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Objective: To assess the impact of the lockdown in Germany due to the COVID-19-pandemic on the incidence and the outcome of neurotrauma emergencies at a tertiary medical center. Material and Methods: From March 16th, 2020 (first lockdown in Germany) to January 31st, 2021, all neurosurgical emergencies were included and compared to a longitudinal case-cohort. Cases were descriptively recorded and retrospectively analyzed with respect to incidence and outcome. Results: All emergencies defined as polytrauma referred to our center decreased by 10% during the pandemic (n=226), whereas neurosurgical emergencies increased by 18.4% (764 vs. 905 cases). Number of specific neurotrauma emergencies increased by 44.4% (63 vs. 91 cases), yet statistically not significant (p=0.245). The duration of treatment in the intensive care unit (ICU) extended from 621 to 1056 days (p=0.34). Conclusion: Reasons for increasing numbers of neurotrauma emergencies were: 1) many surrounding smaller care providers were cancelled during this time, and 2) there was a lack of free intensive care capacities in other hospitals, urging primarily maximum care providers to deal with more referrals. Both these facts and the prolonged treatment on ICUs strenghten the necessity for maximum care providers to keep ICU capacities for non-COVID patients. Specialized neurosurgical expertise should maintain in tertiary medical centers, even or particularly in exceptional circumstances such as the current pandemic.

While several intoxications can be successfully treated with specific antidotes, intoxications with the steroid glycoside digitoxin still represent a major challenge. Besides conventional approaches, CytoSorb® hemoadsorption might be another treatment option. We report on an 81-year-old female patient treated in our intensive care unit (ICU) with severe digitoxin intoxication, acute renal failure, and urinary tract infection (UTI). As physiological digitoxin elimination kinetics are known to appear slow, and also in regard to the renal failure, the decision was made to initiate continuous renal replacement therapy combined with CytoSorb hemoadsorption. The patient was hemodynamically stabilized within the first 4 h of treatment and initially required catecholamines to be stopped within 24 h of treatment. Pre- and post-adsorber drug level measurements showed a rapid elimination of digitoxin. Antibiotic treatment with piperacillin/tazobactam was initiated, and despite CytoSorb hemoadsorption therapy and its known potential to reduce plasma concentrations of several drugs, the UTI was successfully treated. After 3 days of CytoSorb treatment, digitoxin plasma levels were stable and almost normalized, and no clinical signs of intoxication were present. Five days after presentation, the patient was transferred from the ICU in a stable condition. CytoSorb hemoadsorption may be an easily available, efficient, and less cost-intensive therapy option than treatment with the Fab fragment, which is the currently recommended therapy for digitalis intoxications. Therefore, the use of CytoSorb might represent an alternative treatment for life-threatening complications of digitoxin intoxications.

Background Neurointensive medicine is an important subspecialization of neurology. Its growing importance can be attributed to factors such as demographic change and the establishment of new therapeutic options. Part of the neurological residency in Germany is a six-month rotation on an intensive care unit (ICU), which has not yet been evaluated nationwide. The aim of this study was to evaluate kind and feasibility of neurointensive care training in Germany and to discover particularly successful training concepts. Methods In a preliminary study, ten residents and ten instructors were interviewed. Using content analysis, two questionnaires were created, which contained questions about specific teaching methods as well as individual satisfaction. The questionnaires were sent to 187 neurological clinics in Germany, and residents and instructors were asked to participate in the study. The data analysis was performed using SPSS and content analysis for the free-text data. Results Seventy of the 187 clinics contacted did not offer ICU-rotation. At 59,8% (n = 70) of the remaining hospitals, a total of 154 participants (84 residents, 70 educators) could be recruited. General satisfaction with the neurointensive medical training is high in both groups (residents: 3.34 ± 0.54; instructors: 3.79 ± 0.41, evaluated on the basis of a Likert scale from 1 = “not satisfied” to 5 = "fully satisfied"). Specific teaching methods (e.g. simulation trainings, feedback sessions) are perceived as very useful by residents, but rarely take place. Instructors are interested in educational opportunities such as didactic courses. Conclusion This study provides an overview of the ICU-rotation as part of the five-year neurological residency. Neurointensive care rotations usually take place at maximum care hospitals and last at least seven months. Despite frequent time and personnel restrictions, motivation of trainers and residents is high. Nevertheless, teaching methods as simulation training and educational opportunities for instructors must be expanded.

