[Frequency and risk factors associated with post-stroke dementia-an observational study on stroke patients without premorbid cognitive impairment]. / Häufigkeit und Risikofaktoren der Post-Stroke-Demenz ­ eine Beobachtungsstudie zu Schlaganfallpatienten ohne vorbestehende kognitive Defizite.

BACKGROUND: Longitudinal studies on cognitive outcomes after stroke revealed heterogeneous results and the underlying pathology and risk factors for so-called post-stroke dementia are unclear. OBJECTIVE: To assess long-term cognitive performance changes in patients after the first ischemic stroke and to evaluate possible risk factors for post-stroke dementia. MATERIAL AND METHODS: In this study 66 clinically mildly affected patients aged 54-87 years without a history of dementia underwent extensive neuropsychological assessment after first ever ischemic stroke and again 6 months after the event (follow-up assessment). Demographic, clinical and paraclinical parameters were assessed as potential predictors for long-term cognitive outcome. RESULTS: At the group level significant performance improvements were found for most of the neurocognitive domains at the follow-up assessment. The greatest cognitive improvement was found in visuospatial processing. Immediately after stroke 54.5% of patients were considered cognitively impaired (z-scores < -2 in at least 2 neurocognitive domains). At follow-up only 16.7% were considered cognitively impaired according to this criterion and among these only 2 patients (3%) had developed a new, clinically relevant cognitive impairment (i.e. post-stroke dementia). Patients with inferior cognitive performance improvements at follow-up had on average larger brain lesions caused by the stroke as well as a prediabetic metabolic status. DISCUSSION: The probability of developing a post-stroke dementia syndrome is lower than previously assumed in patients with first ever stroke, with only mild clinical disability and without premorbid cognitive impairment. Long-term cognitive impairment could primarily be determined by the size of the lesioned brain area as well as the premorbid (pre)diabetic status.

Immunophenotyping of cerebrospinal fluid cells in ischaemic stroke.

BACKGROUND AND PURPOSE: Post-ischaemic immune cell invasion into the brain is well characterized in animal stroke models and contributes to neuronal damage. Therefore, it represents a promising therapeutic target. Cerebrospinal fluid (CSF) is easily accessible and may reflect cellular events within the parenchyma. However, comprehensive studies on CSF immune cells in patients with stroke are lacking. METHODS: In a retrospective cohort study, we performed extensive immune-cell profiling in CSF and peripheral blood of patients with acute ischaemic stroke and healthy controls. In patients with stroke, infarct size was quantified on follow-up imaging. RESULTS: Overall, 90 patients with ischaemic stroke and 22 controls were included in our study. After stroke, the total protein was increased (537.3 vs. 353.2 mg/L, P = 0.008) and the mean total white cell count was slightly but non-significantly elevated (1.76 vs. 0.50 cells/µL, P = 0.059). Proportions of CSF lymphocytes, monocytes and granulocytes and their respective subsets did not differ between patients with stroke and controls. In addition, there were no associations between proportions of major leukocyte subsets in CSF and the time from symptom onset to CSF sampling, infarct size or infarct localization. CONCLUSIONS: Ischaemic stroke induces only a very slight increase of CSF immune cells without changes in the composition of immune cell subsets, thus indicating that parenchymal inflammation is not sufficiently reflected in the CSF. Our findings suggest that CSF is not a major invasion route for immune cells and that CSF cell analyses are not suitable as biomarkers to guide future immune therapies for stroke.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 2: Oropharyngeal residue, swallow and cough response, and pneumonia.

BACKGROUND AND PURPOSE: Dysphagia is a well-known complication of acute stroke. Given the complexity of cerebral swallowing control it is still difficult to predict which patients are likely to develop swallowing dysfunction based on their neuroimaging. In Part 2 of a comprehensive voxel-based imaging study, whether the location of a stroke lesion can be correlated with further dysfunctional swallowing patterns, pulmonary protective reflexes and pneumonia was evaluated. METHODS: In all, 200 acute stroke cases were investigated applying flexible endoscopic evaluation of swallowing within 96 h from admission. Lesions were mapped using patients' computed tomography/magnetic resonance images and these were registered to a standard space. The percentage of lesioned volume of 137 anatomically defined brain regions was determined on a voxel basis (FSL5.0). Region-specific odds ratios (ORs) were calculated with respect to the presence of oropharyngeal residue, delayed swallow response, insufficient cough reflex and occurrence of pneumonia during hospital stay. Colour-coded lesion location maps of brain regions with significant ORs were created (P < 0.05). RESULTS: Lesion maps for residue and impaired swallow response depicted parietal-temporal areas of the right hemisphere. Limbic structures in the right hemisphere and sensory regions on the left were associated with cough reflex disturbance. There was no overlap of lesion maps for impaired swallow response and insufficient cough reflex or pneumonia, but substantial overlap between the last two conditions. CONCLUSIONS: This study gives new insights on the cortical representation of single components of swallowing and airway protection behaviours. The lesion model may help to risk-stratify patients for dysphagia and pneumonia based on their brain scan.

