[Multiple sclerosis and hepatitis B vaccination : What does the verdict of the European Court of Justice on liability after vaccination mean?] / Multiple Sklerose und Hepatitis-B-Impfung : Was bedeutet das Urteil des EuGH zur Haftung nach Impfung?

In June 2017 the European Court of Justice (ECJ) issued a verdict on the legal assessment of the association between hepatitis B immunization and the subsequent manifestation of multiple sclerosis (MS). This led to a high level of insecurity in the medical field as well as the normal population, especially in MS patients. The aim of this article is to briefly present the evidence-based medical facts and in particular to clearly highlight the legal aspects of the abovenamed ECJ verdict.

Symptomatic treatment in multiple sclerosis-interim analysis of a nationwide registry.

OBJECTIVE: To analyze symptomatic treatment in patients with multiple sclerosis (MS). BACKGROUND: Multiple sclerosis is a chronic inflammatory disease of the central nervous system, with accumulating disability symptoms like spasticity, voiding disorders, depression, and pain might occur. MATERIAL AND METHODS: The nationwide German MS registry was initiated 2001 under guidance of the German MS society (Deutsche MS Gesellschaft). This study was performed as an interim analysis to lay foundation for future work on this topic. A subcohort of 5113 patients was assessed for this interim analysis. The mean age of the patients was 45.3 years; mean EDSS was 4.2. More than two-third of the enrolled patients were females (70.9%). RESULTS: Most frequent symptoms were fatigue (60%), followed by spasticity (52.5%) and voiding disorders (51.7%). The likelihood of treatment was highest for epileptic disorders (68.8%), spasticity (68.5%), pain (60.7%), and depression (58.9%). Multivariate regression analysis showed that retirement was the strongest factor predictive for antispastic treatment (ß=.061, P=.005). CONCLUSION: Almost all patients in this analysis suffer from symptoms due to advanced MS. Treatment for the various symptoms differed tremendously. The likelihood of treatment correlated with the availability of effective therapeutic agents. Clinicians should put more awareness on MS symptoms. Symptomatic treatment may improve quality of life.

Coping with multiple sclerosis-the role of social support.

OBJECTIVE: The aim of this study was to get insights in mechanisms of coping and social support in multiple sclerosis (MS). BACKGROUND: Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. MS strains the patient through its unpredictable course and increasing disability. MATERIAL AND METHODS: A cross-sectional study was conducted. Two hundred and forty-three patients with MS were consecutively examined at two neurological hospitals. Besides sociodemographic variables, the level of impairment, depression, social support, and coping behavior was assessed. RESULTS: Researched patients were on average 44.0 years old (SD=11.6), were diagnosed for 8.2 years (SD=7.1), and had a mean EDSS of 4.0 (SD=2.2). Patients with MS with an EDSS of 3.0-6.0 are using more intensively cognitive or behavioral coping techniques than less (EDSS≤2.5) or stronger impaired patients (EDSS≥6.5). The level of impairment was further correlated with the amount of reported social support. CONCLUSION: Differences in coping behavior could be observed for different levels of impairment through MS. Patients tackle more intensively and more actively with their disease when trying to adapt to increasing disability with an EDSS range between 3.0 and 6.0. In addition, the coping behavior of patients with MS was connected to social support, especially support by family, friends, or other patients with MS. Results refer to the importance of special trainings to enhance coping abilities of patients with MS.

Baseline predictors of persistence to first disease-modifying treatment in multiple sclerosis.