Background: The role of neuroinflammation and autoimmune processes in neurodegenerative diseases is not fully understood. Activation of microglia with expression of proinflammatory cytokines supports the hypothesis that immune processes may play an important role in the pathophysiology of Huntington’s disease (HD) and thus, immunomodulating therapies might have potential neuroprotective properties. Until now, no disease-modifying therapy (DMT) is available for HD. Objective: The aim of this research was to characterize a cohort of patients suffering from both HD and autoimmune demyelinating diseases of the central nervous system (classified as G35-37 in ICD-10; ADD-CNS) in comparison to HD cases without ADD-CNS. In particular, we were interested to investigate potential modulating effects on disease manifestation and progression of HD over time of prescribed immunomodulating medications (DMT). Methods: We analyzed the course of HD regarding motoric, functional, and cognitive aspects, using longitudinal data of up to 2 years from the worldwide registry study ENROLL-HD. Additional cross-sectional data in the largest cohort worldwide of HD patients was analyzed using demographic and molecular genetic parameters. Data were analyzed using analysis of variance (ANOVA) for cross-sectional and repeated-measures ANOVA for longitudinal parameters in IBM SPSS Statistics V.27. Results: Within the ENROLL-HD database, we investigated N = 21,116 participants and identified n = 60 participants suffering from ADD-CNS. Molecular, genetic, and demographic data did not differ between groups. The subgroup of n = 32 participants with motor-manifest HD revealed better cognitive performance in five out of eight cognitive tests at baseline with less progression over time in two tests (all p Conclusion: Patients suffering from motor-manifest HD and simultaneously from ADD-CNS have better cognitive capacities compared with other motor-manifest HD patients. Moreover, DMTs might have beneficial effects on progression of neurodegeneration including the motor phenotype. However, this effect might have been biased by younger age in DMT-treated patients. Pre-manifest HD patients showed more functional impairment as expected due to their additional ADD-CNS disease.

To assess the impact of the lockdown in Germany due to the SARS-CoV2-pandemic on the incidence and the outcome of neurovascular emergencies at a tertiary medical center.From March 16th, 2020 (first lockdown in Germany) to January 31st, 2021, all neurosurgical emergencies were included and compared to a longitudinal case-cohort. Cases were descriptively recorded and retrospectively analyzed with respect to incidence and outcome.All emergencies referred to our tertiary medical center decreased by 10% during the pandemic, whereas, neurosurgical emergencies increased by 18.4% (764 vs. 905 cases). Number of specific non-ischemic neurovascular emergencies increased by 29% (95 vs. 123 cases). The difference was not statistically significant (p = 0.53). Mortality rate increased dramatically by 40% during the pandemic throughout all neurovascular cases. As all included patients were negative PCR-tested for SARS-CoV2 the observed increase is unrelated to the virus infection.Unexpectedly, according to our data neurovascular emergencies raised in number and severity during the pandemic in Germany at our tertiary referral center. Furthermore, the case fatality increased. Even though our data lack proof of evidence for these findings, we might suggest two possible explanations for the absolute increase in numbers: firstly, patients might have refused to seek medical help while suffering only mild symptoms. Furthermore, as numerous lower-level medical centers restricted admissions, the referral times of patients in need of neurosurgical attention increased. We, therefore, suggest that even in a pandemic situation like the SARS-CoV2/COVID-19, it seems of utmost importance to retain dedicated neurovascular competence in designated centers to care for these emergencies.

Objectives In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP. Patients and methods This CUP was initiated in February 2017 – shortly before US Food and Drug administration approval in March 2017 – and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately. Results Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24–73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment. Conclusion This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PM L cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.

