MG sowie den Einsatz von intravenösen Immunglobulin- oder Plasmapherese-Therapien. Bei Fehlen von Kontraindikationen ist zur Kontrolle der myasthenen Symptome jedoch zusätzlich der Einsatz von Langzeit-Immunsuppressiva erforderlich. Dieser Artikel gibt einen Überblick über die aktuellen Entwicklungen und präsentiert therapeutische Strategien in der Behandlung der therapierefraktären MG.
SummaryPatients suffering from disorders of neuromuscular transmission are only rarely admitted to rehabilitation facilities. However, patients suffering from severe muscular weakness of arms or legs, dysphagia, dysarthria, or respiratory insufficiency, especially after myasthenic crisis, will benefit from rehabilitation. Its goal is maximal reduction of existing disabilities that will enable participation in social life. Besides extensive knowledge of the clinical course and potential complications of myasthenic syndromes, a comprehensive rehabilitation concept is an important prerequisite for successful rehabilitation that includes individual and multimodal physical training as well as coping with the disease, public health medical aspects, education, and assistive devices.
The Lambert-Eaton myasthenic syndrome (LEMS) has a prevalence of around 5/1 000 000 and is around 10 - 20 times rarer than myasthenia gravis (MG). Although LEMS does have a number of similarities to MG, there are important differences. The syndrome is characterized by a mostly proximally localised exercise-induced muscle weakness that can lead to respiratory failure, often accompanied by autonomous dysfunction. Disease symptoms are caused by autoantibodies directed against P/Q type voltage-gated calcium channels (VGCC) that are expressed in the presynaptic motor nerve terminals. The diagnosis of LEMS is based on the detection of the pathogenic anti-VGCC antibodies as well as the observation of an increment of at least 60% in the electrophysiological examination of an affected muscle. An increment is defined by an increase of the at-rest reduced compound muscle action potential (CMAP) either after voluntary maximal innervation or after high frequency (>= 20 Hz) stimulation. In almost one-third of patients, LEMS is of paraneoplastic origin. Therefore, an intensive tumour screening is necessary after diagnosis. There are some differences in the clinical presentation between paraneoplastic (pLEMS) and the exclusively autoimmune (aiLEMS) form of LEMS. With respect to this, the DELTA-P-Score and the detection of SOX1-antibody are important. The most frequent tumour associated with LEMS is small cell lung carcinoma (SCLC). Therapy is based on the initial distinction between paraneoplastic and autoimmune etiology. pLEMS requires therapy of underlying neoplasia. Usually, aiLEMS as well as pLEMS patients respond well to 3,4 dia-minopyridine (3,4-DAP), often augmented with pyridostigmine. Similar to treatment of myasthenia gravis, long-term immunosuppressive treatment is usually required to control symptoms effectively. Myasthenic crisis in LEMS can be controlled by intensive care and immunoglobulins, plasmaphereses or immunoadsorption. Based on case reports, more specific immunomodulatory treatment approaches such as the B-cell-depleting therapeutic antibody rituximab should be considered in therapy refractory courses of LEMS. Long-term prognosis of autoimmune LEMS with respect to clinical stabilization with (pharmacological) remission is good, although in around 75% of patients, significant reductions in quality of life remain. Prognosis of tumour-associated LEMS is largely determined by the tumour and its effective therapy. Curative treatment of the tumour disease as well as complete remission of pLEMS is possible.
AbstractDuring recent years, research into the causes of multiple sclerosis (MS), especially in the field of genetic risks of this disease, has made immense advances, thanks to new molecular biology techniques and large consortia. However, the functional relevance of disease-associated risk gene variants remains unclear, and representing about one-third of the overall risk compared to environmental risk factors, plays a smaller role. Thus, the further identification and, where appropriate, prevention of environmental risks is currently the focus of research. Here recently, risk factors for MS have been shown which are closely related to Western diet and lifestyle, such as high consumption of salt and cigarette smoking. In addition, the human gut continues to be the focus of research: with its large surface, the gut offers immense opportunities for interaction between intestinal bacteria, food and their metabolic products, as well as the immune system associated with the gut. In the present paper, we summarize the findings of the constantly growing research field dealing with the gut, nutrition and MS, and discuss how these findings, as shown recently for fatty acids, could have translational-therapeutic potential.
AbstractTherapy of neurological patients comprises, beyond medical treatment, the treatment of functional deficits which result from a neurological disease such as stroke. Physiotherapy aims at enabling bedridden neurological patients to become mobile again using training of movement and coordination. In cooperation with occupational therapists, patients are trained to become able to perform activities of daily living again. In addition, multimodal activating/assisting exercises are mandatory to counteract the deficit-related development of joint contractures. The rationale for these exercises are neurophysiological findings about postlesional cerebral plasticity. Moreover, parametric scales have been developed to assess neurological disturbances and to monitor their resolution in an observer-independent fashion. This allows communication across institutions and to assess the efficacy of physiotherapy and occupational therapy.
Abstract Refractory status epilepticus (RSE) is defined as status epilepticus (SE) persisting over 60 min and resistant to treatment with benzodiazepines and non-sedating antiepileptic drugs. The term super-refractory status epilepticus (SRSE) refers to a refractory episode continuing under general anesthesia for more than 24 h. RSE is treated with a combination of non-sedating AED and i. v. anesthetics; first choice drugs are midazolam, propofol and thiopental. The management of super-refractory status epilepticus (SRSE) is challenging as clear evidence-based guidelines are lacking. Recommendations are mainly based on case reports and small case series. Therapeutic options include ketamine, inhalational anesthetics, steroids and immunoglobulins. Ketogenic diet, electroconvulsive therapy and epilepsy surgery are also considered as potentially effective. A promising new approach is the neurosteroid allopregnanolone. Mortality of RSE and SRSE is largely influenced by the etiology and is markedly higher as compared to non-refractory status epilepticus. It was reported to be about 30% and 50%, respectively.