OBJECTIVES: Patients with multiple sclerosis (MS) require lifelong therapy. However, success of disease-modifying therapies is dependent on patients' persistence and adherence to treatment schedules. In the setting of a large multicenter observational study, we aimed at assessing multiple parameters for their predictive power with respect to discontinuation of therapy. MATERIALS AND METHODS: We analyzed 13 parameters to predict discontinuation of interferon beta-1b treatment during a 2-year follow-up period based on data from 395 patients with MS who were treatment-naïve at study onset. Besides clinical characteristics, patient-related psychosocial outcomes were assessed as well. RESULTS: Among patients without clinically relevant fatigue, males showed a higher persistence rate than females (80.3% vs 64.7%). Clinically relevant fatigue scores decreased the persistence rate in men and especially in women (71.4% and 51.2%). Besides gender and fatigue, univariable and multivariable analyses revealed further factors associated with interferon beta-1b therapy discontinuation, namely lower quality of life, depressiveness, and higher relapse rate before therapy initiation, while higher education, living without a partner, and higher age improved persistence. CONCLUSIONS: Patients with higher grades of fatigue and depressiveness are at higher risk to prematurely discontinue MS treatment; especially, women suffering from fatigue have an increased discontinuation rate.

[Autoimmune-Mediated Encephalomyelitis: a Heterogeneous Entity in Between Neurology and Psychiatry]. / Autoimmunvermittelte Enzephalomyelitiden: Eine heterogene Krankheitsgruppe zwischen Psychiatrie und Neurologie.

Within the last decade, autoantibody-associated encephalitis and encephalomyelitis have stepped into the focus of clinical research and practice. Besides the "classic" autoantibodies against intracellular neuronal antigenes, a growing number of antibodies directed against pre- and postsynaptic surface proteins of neurons have been described since the millennium change. Whereas the "classic" are closely linked to paraneoplastic syndromes, this association is loose for most of the yet known surface antigen-antibodies. The immune-mediated encephalomyelitic syndromes are thus classified not only by their clinical symptoms, but also by their specific antibodies. The definition of the entity of N-methyl-D-aspartate-receptor encephalitis is a prominent example. The presented work gives an overview on the clinical and pathological correlates and the underlying immunologic processes of autoantibody-associated encephalitis from a neuropsychiatric perspective.

[Diagnostic Workup and Treatment of Antibody-Related Encephalomyelitis]. / Diagnostik und Therapie von autoantikörpervermittelten Enzephalomyelitiden.

The results of laboratory tests for antineuronal antibodies in immune-mediated encephalitis nowadays are not only relevant for diagnostic purposes but are instead closely connected to outcome measures and treatment response. Besides the mere detection of antibodies, investigating the cerebrospinal fluid is indispensible to rule out an infectious etiology of encephalitis prior to the initiation of immunosuppressive treatment, whereas imaging studies are relevant to gain information on the temporal course of disease and for ruling out other etiologies, e. g. hippocampal gliomas. This work gives an overview on the clinical course and findings of laboratory, electroencephalography (EEG) and imaging studies in relevant types of autoimmune mediated encephalitis. Furthermore, it gives a synopsis on contemporary treatment strategies.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

Effects of intrathecal triamincinolone-acetonide treatment in MS patients with therapy-resistant spasticity.

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease affecting young people and is a major cause of disability. In the course of time, disability progresses and symptoms like spasticity may occur. Spasticity is a major cost factor in MS patients. Various agents are approved for the treatment of spasticity, but each of those agents may have several side effects. Intrathecally administered steroids (triamcinolone-acetonide (TCA)) may be efficient in treating spasticity in patients with lesions in the spinal cord and no response to first-line therapeutics. The aim of this study is to show effects of TCA treatment on clinical parameters in patients with MS. METHODS: This multicentre open label study included 54 patients with MS. The clinical outcome parameters were spasticity, disability, maximum walking distance, bladder function and quality of life. All patients received physiotherapy in addition to TCA treatment to obtain optimal effects on clinical parameters. RESULTS: Spasticity, maximum walking distance as well as disability improved significantly (P ⩽ 0.001) during TCA applications. Bladder function improved in every seventh patient. CONCLUSION: We observed the effects of intrathecally administered TCA on different clinical parameters including bladder function. TCA administration is a safe method to treat different symptoms in MS patients. Longitudinal trials with repeated TCA cycles are needed to show long-term effects. Besides TCA treatment, physiotherapy contributes to the improvement of clinical parameters.

[Infection risks in multiple sclerosis therapy by infusion of disease modifying drugs]. / Infektiologische Risiken in der Multiple-Sklerose-Therapie durch infundierbare Immuntherapeutika.