Background With ocrelizumab another drug is available for the treatment of multiple sclerosis (MS). Little is known on the long-term use of ocrelizumab on immune cell subsets, and no surrogate markers are available. Rituximab (RTX) has been in off-label use for the treatment of MS, neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) for > 10 years. Objective We evaluated the long-term depletion and repopulation rate of peripheral CD19+ B-cells as a potential surrogate for the clinical outcome, and whether it may serve for dosage and time-to-infusion decision making. Methods We evaluated the CD19+ and CD4+/8+ T-cell counts in n = 153 patients treated with RTX (132 MS, 21 NMO/NMOSD). The dosages ranged from 250 to 2000 mg RTX. Depletion/repopulation rates of CD19+ B-cells as well as long-term total lymphocyte cell counts, were assessed and corroborated with EDSS, ARR (annualized relapse rate), MRI, and time to reinfusion. Results CD19+ B-cells’ repopulation rate significantly varied depending on the dosage applied leading to individualized application intervals (mean 9.73 ± 0.528 months). Low/absent CD19+ B-cell counts were associated with reduced ARR, EDSS, and GD+-MRI-lesions. Long-term B-cell-depleting therapy led to a transiently skewed CD4+/8+ T-cell ratio due to reduced CD4+ T-cells and absolute lymphocyte counts, which recovered after the second cycle. Conclusion Our data suggest that CD19+ B-cell repopulation latency may serve as surrogate marker for individualized treatment strategies in MS and NMO/NMOSD, which proved clinically equally effective in our cohort as evaluated by previous studies.

ZusammenfassungIn der Behandlung der myotonen Dystrophien, nicht dystrophen Myotonien und periodischen Paralysen haben sich in den letzten Jahren einige neue Aspekte ergeben, die in der aktualisierten Leitlinie zu myotonen Dystrophien, nicht dystrophen Myotonien und periodischen Paralysen zusammenfassend dargestellt sind.Nach wie vor besteht eine europaweit nur sehr eingeschränkte Verfügbarkeit von Mexiletin, welches in Deutschland nur noch über die Auslandsapotheke aus z. B. Japan, den USA oder Kanada in einer Dosierung von 100 mg oder 200 mg bezogen werden kann, wenngleich die Wirksamkeit von Mexiletin bei myotoner Dystrophie Typ 1 in einer amerikanischen Studie erneut bestätigt wurde (Logigian et al., 2010).In einer rezenten Studie konnte gezeigt werden, dass der Carboanhydrasehemmer Dichlorphenamid sowohl bei hypokaliämischer als auch bei hyperkaliämischer periodischer Paralyse die Attackenfrequenz senkt, allerdings war der Unterschied bei der hyperkaliämischen Lähmung nicht signifikant (Sansone et al., 2016). Bei dieser Studie handelt es sich um die Kombination zweier randomisierter Untersuchungen über 9 Wochen, kombiniert mit einer einjährigen Extensionsphase, bei der alle Teilnehmer Dichlorphenamid erhielten. Die Studie wurde gegen Placebo durchgeführt; der ursprünglich geplante Vergleich mit Acetazolamid wurde abgebrochen, weil die an der Studie teilnehmenden Patienten Dichlorphenamid aufgrund subjektiv besserer Wirksamkeit vorzogen und deshalb keine Gruppe für einen Vergleich Dichlorphenamid/Acetazolamid gebildet werden konnte. Die Hauptnebenwirkungen waren Parästhesien, Nierensteinbildung und eine Verlangsamung des Denkens. Die Studie erlaubte keine Rückschlüsse auf die Beziehung zwischen Wirksamkeit und Genotyp; die häufigste Mutation war T704 M (Nav1.4) bei der hyperkaliämischen Lähmung und R528H (Cav1.1) und R1239H (Cav1.1) bei der hypokaliämischen Lähmung. Ein Patient in der hypokaliämischen Gruppe mit der Mutation pR222 W (Nav1.4) verschlechterte sich. Dichlorphenamid ist inzwischen als Keveyis in den USA im Handel. In der Europäischen Union ist Dichlorphenamid (noch) nicht zugelassen; es hat aber den Status einer „orphan drug“ und ist somit verordnungsfähig.In einer doppelblinden randomisierten placebokontrollierten Studie mit 22 Patienten mit nicht dystrophen Myotonien konnte gezeigt werden, dass Lamotrigin in einer Dosierung von 300 mg/d die myotone Symptomatik signifikant gegenüber dem Ausgangsbefund verbesserte (Anderson G et al., 2017).Eine offene Behandlungsstudie mit Ranolazin, einem Piperazinderivat, in einer Dosierung von 2 × 500 mg bei 13 Patienten mit Chloridkanalmyotonie ergab eine signifikant reduzierte EMG-Myotonie, eine nach Patientenangaben signifikant reduzierte Muskelsteifigkeit und geringer auch reduzierte Muskelschwäche und eine reduzierte Myotonie in den klinischen Tests (Arnold WD et al., 2017).