[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.

Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.

BACKGROUND: Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

The impact of lesion location on dysphagia incidence, pattern and complications in acute stroke. Part 1: dysphagia incidence, severity and aspiration.

BACKGROUND AND PURPOSE: Although early identification of patients at risk for dysphagia is crucial in acute stroke care, predicting whether a particular patient is likely to have swallowing problems based on the brain scan is difficult because a comprehensive model of swallowing control is missing. In this study whether stroke location is associated with dysphagia incidence, severity and the occurrence of penetration or aspiration was systematically evaluated relying on a voxel-based imaging analysis approach. METHODS: Two hundred acute stroke patients were investigated applying fiberoptic endoscopic evaluation of swallowing within 96 h from admission. Lesion masks were obtained from each patient's brain scan and registered to standard space. The percentage of lesioned volume of 137 atlas-based brain regions was determined in each case. Region-specific odds ratios were afterwards calculated with respect to presence of dysphagia, its severity and occurrence of penetration or aspiration. RESULTS: In all, 165 patients were diagnosed with dysphagia, 80 of whom had severe swallow impairment. For each investigated item there were significant differences of regional percentage infarction in distinct brain areas between affected patients and those who did not present with that specific dysfunction. In particular, right hemispheric lesions of the pre- and post-central gyri, opercular region, supramarginal gyrus and respective subcortical white matter tracts were related to dysphagia, with post-central lesions being especially associated with severe swallowing impairment. CONCLUSIONS: Distinct brain lesion locations are related to the incidence, severity and pattern of swallowing dysfunction.

[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.

[Current aspects of therapy conversion for multiple sclerosis]. / Aktuelles zur Therapieumstellung bei Multipler Sklerose.

In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.

Monomethylfumarate reduces in vitro migration of mononuclear cells.

Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.

[Prognostic and predictively relevant factors for multiple sclerosis]. / Prognostische und prädiktiv relevante Faktoren bei der Multiplen Sklerose.

The immunotherapy of multiple sclerosis (MS) is currently one of the most dynamic fields in clinical neurology. The comprehensive number of well-established and new innovative treatment options are a challenge for an intensive preoccupation with the differential indications and an activity-driven treatment control. In this context this review summarizes the known predictors of the natural course of MS and gives a review of challenges to be expected in association with predictors of treatment control.

HLA-G 2012 conference: the 15-year milestone update.

The non-classical human leukocyte antigen (HLA) Class I molecule HLA-G is best known for its tolerogenic function at the maternal-fetal interface, where it protects the fetus from destruction by the immune system of its mother. Yet, HLA-G has been the topic of intense investigations and its functions reach much further than originally believed. International conferences on HLA-G have taken place every 3 years since 1998, and the Sixth International Conference on HLA-G, that took place in Paris in July 2012. It counted 180 attendees from 28 countries, 35 speakers in plenary sessions, and 63 presentations of research in symposia and poster sessions, bringing new insight in HLA-G research. Here we summarize the major advances on the function and nature of HLA-G molecule that were reported, with particular interest on the findings in new mechanisms of action through regulatory cells, its relevance in cancer as well as in the molecular structure and functions of HLA-G, which are key for its clinical application.

Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy.

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

[Alemtuzumab for relapsing-remitting multiple sclerosis. Results of two randomized controlled phase III studies]. / Alemtuzumab bei schubförmig-remittierender multipler Sklerose. Ergebnisse von 2 randomisierten kontrollierten Phase-III-Studien.

In November 2012 the results of 2 clinical phase III trials were published which addressed the effects of alemtuzumab in patients with relapsing-remitting multiple sclerosis (MS). In the CARE-MS-I study patients with early untreated MS (EDSS ≤ 3.0, disease duration < 5 years) were included, whereas CARE-MS-II investigated the effects of alemtuzumab in patients with persisting disease activity under standard disease-modifying treatment (EDSS ≤ 5.0, disease duration < 10 years). These groups were compared to patients under treatment with frequently applied interferon ß 1a (3 times 44 µg subcutaneous). Both studies clearly demonstrated a superiority of alemtuzumab compared to interferon in terms of reduction of relapse rate as well as the number of new or enlarging T2 lesions and gadolinium-enhancing lesions. Moreover, the CARE-MS-II study showed a significant delay in disease progression by alemtuzumab. The portfolio and the frequency of relevant side effects, such as infusion-related reactions, development of secondary autoimmunity or infections were within the expected range. Taken together these studies confirm the high anti-inflammatory efficacy of alemtuzumab and hence provide the first evidence of superiority of a monotherapy in direct comparison to standard disease-modifying treatment in two phase III trials in relapsing-remitting MS. These data in the context of the mode of action of alemtuzumab provide evidence for the relevance of immune cells, especially T cells, in the pathophysiology of MS. Experience with long-term effects of alemtuzumab, e.g. from the phase II extension trial as well as the side effect profile argue in favor of a sustained reprogramming of the immune system as a consequence of immune cell depletion by alemtuzumab.