The increased risk of developing infections when using disease-modifying drugs for treatment of multiple sclerosis (MS) is a major challenge in the daily clinical routine. In the growing field of treatment options specific knowledge of treatment-related risks of infections and appropriate preventive and countermeasures is mandatory. Current clinical experience shows that an individual risk stratification is necessary when choosing treatment options and while monitoring during and after treatment administration. The determination of the individual risk of infection in the context of serial use of disease-modifying drugs remains a challenging issue. In addition to the mechanisms of action, the warning notices and current recommendations on infection prophylaxis when using intravenous disease-modifying drugs, such as alemtuzumab, natalizumab and mitoxantron, are presented in detail.

[Immunotherapy and infectious issues in multiple sclerosis. Self-injectable and oral drugs for immunotherapy]. / Immuntherapien und infektiologische Probleme bei Multipler Sklerose. Selbst injizierbare und orale Immuntherapeutika.

Immunotherapy is generally associated with an increased risk for the development of infections. Due to the continuously expanding spectrum of new and potent immunotherapy treatment options for multiple sclerosis (MS), this article describes the currently known risks for treatment-related infections and the current recommendations for prevention of corresponding problems with drugs used in treatment strategies for MS and their mechanisms of action. The new treatment options in particular are linked to specific and severe infections; therefore, intensive and long-lasting monitoring is required before, during and after treatment and multidisciplinary surveillance of patients is needed. This article gives a detailed review of drug-specific red flags and current recommendations for the prophylaxis of infections associated with treatment of relapsing-remitting MS and when using self-injectable and oral disease-modifying immunotherapeutic drugs.

[Fatigue in patients with multiple sclerosis--pathogenesis, clinical picture, diagnosis and treatment]. / Fatigue bei Patienten mit Multipler Sklerose--Pathogenese, Klinik, Diagnostik und Therapie.

Fatigue is a frequent and restricting symptom of multiple sclerosis (MS). Starting from its pathogenetic mechanisms, the article develops an approach to the differential diagnosis of fatigue in MS patients. Over the past years, the use of functional imaging techniques has given important information on the mechanisms of this highly variable clinical picture. Considering our improved understanding of the interdependency of immune pathology and the clinical presentation of neuropsychological disorders, the relationship between immunomodulatory treatments and fatigue is receiving increased attention. Therefore, this article not only reports on the most recent data on pharmacological, physical and psychological interventions in the symptomatic treatment of fatigue, but also puts a special accent on data concerning the interactions between the rapidly growing number of immunomodulatory treatments in MS.

Monoclonal antibodies in treatment of multiple sclerosis.

Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing-remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing-remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab.

Multiple sclerosis treatment and infectious issues: update 2013.

Immunomodulation and immunosuppression are generally linked to an increased risk of infection. In the growing field of new and potent drugs for multiple sclerosis (MS), we review the current data concerning infections and prevention of infectious diseases. This is of importance for recently licensed and future MS treatment options, but also for long-term established therapies for MS. Some of the disease-modifying therapies (DMT) go along with threats of specific severe infections or complications, which require a more intensive long-term monitoring and multi-disciplinary surveillance. We update the existing warning notices and infectious issues which have to be considered using drugs for multiple sclerosis.

CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently defined inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and in particular the pons. The condition features a combination of clinical symptoms essentially referable to brainstem pathology and a characteristic magnetic resonance imaging (MRI) appearance with punctate and curvilinear gadolinium enhancement 'peppering' the pons. The radiological distribution is focused in the pons and adjacent rhombencephalic structures such as the cerebellar peduncles, cerebellum, medulla and the midbrain. While the lesion burden with a perivascular pattern is typically most dense in these pontine and peripontine regions, enhancing lesions may additionally extend into the spinal cord and supratentorial structures such as the thalamus, basal ganglia, capsula interna, corpus callosum and the cerebral white matter. Another core feature is clinical and radiological responsiveness to glucocorticosteroid (GCS)-based immunosuppression. As withdrawal of GCS treatment results commonly in disease exacerbation, long-term immunosuppressive therapy appears to be mandatory for sustained improvement. Diagnosis of CLIPPERS is challenging, and requires careful exclusion of alternative diagnoses. A specific serum or cerebrospinal fluid (CSF) biomarker for the disorder is currently not known. Pathogenesis of CLIPPERS remains poorly understood, and the nosological position of CLIPPERS has still to be established. Whether CLIPPERS represents an independent, actual new disorder or a syndrome that includes aetiologically heterogeneous diseases and/or their prestages remains a debated and not finally clarified issue. Clinicians and radiologists should be aware of this condition and its differential diagnoses, given that CLIPPERS constitutes a treatable condition and that patients may benefit from an early introduction of GCS ensued by long-term immunosuppression. Based on previous reports in literature - currently encompassing more than 50 reported cases of CLIPPERS - this review addresses clinical features, diagnostic criteria, differential diagnoses and therapeutic management of this peculiar disorder.

Requirement for safety monitoring for approved multiple sclerosis therapies: an overview.

During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.

Spasticity in patients with multiple sclerosis--clinical characteristics, treatment and quality of life.

AIMS: To gain real-life data on demographic and clinical characteristics, treatment patterns, treatment satisfaction and quality-of-life of multiple sclerosis-related spasticity (MSS) in Germany. MATERIAL AND METHODS: MObility ImproVEment (MOVE 1), a cross-sectional burden-of-disease study, combines retrospective 12-month chart documentation with questionnaires for both, patients and physicians. Data were collected at office-based neurologists, MS outpatient clinics and rehabilitation centres in Germany. Structured documentation forms, questionnaires and validated instruments were used for data collection. Patients with mild to severe MSS were included. Participants documented the clinical characteristics, impact of MSS on daily living, quality-of-life, treatment patterns and satisfaction with available drug treatment stratified by severity of MSS. Severity was assessed by patients and physicians. RESULTS: Of 419 patients enrolled at 42 centres from 4/2011 to 9/2011, 414 were available for analysis (mean age: 48.5 years; female: 64%). Most disturbing symptoms associated with spasticity reported by physicians and patients were stiffness (74%) and mobility restrictions (66%). Mean EQ-5D score fell from 0.6 to 0.3 with increasing severity of spasticity, while percentage of subjects with spasticity-related impairment of activities every day rose from 10% in patients with mild to 85% in patients with severe spasticity. At time of enrolment, 55% of patients received pharmacotherapy and 78% physiotherapy. These percentages increased with increasing severity (drugs: 39-84%; physiotherapy: 65-86%). Overall, 41% of physicians and 36% of patients were partial dissatisfied or dissatisfied with the effectiveness of available anti-spastic pharmacotherapy. CONCLUSIONS: Spasticity and its symptoms impair personal well-being and quality-of-life. Treatment of spasticity with drugs and physiotherapy is common, but satisfaction with the currently available anti-spastic pharmacotherapy is low.

[Multiple sclerosis, neuromyelitis optica and spasticity: control of specific symptoms and quality of life]. / Multiple Sklerose, Neuromyelitis optica und spastische Bewegungsstörungen: Spezifische Symptomkontrolle und Lebensqualität.

Spastic movement disorders show a high lifetime prevalence among patients suffering from multiple sclerosis and neuromyelitis optica. Due to the high number of factors interacting with the individual manifestations of spasticity, its symptomatic treatment affords continuous and careful balancing of therapeutic measures. A trend observed over the past few years is to base symptomatic treatment of MS on subjective assessments of functional disorders rather than on specific individual pathological signs and symptoms. This has led to a more generous and more patient-oriented perspective. Therefore, a detailed analysis, characterisation and evaluation of the individual clinical course of the disease is not only indispensable, but is actually gaining even more importance in avoiding uncontrolled polypharmacy with correspondingly increased risks for side effects.