ZusammenfassungIn den letzten 10 Jahren wurden in Deutschland mehrere neuroimmunologische Register aufgebaut. Grundlegendes Ziel ist es, mehr über den Verlauf der entsprechenden Erkrankung, insbesondere unter therapeutischen Bedingungen, oder auch Nebenwirkungen eingesetzter Immuntherapeutika zu erfahren, im besten Fall prädiktive Marker zu identifizieren. Sechs dieser Register möchten wir im folgenden Artikel vorstellen.Das Deutsche Netzwerk zur Erforschung autoimmuner Enzephalitiden (GENERATE) mit mehr als 40 beteiligten Zentren und 570 dokumentierten Patienten (Stand September 2016) sammelt klinische Daten und Biomaterialien von Patienten mit autoimmunen Enzephalitiden mit bekannten und unbekannten Antikörpern. Es koordiniert und vermittelt die Verbindung zwischen Wissenschaftlern und Klinikern und dient als Plattform zur Entwicklung gemeinsamer Leitlinien und Prozeduren.Die NeuroMyelitis Optica Studiengruppe (NEMOS) hat ein nationales Register für Patienten mit Neuromyelitis optica und Neuromyelitis optica Spektrum-Erkrankungen aufgebaut. Am Register sind neben 22 Kliniken der Maximalversorgung auch 17 regionale Krankenhäuser und etliche Praxen beteiligt, aktuell sind etwa 250 Patienten erfasst. Mit „NationNMO“ baut NEMOS derzeit innerhalb des Kompetenznetzes Multiple Sklerose eine prospektive Kohorte auf. Die besten Behandlungsstrategien sowohl für akute Schübe als auch deren Prophylaxe stehen im Fokus der aktuellen Forschungsarbeit von NEMOS.Das Kompetenznetz Multiple Sklerose hat eine multizentrische, prospektive Kohortenstudie für therapienaive Patienten mit klinisch isoliertem Syndrom (KIS) und früher schubförmiger Multipler Sklerose (MS) initiiert (NationMS), mit dem Ziel der langfristigen Beobachtung und klinischer wie paraklinischer Charakterisierung der Patienten. Von August 2010 bis Dezember 2014 wurden in 22 universitären und nicht-universitären Zentren 1212 Patienten in die NationMS-Kohorte eingeschlossen, von denen standardisierte klinische Daten, Biomaterial und MRT-Bilddaten asserviert wurden.Die Deutsche Multiple Sklerose Gesellschaft, Bundesverband e. V. begann 2001 die Etablierung eines MS-Registers als ein Langzeitprojekt, um eine einheitliche, verlässliche Übersicht über die MS-Erkrankung in Deutschland zu erhalten. Nach einer umfassenden Revision im Jahre 2014 ist nun das primäre Ziel, ein dauerhaftes Datenrepositorium für die Versorgungsforschung zu etablieren, welches die Erfassung, Speicherung und Bereitstellung von Daten von MS-Erkrankten über Jahrzehnte gewährleistet und somit die Darstellung von Langzeitverläufen ermöglicht. In über 170 deutschlandweiten Zentren konnten bisher mehr als 48 000 Patienten eingeschlossen werden.Ebenfalls vom Kompetenznetz Multiple Sklerose wurde Anfang 2013 das Immuntherapieregister REGIMS initiiert. Primäres Ziel von REGIMS ist die Erfassung der Inzidenz, Art und Eigenschaft von unerwünschten Ereignissen aktueller und zukünftiger Immuntherapeutika in der Behandlung von Patienten mit einer gesicherten MS-Diagnose oder KIS-Patienten. Zum 01.01.2017 umfasste das Register 36 aktive Zentren mit über 700 eingeschlossenen Patienten.Das Deutsche Multiple Sklerose und Kinderwunschregister (DMSKW) hat das Ziel, Sicherheitsinformationen zur Exposition mit immunmodulierenden Therapien in der Schwangerschaft zu gewinnen. Neben Sicherheitsaspekten interessieren auch der Verlauf der MS in der Schwangerschaft und postpartum, sowie die Identifikation modifizierbarer Schubrisikofaktoren. In das DMSKW konnten bisher 1500 Schwangerschaften eingeschlossen werden, pro Jahr kommen mindestens 250 prospektiv verfolgte Schwangerschaften hinzu. Alle in diesem Artikel vorgestellten Register leisten einen wichtigen Beitrag zur Erforschung verschiedener neuroimmunologischer Erkrankungen. Viele Kollegen, sowohl in der Klinik als auch in der Praxis, unterstützen die hier vorgestellten Register. Ziel ist es, den Verlauf und den Einfluss therapeutischer Entscheidungen besser zu verstehen, aber auch die Beratung und Versorgung dieser Patienten zu verbessern.