[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.

Factors associated with treatment escalation among MS specialists and general neurologists: Results from an International cojoint study.

BACKGROUND: Previous studies in multiple sclerosis (MS) showed that therapeutic inertia (TI) affects 60-90% of neurologists and up to 25% of daily treatment decisions. The objective of this study was to determine the most common factors and attribute levels associated with decisions to treatment escalation in an international study in MS care. METHODS: 300 neurologists with MS expertise from 20 countries were invited to participate. Participants were presented with 12 pairs of simulated MS patient profiles described by 13 clinically relevant factors. We used disaggregated discrete choice experiments to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. RESULTS: Overall, 229 neurologists completed the study (completion rate: 76.3%). The top 3 weighted factors associated with treatment escalation were: previous relapses (20%), baseline expanded disability status scale [EDSS] (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (≤ 3%). We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-MS specialists. CONCLUSIONS: Our results provide critical information on factors influencing neurologists' treatment decisions and should be applied to continuing medical education strategies.

Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) may be implicated in the immunopathogenesis of multiple sclerosis (MS) inducing demyelination in the animal model of MS. In adults reported anti-MOG antibody frequencies have been variable across a number of studies and can also be detected in controls. OBJECTIVE: To measure antibodies against MOG in paediatric patients with demyelinating disorders of the central nervous system and in controls. METHODS: Serum antibodies against MOG and myelin basic protein were measured by ELISA, flow cytometry (FACS) and in the liquid phase in 11 children with acute disseminated encephalomyelitis (ADEM), 22 children with MS, seven children with acute viral encephalitis and 13 healthy controls. The serostatus of Epstein-Barr virus (EBV) infections were assessed. RESULTS: Anti-MOG antibodies, measured either by ELISA or FACS were exclusively detected in children with demyelination. In ADEM these antibodies were highly reactive. Anti-MBP reactivity was detectable equally in all groups. The presence of either autoantibodies did not associate with EBV serostatus, age, gender or disease course. CONCLUSIONS: This study independently corroborates recently published results of seroprevalence and specificity of the assay. Due to their low sensitivity anti-MOG antibodies will not serve as disease-specific biomarkers, but could help to support the diagnosis of ADEM in difficult cases.

[Pregabalin and gabapentin in multiple sclerosis: clinical experiences and therapeutic implications]. / Ionenkanalmodulatoren bei Multipler Sklerose : Bestandsaufnahme der Anwendung in der Praxis.

BACKGROUND: Due to a plethora of additional symptoms patients with multiple sclerosis (MS) receive symptomatic treatment besides disease-modifying therapies. Among the substances which are commonly used are ion channel modulators (e. g. pregabalin, gabapentin, carbamazepine). The aim of this study was to investigate the use of these drugs in clinical practice in a larger patient cohort. PATIENTS: Data from 533 MS patients [439 without and 94 patients with add-on therapy (treatment group)] were evaluated retrospectively. All patients received a detailed neurological examination including evaluation of EDSS scores. RESULTS: Pregabalin and gabapentin are used most commonly. Abnormal sensations are the most frequent reason for therapy initiation. Patients with higher EDSS values and/or under mitoxantrone treatment most frequently receive additional therapy. CONCLUSION: So far, it is not known whether the investigated agents exert a beneficial influence on the disease course of MS itself beyond a mere symptomatic treatment. Further research efforts and clinical studies are necessary to address this question.

[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.

[Therapeutic monoclonal antibodies in clinical neurology]. / Therapeutische monoklonale Antikörper in der Neurologie.

Recombinant monoclonal antibodies break new ground in the treatment of immune-mediated nerve and muscle disorders but also of neurodegenerative diseases, in the field of neuro-oncology and in pain therapy, as they allow molecular targeting of defined cell populations or key pathophysiological molecules. However, safety risks might accompany a high efficacy. Basic understanding of this increasingly important class of agents and a steady update of knowledge, in particular on safety aspects, are therefore key requirements for responsible use based on an individual benefit-risk assessment.