German guideline for diagnosis and treatment of multiple sclerosis - a survey focusing neurologists in daily practise.

We performed a web-based survey among German-speaking neurologists to evaluate the acceptance of the 2021 German guideline in the diagnosis and treatment of multiple sclerosis. Based on 327 replies in total, the current survey largely reproduced the findings of an earlier, smaller survey on the prefinal consultation version of the guideline and confirmed high acceptance rates. Half of the participants were practising neurologists. Neurologists from MS centers with more than 500 patients per year (n=26) were more critical of the guideline. They reiterated some of the criticisms of the previous feedback, and, in particular, felt that safety aspects are overemphasized in the guideline, thereby superseding early aggressive therapy.

Development and evaluation of evidence-based patient information handbooks about multiple sclerosis immunotherapies.

BACKGROUND: Multiple sclerosis treatment options are increasing. Evidence-based patient information (EBPI) are therefore crucial to enable patient involvement in decision making. Based on earlier work on decision support, patient information handbooks on 8 MS immunotherapies were developed, piloted and evaluated with support from the German Clinical Competence Network MS and the German MS Society. METHODS: Handbooks were structured according to EBPI concepts. Drafts were commented by patient representatives and neurologists with an MS expertise. Executive boards of the German MS Society and the Competence Network as well as pharmaceutical companies' feedback was included. Handbooks were distributed among MS neurologists by the German MS Society. Evaluation followed applying a mixed methods approach with interviews, focus groups and surveys. One survey addressed persons with MS (pwMS) based on a questionnaire included in each handbook. Neurologists who received printed patient handbooks were invited to give feedback in a second survey. RESULTS: Eight handbooks were developed providing absolute and relative risk information in numbers and figures as well as monitoring needs and drug fact boxes. Despite the high amount of information and the display of low absolute risk reduction rates of treatments, handbooks were overall appreciated by pwMS (n=107) and mostly also by physicians (n=24). For more than 70% of the pwMS the information was new, understandable and supportive for decision making. But patients felt uncomfortable with relative risk information. However, response rates in the evaluation were low, exposing the challenges when implementing EBPI into clinical care. Therefore, conclusions must be considered preliminary. CONCLUSION: EBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.

Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis.

BACKGROUND: In May 2021, a new guideline on the diagnosis and treatment of multiple sclerosis and related disorders was released in Germany. Since the success of a guideline depends on how it integrates into everyday clinical practice, the German Society for Neurology (DGN) has launched a multimethod implementation project. Here we report on the results based on the consultation version of the guideline. METHODS: We used qualitative and quantitative data analyses to capture the nature and extent of barriers and facilitating factors to the implementation. We centered on the guideline's chapter A on diagnosis, relapse therapy, and immunotherapy of multiple sclerosis. We performed nine online focus group discussions and a web-based survey and analyzed emails and letters with comments from stakeholders and independent parties that were sent spontaneously or by invitation. RESULTS: 94 neurologists answered the survey, and ≥70% agreed with the recommendations of the guideline on each major content topic. Barriers to implementation were detected in group discussions and written input. The most controversial issues of the guideline were "early treatment", "criteria for starting or switching therapy", "stepwise escalation versus early aggressive treatment", "classification of drugs into three categories of efficacy" and the scenarios on "treatment cessation". Some appreciated the highly structured recommendations, but others felt that the guideline restricts the free choice of therapy, or they were afraid of recourse claims. Some considered the guideline as too cautious regarding treatment initiation, possibly delaying necessary therapies. Others appreciated that conflicts of interests of the guideline's authoring group were minimized and thought that the new guideline is clearer, more extensive and practical. CONCLUSION: In contrast to the survey, feedback in the focus group discussions and from individuals was diverse and sometimes more critical. Based on the overall feedback rate of about 250 people in relation to the number of 6500 board-certified neurologists in Germany, the overall appreciation of the guideline can only be considered as an indicator and not proof of acceptance. Results of this analysis were incorporated into several adjustments to the final guideline of 2021. Since the guideline is to be updated regularly under the auspices of a "living guideline", active interaction with users will continue to matter and help to improve it.

[The critically ill CAR T-cell patient : Relevant toxicities, their management and challenges in critical care]. / Der kritisch kranke Patient nach CAR-T-Zell-Therapie : Relevante Nebenwirkungen, deren Management und Herausforderungen an die Intensivmedizin.