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Huntington's disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htte1). Above a threshold of 37 glutamine residues, htte1 starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htte1 (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htte1. Here, we identify N17 as a potential target for novel therapeutic intervention using the molecular tweezer CLR01. A combination of biochemical experiments and computer simulations shows that binding of CLR01 induces structural rearrangements within the htte1 monomer and inhibits htte1 aggregation, underpinning the key role of N17 in modulating htte1 toxicity.

The transgenic mouse model R6/2 exhibits Huntington's disease (HD)-like deficits and basic pathophysiological similarities. We also used the pheochromocytoma-12 (PC12)-cell-line-model to investigate the effect of laquinimod on metabolic activity. Laquinimod is an orally administered immunomodulatory substance currently under development for the treatment of multiple sclerosis (MS) and HD. As an essential effect, increased levels of BDNF were observed. Therefore, we investigated the therapeutic efficacy of laquinimod in the R6/2 model, focusing on its neuroprotective capacity. Weight course and survival were not influenced by laquinimod. Neither were any metabolic effects seen in an inducible PC12-cell-line model of HD. As a positive effect, motor functions of R6/2 mice at the age of 12 weeks significantly improved. Preservation of morphologically intact neurons was found after treatment in the striatum, as revealed by NeuN, DARPP-32, and ubiquitin. Biochemical analysis showed a significant increase in the brain-derived neurotrophic factor (BDNF) level in striatal but not in cortical neurons. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. Besides influences on the immune system, influence on BDNF-dependent pathways in HD are discussed.

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.

Strahlenfolgen sind definiert als Schadigungen des Gewebes durch ionisierende Strahlung, wobei in Abhangigkeit von der bestrahlten Korperregion besonders Haut-, Nerven- und Muskelgewebe betroffen sind. Nach dem zeitlichen Auftreten lassen sich fruhe Bestrahlungsfolgen, die innerhalb von wenigen Wochen bis einigen Monaten nach der Strahlenexposition auftreten, unterscheiden von Spatschaden nach Monaten oder sogar Jahren. Sekundare Veranderungen der Wirbelsaule sowie Paresen der Rumpfmuskulatur sind seltene Folge einer Strahlenbehandlung, die typischerweise nach Behandlung eines Morbus Hodgkin auftreten. Klinisch kann eine „Kamptokormie“ oder ein „Dropped-Head Syndrome“ (DHS) imponieren. Bei einer entsprechenden Vorgeschichte ist eine postradiogene Schadigung differenzialdiagnostisch von Myositiden, Gliedergurtelmuskeldystrophien, der Faszioskapulohumeralen Muskeldystrophie (FSHD) oder einem adulten Saure-Maltase-Mangel abzugrenzen. Wir prasentieren hier einen Fall mit postradiogenen Paresen der Schulter-Nacken-Muskulatur bei 30 Jahre zuvor therapiertem Hodgkin-Lymphom.

