B. Tackenberg

Classifications and treatment responses in chronic immune-mediated demyelinating polyneuropathy.

Background: Chronic immune-mediated demyelinating polyneuropathy (CIP) represents a heterogeneous pool of motor, sensory, sensorimotor, symmetric, or asymmetric syndromes. Objective: To evaluate published diagnostic classifications and characterize predictors of treatment response. Methods: One hundred two of 158 patients with a working diagnosis of CIP were included and clinically characterized because they had electrophysiologic and/or histologic evidence of demyelination. The biostatistical profile of patients with symmetric clinical manifestation was analyzed using three proposed classifications (American Academy of Neurology [AAN] criteria, modified AAN criteria, European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS] criteria). Treatment responses to IV immunoglobulins (IVIg) and their positive predictors were investigated. Results: Sensitivities (0.52 [AAN] vs 0.83 [modified AAN] vs 0.95 [EFNS/PNS]) and negative predictive values (0.68 vs 0.85 vs 0.92) differed markedly, whereas specificities (0.94 vs 0.90 vs 0.96) and positive predictive values (0.89 vs 0.89 vs 0.97) were similar. In CIP patients treated with IVIg, a positive response was found in 62 of 76 (82%). Patients with a monophasic or relapsing–remitting course or a more than twofold CSF protein increase had the highest probability to respond to IVIg, most evident when using the modified AAN criteria. Conclusions: The European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy improve treatment of patients with chronic immune-mediated demyelinating polyneuropathy, particularly with respect to diagnostic issues. To predict IV immunoglobulin treatment response, the modified American Academy of Neurology criteria are the most valuable classification provided an increased CSF protein level.

Dysregulated Epstein-Barr virus infection in patients with CIDP

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host-pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP.

Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie

ZusammenfassungMit der Zulassung verschiedener Substanzen zur Immuntherapie der multiplen Sklerose (MS) haben sich die Behandlungsmöglichkeiten in den letzten Jahren deutlich verbessert. Allerdings ist die Auswahl des individuell geeigneten Präparats sowie die Therapieüberwachung für den behandelnden Arzt zunehmend komplexer geworden. Dies gilt insbesondere für das Monitoring hinsichtlich einer therapiebedingten Kompromittierung des Immunsystems. Der folgende Artikel von Mitgliedern des Kompetenznetzes Multiple Sklerose (KKNMS) und der Task Force „Versorgungsstrukturen und Therapeutika“ fasst die praktischen Empfehlungen für die zugelassenen Immuntherapeutika für milde/moderate sowie (hoch)aktive Verläufe der multiplen Sklerose zusammen. Ein Schwerpunkt liegt auf der Erläuterung der substanzspezifischen Relevanz bestimmter Laborparameter im Hinblick auf Wirkmechanismus und Nebenwirkungsprofil. Um in der klinischen Praxis die richtigen Konsequenzen ziehen zu können, sollen zu erwartende Blutbildveränderungen, aber auch unerwünschte Laborveränderungen und deren Ursache und Relevanz, erläutert werden.AbstractWith 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.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action].

ZusammenfassungMit der Zulassung verschiedener Substanzen zur Immuntherapie der multiplen Sklerose (MS) haben sich die Behandlungsmöglichkeiten in den letzten Jahren deutlich verbessert. Allerdings ist die Auswahl des individuell geeigneten Präparats sowie die Therapieüberwachung für den behandelnden Arzt zunehmend komplexer geworden. Dies gilt insbesondere für das Monitoring hinsichtlich einer therapiebedingten Kompromittierung des Immunsystems. Der folgende Artikel von Mitgliedern des Kompetenznetzes Multiple Sklerose (KKNMS) und der Task Force „Versorgungsstrukturen und Therapeutika“ fasst die praktischen Empfehlungen für die zugelassenen Immuntherapeutika für milde/moderate sowie (hoch)aktive Verläufe der multiplen Sklerose zusammen. Ein Schwerpunkt liegt auf der Erläuterung der substanzspezifischen Relevanz bestimmter Laborparameter im Hinblick auf Wirkmechanismus und Nebenwirkungsprofil. Um in der klinischen Praxis die richtigen Konsequenzen ziehen zu können, sollen zu erwartende Blutbildveränderungen, aber auch unerwünschte Laborveränderungen und deren Ursache und Relevanz, erläutert werden.AbstractWith 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.

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.ZusammenfassungIn den letzten Jahren ist mit der Zulassung neuer Substanzen die Zahl der verfügbaren verlaufsmodifizierenden Immuntherapien der Multiplen Sklerose deutlich gestiegen. Therapieumstellungen stellen damit eine zunehmende Herausforderung dar. Die Behandlungsoptionen weisen teilweise komplexe Nebenwirkungsprofile auf und erfordern ein langfristiges und umfangreiches Monitoring. In Übereinstimmung mit den Empfehlungen des Krankheitsbezogenen Kompetenznetzes Multiple Sklerose und der Deutschen Multiple Sklerose Gesellschaft sowie den Leitlinien für Diagnostik und Therapie der Multiplen Sklerose der Deutschen Gesellschaft für Neurologie und den neusten Forschungsergebnissen erstellen wir in diesem Artikel eine Übersicht zur Therapieumstellung von Immuntherapien der Multiplen Sklerose. Dabei muss zum gegenwärtigen Zeitpunkt festgehalten werden, dass für die meisten der angegebenen Vorgehensweisen bei Therapieumstellungen keine Studien zugrunde liegen, sondern die Empfehlungen auf theoretischen Überlegungen beruhen und damit Empfehlungen auf dem Niveau eines Expertenkonsenses entsprechen, der aktuell wesentlich ist für den klinischen Alltag.AbstractIn 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.