BACKGROUND: CAR­T cell therapy has been implemented as clinical routine treatment option during the last decade. Despite beneficial outcomes in many patients severe side effects and toxicities are seen regularly that can compromise the treatment success. METHODS: Literature review: CAR T­cell therapy, toxicities and their management RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) are seen regularly after CAR T­cell treatment. CRS symptoms can range from mild flu-like symptoms to severe organ dysfunction requiring vasopressor therapy, mechanical ventilation and other intensive care support. ICANS symptoms usually develop later and can range from disorientation and aphasia to potentially life-threatening brain edema. IL­6 is a key factor in the pathophysiology of CRS. The pathophysiology of ICANS is not fully understood. The ASTCT consensus grading is recommended to stratify patients for different management options. An interdisciplinary team including hematologist, intensivist, neurologists and other specialties is needed to optimize the treatment. DISCUSSION: Severe and potentially life-threatening toxicities occur regularly after CAR T­cell therapy. Treatment strategies for CRS and ICANS still need to be evaluated prospectively. Due to the increasing number of patients treated with CAR T­cells the number of patients requiring temporary intensive care management due to CRS and ICANS is expected to increase during the next years.

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis.

Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.

[Weaning Unit of the University Medicine Greifswald - Institutional Structure and Weaning Results from Prolonged Ventilation over 10 Years]. / Weaningzentrum Greifswald ­ Struktur und Ergebnisse bei der Entwöhnung von der Langzeitbeatmung über zehn Jahre.

The increasing importance of intensive care medicine including mechanical ventilation has been accompanied by the demand of weaning opportunities for patients undergoing prolonged mechanical ventilation. Consequently, specialised clinical institutions, focusing on the weaning from mechanical ventilation, have been established since the 1980 s.The present article illustrates the structural development and results of such a specialised institution at the University Medicine Greifswald, using data of 616 patients collected within the past ten years (2006 - 2015). Across the years, a shift in the underlying disease leading to mechanical ventilation can be found, with rising numbers of patients suffering from pneumonia/sepsis and declining numbers of patients who underwent cardiac surgery in advance. The days with mechanical ventilation outside (p = 0.004) and within the investigated institution (p = 0.02) are significantly declining. The percentage of successfully weaned patients increased from 62.7 % (2006 - 2010) to 77.3 % (2011 - 2015), p < 0.001. Consecutively, the percentage of patients who remained mechanically ventilated decreased from 16.4 % to 9.6 % (p < 0.001) and the share of in-hospital deceased patients significantly declined from 20.9 % to 13.0 % (p < 0.001). Furthermore, the one-year-survival after hospital discharge in successful weaned patients was 72 percent. The present data, collected at the University Medicine Greifswald are quite comparable to data of other German institutions that are specialised on weaning from mechanical ventilation.

[Lung Health Data of the Study of Health in Pomerania - a Review of Samples, Methods and First Results]. / Pneumologisch relevante Daten aus der "Study of Health in Pomerania" (SHIP) ­ eine Übersicht zu den Kohorten, Methoden und ersten Ergebnissen.

Investigating reasons for differing life expectancy and prevalence of cardiovascular risk factors between old and new states of the Federal Republic of Germany an epidemiological study in Western Pomerania - the population-based project Study of Health in Pomerania (SHIP) - was planned.Prevalence and incidence of common risk factors, subclinical disorders and clinical diseases have been assessed since 1997 in five-year intervals. The third follow up (SHIP-3) was assessed between 2014 and 2016. In addition, an independent representative population sample was investigated between 2008 - 2012 (SHIP-TREND). Recently, the first follow up of this cohort has been started (SHIP-TREND-1). This paper reports the methodological approaches for detecting pneumological relevant morbidities in this population-based study. It aims to offer insights for potential cooperation with interested research groups.

[Progressive multifocal leukoencephalopathy]. / Progressive multifokale Leukenzephalopathie.

Progressive multifocal leukoencephalopathy (PML) is a disease of immunosuppressed patients caused by the JC polyomavirus (JCPyV). Due to the elevated risk in patients treated with natalizumab for multiple sclerosis (MS) and also treatment with other biologicals for different indications, the relevance of PML has increased in recent years. This article summarizes the published knowledge on the biology and pathogenesis of PML with a focus on the role of cerebrospinal fluid diagnostics in the work-up for PML and the current PML case definition. Current recommendations regarding risk management are discussed, as are possible therapies and prevention.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

[Pegylated interferon beta 1a. A new therapy option for treatment of relapsing-remitting multiple sclerosis]. / Pegyliertes Interferon-beta 1a. Eine neue Therapieoption zur Behandlung der schubförmigen multiplen Sklerose.