OBJECTIVE To report a case of recurrent trimethoprim-sulfamethoxazole-induced aseptic meningitis with associated ampicillin-induced myoclonic twitches. MATERIALS AND METHODS The patient was investigated using cerebral computed tomography, magnetic resonance imaging, cerebrospinal fluid examination, and electroencephalography. Written informed consent was obtained from the patient for access to clinical files for research purposes and publication. RESULTS We present a middle-aged woman with two recurrent episodes of aseptic meningitis after treatment with trimethoprim-sulfamethoxazole. Additionally, she developed myoclonic twitches as a rare side effect of ampicillin. CONCLUSION Aseptic meningitis is a rare adverse reaction to medications like antibiotics. The pathogenesis of trimethoprim-sulfamethoxazole-induced aseptic meningitis is not yet completely understood, but an immune-mediated hypersensitivity reaction is suspected. If patients with an antibiotic therapy due to a systemic or local infection present with severe headache, not only common diagnosis of a parainfectious headache, but also antibiotic-induced aseptic meningitis should be considered. .

Several neuroimmunological registries have been established in Germany during the last 10 years. The common aim is to investigate the course of different diseases, mainly under various therapeutic conditions, to identify predictive factors as well as the side effects of immunomodulating therapies. Six nationwide neuroimmunological registries will be presented in this article. The German Network for Research on Autoimmune Encephalitis (GENERATE) with more than 40 participating clinical centers and 570 documented patients (September 2016) collects data and biomaterials of autoimmune encephalitis with known and unknown antibodies. The registry coordinates and mediates between scientists and clinicians and acts as a platform for the development of guidelines and procedures. The neuromyelitis optica study group (NEMOS) has established a national registry for patients with neuromyelitis optica and neuromyelitis optica spectrum disorders. In addition to 22 academic hospitals, 17 regional hospitals and several practices are participating. Currently, 250 patients are enrolled. Moreover, NEMOS is now establishing a prospective patient cohort (NationNMO) within the competence network multiple sclerosis. Current research focuses on treatment strategies for relapses and interval therapy of neuromyelitis optica. The competence network multiple sclerosis has initiated a multi-center, prospective cohort study of patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (MS) (NationMS), with the aim of long-term follow-up and clinical and paraclinical characterization of the patients. Between August 2010 and December 2014, 1,212 patients in 22 university und non-university centers were enrolled in the NationMS cohort. Standardized clinical data as well as biomaterial and MRI images were collected and stored. The German MS Society (DMSG, Bundesverband e.V.) established in 2001 a long-term project to obtain a consistent and reliable overview of MS patients in Germany. Since 2014 the registry has been revised comprehensively, with the main purpose of establishing a permanent data repository for healthcare research while ensuring the collection, storage and provision of data over decades and enabling the description of long-term outcomes. Currently, more than 170 German centers are participating and over 48,000 patients are enrolled in the registry. Since 2013, the competence network multiple sclerosis has established the immunotherapy registry REGIMS with the objective to obtain information on incidence, type and characteristics of adverse events of new immunomodulating therapies for patients with multiple sclerosis or clinical isolated syndrome. As of January 2017 more than 700 patients have been recruited from 36 active centers. The German Multiple Sclerosis and Pregnancy Registry aims to obtain safety information of disease modifying drug exposure during pregnancy. In addition to safety aspects, disease course during pregnancy and postpartum and the identification of predictors of disease activity are investigated. During the last ten years 1,500 pregnant MS patients were prospectively enrolled in the registry and at least 250 new pregnancies are followed every year. These six registries make an important epidemiological and scientific contribution. Numerous colleagues from clinics and practice support these registries. The objective is the closer understanding of the disease course, the influence of therapeutic decisions and thus the improvement of counseling and care.