Pegyliertes Interferon-beta 1a

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-β1a) 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-β1a significantly reduces the annual relapse rate and disability progression. The safety and tolerability profile of PEG-IFN-β1a was found to be similar to that of conventional IFN-β 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-β1a 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-β at a reduced dosage frequency.ZusammenfassungDie Pegylierung pharmakologischer Substanzen wurde in den 1970er Jahren als ein Verfahren entwickelt, um deren Wirkung zu verbessern und deren Elimination und damit Applikationsfrequenz zu reduzieren. Prominentes Beispiel ist die Pegylierung von Interferon(IFN)-α, das Ende der 1990er Jahre die Behandlung der viralen Hepatitis revolutionierte. Inzwischen ist es gelungen, ein pegyliertes Interferon-beta (PEG-IFN-β1a) zur Therapie der Multiplen Sklerose (MS) herzustellen, dessen Wirksamkeit und Sicherheit in einer Phase-III-Studie untersucht wurde (ADVANCE-Studie). Die Einjahresergebnisse dieser randomisierten, doppelblinden, multizentrischen und placebokontrollierten Studie bei mehr als 1500 MS-Patienten zeigen, dass die Gabe subkutanen PEG-IFN-β1a die jährliche Schubrate sowie auch die Behinderungsprogression signifikant reduziert. Das Sicherheits- und Verträglichkeitsprofil von PEG-IFN-β1a war dabei vergleichbar mit dem konventioneller IFN-β-Präparate, die häufigsten unerwünschten Ereignisse waren grippeähnliche Symptome und Rötungen an der Injektionsstelle. Die Ergebnisse dieser Studie unterstreichen, dass PEG-IFN-β1a eine interessante neue Therapieoption zur Behandlung der schubförmigen MS darstellt, die eine hohe Interferonwirksamkeit mit dem bekannten Verträglichkeits- und Sicherheitsprofil der IFN-β-Therapie bei niedriger Applikationsfrequenz vereint.SummaryPegylation 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-β1a) 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-β1a significantly reduces the annual relapse rate and disability progression. The safety and tolerability profile of PEG-IFN-β1a was found to be similar to that of conventional IFN-β 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-β1a 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-β at a reduced dosage frequency.

Current aspects of therapy conversion for multiple sclerosis

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.ZusammenfassungIn den letzten Jahren ist mit der Zulassung neuer Substanzen die Zahl der verfügbaren verlaufsmodifizierenden Immuntherapien der Multiplen Sklerose deutlich gestiegen. Therapieumstellungen stellen damit eine zunehmende Herausforderung dar. Die Behandlungsoptionen weisen teilweise komplexe Nebenwirkungsprofile auf und erfordern ein langfristiges und umfangreiches Monitoring. In Übereinstimmung mit den Empfehlungen des Krankheitsbezogenen Kompetenznetzes Multiple Sklerose und der Deutschen Multiple Sklerose Gesellschaft sowie den Leitlinien für Diagnostik und Therapie der Multiplen Sklerose der Deutschen Gesellschaft für Neurologie und den neusten Forschungsergebnissen erstellen wir in diesem Artikel eine Übersicht zur Therapieumstellung von Immuntherapien der Multiplen Sklerose. Dabei muss zum gegenwärtigen Zeitpunkt festgehalten werden, dass für die meisten der angegebenen Vorgehensweisen bei Therapieumstellungen keine Studien zugrunde liegen, sondern die Empfehlungen auf theoretischen Überlegungen beruhen und damit Empfehlungen auf dem Niveau eines Expertenkonsenses entsprechen, der aktuell wesentlich ist für den klinischen Alltag.AbstractIn 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.

Treatment choices and neuropsychological symptoms of a large cohort of early MS

Objective To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results Of 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06–40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0–2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0–377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients.

Afferent visual pathway affection in patients with PMP22 deletion-related hereditary neuropathy with liability to pressure palsies.

Background The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Methods Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). Results All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. Conclusion PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation.

Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie. Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen

ZusammenfassungMit der Zulassung verschiedener Substanzen zur Immuntherapie der multiplen Sklerose (MS) haben sich die Behandlungsmöglichkeiten in den letzten Jahren deutlich verbessert. Allerdings ist die Auswahl des individuell geeigneten Präparats sowie die Therapieüberwachung für den behandelnden Arzt zunehmend komplexer geworden. Dies gilt insbesondere für das Monitoring hinsichtlich einer therapiebedingten Kompromittierung des Immunsystems. Der folgende Artikel von Mitgliedern des Kompetenznetzes Multiple Sklerose (KKNMS) und der Task Force „Versorgungsstrukturen und Therapeutika“ fasst die praktischen Empfehlungen für die zugelassenen Immuntherapeutika für milde/moderate sowie (hoch)aktive Verläufe der multiplen Sklerose zusammen. Ein Schwerpunkt liegt auf der Erläuterung der substanzspezifischen Relevanz bestimmter Laborparameter im Hinblick auf Wirkmechanismus und Nebenwirkungsprofil. Um in der klinischen Praxis die richtigen Konsequenzen ziehen zu können, sollen zu erwartende Blutbildveränderungen, aber auch unerwünschte Laborveränderungen und deren Ursache und Relevanz, erläutert werden.AbstractWith 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.