Pegylation of pharmacological substances was developed in the 1970s as a way of improving their efficacy and elimination and hence reducing the dosage frequency. A prominent example is pegylation of IFNα, which revolutionized the treatment of virus hepatitis in the late 1990s. Efforts have now succeeded in producing a pegylated interferon beta (PEG-IFN-ß1a) to treat multiple sclerosis (MS) and the efficacy and safety have been investigated in a phase III trial called the ADVANCE study. The 1-year results of this randomized, double blind, multicenter, placebo-controlled study in more than 1500 MS patients show that administration of subcutaneous PEG-IFN-ß1a significantly reduces the annual relapse rate and disability progression. The safety and tolerability profile of PEG-IFN-ß1a was found to be similar to that of conventional IFN-ß drugs. The most common adverse events were flu-like symptoms and redness at the injection site. The results of this study underscore that PEG-IFN-ß1a is an interesting new therapeutic option in the treatment of relapsing-remitting MS that combines highly effective interferon with the established tolerability and safety profile of IFN-ß at a reduced dosage frequency.

[Teriflunomide for treatment of multiple sclerosis]. / Teriflunomid zur Behandlung der Multiplen Sklerose.

Interferon beta and glatiramer acetate are still considered to be the first-line therapeutics for treatment of relapsing forms of multiple sclerosis (MS). The use of new compounds, such as natalizumab or fingolimod, is restricted to severe forms of relapsing MS or cases refractory to first-line treatment owing to substance-specific risk-benefit considerations. Teriflunomide is a new compound which has recently been approved as a first-line treatment of relapsing forms of MS in the USA and Australia. It is characterized by a once daily oral administration and a comparably well-established long-term safety profile. The main therapeutic effect is considered to be mediated via the inhibition of the de novo synthesis of pyrimidine in proliferating immune cells. The pro-drug of teriflunomide, leflunomide, has a label for treating rheumatoid arthritis (RA) for many years. Two recently published phase III clinical trials (TEMSO, TOWER) tested teriflunomide in patients with relapsing forms of MS and efficacy was demonstrated, with positive effects on relapse rates and disease progression using 14 mg/day. Overall, the safety profile in these studies was favorable as expected from experiences with leflunomide in RA. In patients treated with teriflunomide regular monitoring of blood cell counts and liver enzymes is required. Teriflunomide must not be used during pregnancy. In this article the recent phase II and phase III clinical trial data are reviewed and the potential of teriflunomide for the treatment of relapsing forms of MS is discussed.

[The Study of Health in Pomerania (SHIP) reference values for cardiopulmonary exercise testing]. / Referenzwerte für die Spiroergometrie - Ergebnisse der Study of Health in Pomerania (SHIP).

The interpretation of gas exchange measured by cardiopulmonary exercise testing (CPET) depends on reliable reference values. Within the population based Study of Health in Pomerania (SHIP) CPET was assessed in 1706 volunteers. The assessment based on symptom limited exercise tests on a bicycle in a sitting position according to a modified Jones protocol. CPET was embedded in an extensive examination program. After the exclusion of active smokers and volunteers with evidence of cardiopulmonary and musculoskeletal disorders the reference population comprised 616 healthy subjects (333 women) aged 25 to 85 years. Reference equations including upper and/or lower limits based on quantile regression were assessed. All values were corrected for the most important influencing factors.This study provides reference equations for gas exchange and exercise capacity assessed within a population in Germany.

[Cannabinoids for symptomatic therapy of multiple sclerosis]. / Cannabinoide zur symptomatischen Therapie der Multiplen Sklerose.

Spasticity represents a common troublesome symptom in patients with multiple sclerosis (MS). Treatment of spasticity remains difficult, which has prompted some patients to self-medicate with and perceive benefits from cannabis. Advances in the understanding of cannabinoid biology support these anecdotal observations. Various clinical reports as well as randomized, double-blind, placebo-controlled studies have now demonstrated clinical efficacy of cannabinoids for the treatment of spasticity in MS patients. Sativex is a 1:1 mix of delta-9-tetrahydocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which recently received a label for treating MS-related spasticity in Germany. The present article reviews the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option in MS.

Airflow limitation, lung volumes and systemic inflammation in a general population.