In Huntington's disease (HD), a neurodegenerative-inherited disease, chorea as the typical kind of movement disorder is described. Beside chorea, however, all other kinds of movement disturbances, such as bradykinesia, dystonia, tremor or myoclonus can occur. Aim of the current study was to investigate alterations in the echogenicity of basal ganglia structures in different Huntington's disease phenotypes. 47 patients with manifest and genetically confirmed HD were recruited. All participants underwent a thorough neurological examination. According to a previously described method, classification into predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes was performed depending on subscores of the Unified Huntington's Disease Rating Scale. In addition, findings in juvenile HD were compared to adult HD. Transcranial sonography was performed by investigators blinded to clinical classification. There were no significant differences in basal ganglia echogenicities between the three phenotypes. Size of echogenic area of substantia nigra (SN) correlated positively with CAG repeat and bradykinesia subscore, and negatively with age of onset and chorea subscore. Comparing juvenile and adult HD subtypes, SN hyperechogenicity was significantly more often detectable in the juvenile form (100 vs. 29.3 %, p = 0.002). Regarding echogenicity of caudate or lentiform nuclei, no significant differences were detected. HD patients with the juvenile variant exhibit marked hyperechogenicity of substantia nigra. No significant differences in basal ganglia echogenicities between predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes were detected.

Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY13-36 in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage of Y2R using selective non-peptide small molecule Y2R antagonist SF31 in vivo and in vitro. Our results showed that activation of Y2R with intranasal NPY or NPY13-36 led to an improved motor function in R6/2 mice as revealed by rotarod performance, vertical pole test, and hindlimb clasping behaviour. Also, intranasal NPY or NPY13-36 led to a decrease in aggregated mHtt and mediated increase in dopamine and cAMP-regulated phosphoprotein, 32kDa (DARPP-32), brain-derived neurotrophic factor (BDNF), and activated extracellular signal-regulated protein kinases (pERK1/2) levels in R6/2 mice. Intranasal NPY or NPY13-36 had no effect on body weight but showed positive effects on survival in R6/2 mice. Furthermore, intranasal NPY or NPY13-36 attenuated induction of proinflammatory cytokine and inflammatory mediators in R6/2 mice. In contrast, antagonizing by using SF31 exacerbates phenotypic severity in R6/2 mice and treatment effects with either intranasal NPY or NPY13-36 were significantly blocked.In vitro, using inducible PC12/HttQ103-EGFP cells, treatment with NPY or NPY13-36 protected against mHtt-mediated neuromorphological defects (neurite length and soma area) and neurotoxicity but had no effect on mHtt inclusion body formation. Conversely, co-treatment with SF31 significantly inhibited these effects. Together, our findings extend previous evidence of the beneficial effects of NPY in R6/2 mice, and more importantly, suggest that targeted activation of Y2R receptor might be a promising disease-modifying target for HD and other neurodegenerative diseases.