[The Rostock Headache Questionnaire ("Rokoko")--validation of a tool to screen and to qualify primary headaches]. / Der Rostocker Kopfschmerzfragen-Komplex ("Rokoko")--Validierung einer schnellen diagnostischen Hilfe bei der Einordnung primärer Kopfschmerzen.

Primary headache disorders should be diagnosed based on the detailed history of the patient. However, only few questions are necessary to allocate the symptoms to migraine, tension-type headache or other primary headaches in most cases. The "Rostock Headache Questionnaire" (Rokoko) is suitable for being completed by the investigator or the patient him/herself within a few minutes. Validation parameters of a sample of n = 87 patients (median: 44 years), diagnosed by headache experts in a personal interview ("gold standard"), are presented. Sensitivity and specificity for migraine without aura (0.87/0.51), migraine with aura (0.71/0.95), tension-type headache (0.57/0.93), or a combination of both (0.22/0.93) are based on the parameters pain frequency (recurrent vs. permanent), and the presence or absence of aura symptoms. To differentiate tension-type headache into episodic or chronic forms, the questionnaire can be analysed individually based on the frequency of headache days. The questionnaire enables the fast acquisition of relevant data in headache diagnosis and headache research with sufficient sensitivity and specificity. In addition, further information about triggering and symptoms of headaches can be assessed. The questionnaire can be used both by neurologists or psychiatrists and by general practitioners. The questionnaire does not replace the physical examination.

[Importance and treatment of spasticity in multiple sclerosis : results of the MOVE 1 study]. / Bedeutung und Behandlung der Spastik bei Multipler Sklerose : Ergebnisse der MOVE-1-Studie.

BACKGROUND: The impact of spasticity induced by multiple sclerosis (MS) on patients and the applied treatment options have so far been insufficiently studied. METHODS: This was a multicentre, retrospective, nationwide study of the care situation of MS spasticity in Germany from the perspective of both patients and physicians. RESULTS: In this study 414 patients (mean age 48.6 years, 64.3 % women) from 42 centres were analyzed: 27 % suffered from mild, 44 % from moderate and 29 % from severe spasticity. The most common comorbidities were depression and anxiety (25.6 %) and 94.9 % suffered from concomitant symptoms (e.g. fatigue and bladder disorders). The severity of spasticity and its consequences were assessed by both patients and physicians and 54.8 % of physicians were dissatisfied with available treatment options. The most frequently cited disadvantages of currently available antispastic treatment were adverse effects (95.2 %) und insufficient effectiveness (88.1 %) and one third of patients sought help by self-medication. CONCLUSIONS: This initial assessment of MS-induced spasticity in Germany showed that patients experienced severe impairment due to spasticity. Available treatment options were assessed as dissatisfying.

[Cognitive deficits and dementia in patients with multiple sclerosis: status quo and open questions]. / Kognitive Teilleistungsstörungen und Demenz bei Patienten mit Multipler Sklerose: Status quo und offene Fragen.

Multiple sclerosis (MS) is the most common chronic immune-mediated disease which goes along with serious somatic and psychic symptoms. Whereas recent research rather focussed on the neurological symptoms of MS, there is nowadays an increasing interest among researchers in psychological symptoms of the disease. It is known that about half of the MS patients suffer from cognitive deficits, and that cognitive decline has a disadvantageous impact on lifestyle and quality of life in affected persons. So far, cognitive deficits in subjects with MS have been described as rather isolated, specific cognitive disturbances with otherwise intact intellectual abilities, while global deterioration of mental skills in terms of dementia is considered as being rather rare. In the present article, we describe cognitive domains which are typically impaired in subjects with MS and reflect on the question if the diagnosis of dementia might be underrepresented in MS patients due to several reasons (e.g., progression of cognitive deficits in the course of the disorder, adhering very closely to memory deficits as cardinal symptom of dementia, lack of longitudinal studies of cognitive performance levels). Furthermore, we recommend a multistage neuropsychological diagnostic procedure for clinical practice which aims at diagnosing cognitive deficits already in early stages of the illness. In so doing, practitioners may be able to offer adequate therapies to affected persons in all stages of the disorder in order to improve psychosocial functional levels.