Although several levels of evidence have suggested an association between systemic inflammation and spirometric lung volumes, data addressing the potential interrelationship between airflow limitation and inflammatory markers are sparse and remain controversial. Potential associations between high-sensitivity C-reactive protein (hsCRP), fibrinogen and lung function were investigated in 1,466 individuals aged 25-85 yrs, representing a general population. Within this cross-sectional population, data on body plethysmography, spirometry, helium dilution and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were analysed. After adjustment for potential confounding factors, such as smoking, obesity and cardiorespiratory fitness, there was an inverse association of hsCRP with forced expiratory and static lung volumes. In neither apparently healthy nor the entire population was inflammation associated with airflow limitation in central airways. In smokers only, higher hsCRP and fibrinogen were associated with an impaired D(L,CO). This study shows that higher levels of hsCRP are associated with decreased lung volumes in a general population over a wide age range. A consistent interrelationship of central airflow limitation and inflammation was not verifiable. Smoking is related to an impaired D(L,CO) in association with an increase in systemic inflammation.

[Alemtuzumab: a further option for treatment of multiple sclerosis]. / Alemtuzumab: eine weitere Chance zur Therapie der Multiplen Sklerose.

Alemtuzumab is a humanized monoclonal therapeutic antibody that targets the CD52 antigen which s expressed on most cells of the lymphoid lineage, exclusive of precursors. Alemtuzumab rapidly depletes CD52(+) cells from the peripheral blood. This depletion is long-lasting, and cells repopulate in a specific pattern with B cells and regulatory T cells peaking first. Alemtuzumab was examined for clinical utility in two open-labelled intervention trials in multiple sclerosis (MS). Because of very promising results its clinical efficacy was further explored in a clinical phase-II trial using s.c. interferon beta-1a as the active comparator. Severe or opportunistic infections were surprisingly rare given the long-term lymphopenia. However, up to 30% of patients developed some antibody-mediated autoimmunity. The thyroid gland was the most frequently affected organ. Immune-mediated thrombocytopenic purpura and Goodpasture's syndrome were additionally observed. This review summarizes the pre-clinical and clinical development of alemtuzumab and discusses potential modes of action as well as the pathogenetic link to the treatment emergent autoimmune phenomena.

[Superficial siderosis of the central nervous system in a patient with hemochromatosis and Wilson's disease]. / Superfizielle Siderose des zentralen Nervensystems bei einem Patienten mit Hämochromatose und Morbus Wilson.

HISTORY AND FINDINGS ON ADMISSION: A 55-year-old patient with a history of Wilson's disease and biopsy proven hemochromatosis complained of hearing loss, vertigo, and gait disturbance. Clinical examination confirmed hearing loss, revealed cerebellar syndrome and bilateral pyramidal tract disturbances. INVESTIGATIONS: Neurophysiology confirmed pathological findings on clinical examination. Cerebral magnetic resonance imaging (MRI) disclosed deposition of hemosiderin suggestive for superficial siderosis of the central nervous system. Cerebrospinal fluid findings were normal. DIAGNOSIS: The triad of hearing loss, cerebellar syndrome, and pyramidal tract disturbances associated with typical findings on MRI led to diagnosis of superficial siderosis. CLINICAL COURSE AND THERAPY: Etiology in this case remained unclear; no source of bleeding was detected. Thus, no causal therapeutic option was available. CONCLUSION: A unique case of superficial siderosis in a patient with a history of Wilson's disease and hemochromatosis is presented. Unexpected new symptoms in a successfully treated Wilson's disease patient require further diagnostic work-up not to miss potentially curable differential diagnoses. Thus, regular neurological follow-up visits of Wilson's disease patients are required.

[Progressive multifocal leukoencephalopathy under natalizumab. Initial possibilities for risk stratification?]. / Progressive multifokale Leukenzephalopathie unter Natalizumab. Erste Möglichkeiten einer Risikostratifizierung?

Natalizumab (Tysabri®) is the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS) but while treatment is highly efficient, it carries the risk of progressive multifocal leukoencephalopathy (PML). Based on reports of confirmed cases of PML, the risk of PML might increase beyond 24 months of treatment. Thus, attempts to stratify patients treated with natalizumab into those carrying higher or lower risk for developing PML are currently being undertaken. Among these strategies JC virus serology might potentially be the first tool available. As a large variety of methods have been published resulting in controversial results for JC virus seroprevalence, standardized testing will be mandatory when applying this method in clinical practice. In addition, risk management strategies for the seropositive majority of patients need to be redefined and optimized further.