\(\textbf {Background:}\) Progressive multifocal leukoencephalopathy (PML) is a severe complication of immunosuppressive therapies, especially of natalizumab in relapsing–remitting multiple sclerosis (MS). Metabolic changes within PML lesions have not yet been described in natalizumab-associated PML in MS patients. \(\textbf {Objective:}\) To study metabolic profiles in natalizumab-associated PML lesions of MS patients by \( ^{1}\)H magnetic resonance spectroscopy (\( ^{1}\)H-MRS) at different stages during the PML course. To assess changes associated with the occurrence of the immune reconstitution inflammatory syndrome (IRIS). \(\textbf {Methods:}\) 20 patients received \( ^{1}\)H-MRS and imaging at 3 T either in the pre-IRIS, IRIS, early-post-PML, or late post-PML setting. Five of these patients received individual follow-up examinations, including the pre-IRIS or IRIS phase. Clinical worsening was described by changes in the Karnofsky Performance Scale (KPS) and the expanded disability status scale (EDSS) 1 year before PML and scoring at the time of \( ^{1}\)H-MRS. \(\textbf {Results:}\) In PML lesions, increased levels of the Lip/Cr ratio, driven by rising of lipid and reduction of Creatine, were found before the occurrence of IRIS (\(\it p\) = 0.014) with a maximum in the PML–IRIS group (\(\it p\) = 0.004). By contrast, marked rises of Cho/Cr in PML lesions were detected exclusively during the IRIS phase (\(\it p\) = 0.003). The Lip/Cr ratio decreased to above-normal levels in early-post-PML (\(\it p\) = 0.007, compared to normal appearing white matter (NAWM)) and to normal levels in the late-post-PML group. NAA/Cho was reduced compared to NAWM in the pre-IRIS, IRIS, and early-post-PML group. In NAA/Cr, the same effect was seen in the pre-IRIS and early-post-PML group. These cross-sectional results were confirmed by the individual follow-up examinations of four patients. NAA/Cho, Cho/Cr, and the lipid rise relative to NAWM in PML lesions were significantly correlated with the residual clinical worsening (KPS change) in post-PML patients (Spearman correlations \(\it p\) = 0.481, \(\it p\) = 0.018; \(\it p\) = −0.505, \(\it p\) = 0.014; and \(\it p\) = −0.488, \(\it p\) = 0.020). \(\textbf {Conclusion:}\) \( ^{1}\)H-MRS detected clinically significant dynamic changes of metabolic patterns in PML lesions during the course of natalizumab-associated PML in MS patients. Lip/Cr and Cho/Cr may provide additional information for detecting the onset of the IRIS phase in the course of the PML disease.

Background: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce. Methods: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON). Results: A total of 24 patients were analyzed, 23 with relapsing–remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7–10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, p < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments. Conclusions: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.

The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities. We also used the pheochromocytoma-12 (PC12)-cell-line-model to investigate the effect of laquinimod on metabolic activity. Laquinimod is an orally administered immunomodulatory substance currently under development for the treatment of multiple sclerosis (MS) and HD. As an essential effect, increased levels of BDNF were observed. Therefore, we investigated the therapeutic efficacy of laquinimod in the R6/2 model, focusing on its neuroprotective capacity. Weight course and survival were not influenced by laquinimod. Neither were any metabolic effects seen in an inducible PC12-cell-line model of HD. As a positive effect, motor functions of R6/2 mice at the age of 12 weeks significantly improved. Preservation of morphologically intact neurons was found after treatment in the striatum, as revealed by NeuN, DARPP-32, and ubiquitin. Biochemical analysis showed a significant increase in the brain-derived neurotrophic factor (BDNF) level in striatal but not in cortical neurons. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. Besides influences on the immune system, influence on BDNF-dependent pathways in HD are discussed.

Background: Administration of intravenous immunoglobulins (IVIgs) is established for long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Prevention of secondary axonal loss going along with permanent clinical disability and muscular atrophy is a major aim in CIDP therapy. To assess long-term clinical efficacy of IVIg treatment despite heterogenous disease course and variable complaints reported by the patients, long-term electrophysiological monitoring was performed for systematic evaluation of therapeutic efficacy of IVIg. Methods: A total of 21 patients with CIDP treated with IVIg 1 g/kg bodyweight every 3–6 weeks were examined electrophysiologically every 12 months over a period of 2 years. Results: Assessment of clinical symptoms, using the Inflammatory Neuropathy Cause and Treatment (INCAT) and Hughes functional grading score (F-score) revealed improvement of motor and sensory symptoms over a period of 2 years. As electrophysiological results remained stable, IVIg treatment seems to be suitable to prevent axonal loss in CIDP. Conclusions: This study confirms efficacy of IVIg as firstline therapy in CIDP. Doses and frequency of IVIg application should be adapted based on clinical evaluation and analysis of long-term electrophysiological findings.