Unter paraneoplastischen neurologischen Syndromen (PNS) versteht man verschiedene Erkrankungen des zentralen, peripheren und autonomen Nervensystems sowie der neuromuskulären Übertragung und der Muskulatur. Sie beruhen auf einer Immunreaktion, die sich einerseits gegen Tumorgewebe (Abwehr der Krebserkrankung) und andererseits gegen körpereigenes neuronales Gewebe (Autoimmunreaktion) richtet. Psychiatrische Manifestationen, zu denen affektive Symptome (u. a. Stimmungslabilität, Depression, Angst), kognitive Beeinträchtigungen (u. a. Aufmerksamkeit, Gedächtnis, Sprache), psychotische Symptome (u. a. Halluzination, Realitätsverlust) sowie Wesens- und Verhaltensänderungen zählen, müssen bei PNS im Hinblick auf die Diagnose mitgedacht werden, insbesondere wenn das limbische Netzwerk mitbetroffen ist. Sowohl für das neurologische als auch für das onkologische Outcome ist eine frühzeitige Diagnose entscheidend, speziell bei High-Risk-PNS. Der vorliegende Beitrag thematisiert klinische Syndrome ebenso wie Pathophysiologie und Einteilung, erörtert das klinische Spektrum sowie die klinische Bedeutung psychiatrischer Symptome bei PNS und erläutert Therapiemöglichkeiten.

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Zusammenfassung Hintergrund Neurofibromatose Typ 1 (NF1) präsentiert sich bereits im Kindesalter mit einer Vielzahl potenzieller Symptome. Neben der Entstehung von Tumoren, insbesondere im Bereich des Nervensystems, rücken besonders orthopädische, neurokognitive/schulische und psychosoziale Aspekte in den Fokus. Zielsetzung In Österreich fehlten bisher klare Leitlinien für die Betreuung von Kindern und Jugendlichen mit NF1. Die Entwicklung eines Vorsorgebogens soll ein einheitliches Vorgehen ermöglichen. Methodik Das im Jahr 2021 etablierte österreichische NF Netzwerk, bestehend aus Expert:innen und Mitgliedern der Patientenorganisation NF Kinder, erzielte durch wiederholte Diskussionsrunden einen Konsens bezüglich der optimalen Vorsorge für Kinder und Jugendliche mit NF1. Der Vorsorgebogen richtet sich an Gesundheitspersonal, das Menschen mit NF1 betreut. Ergebnisse Der pädiatrische Vorsorgebogen ist in die Bereiche Klinik/Labor/Radiologie und Konsil gegliedert. Er zeigt auf, wann und welche Untersuchungen oder Kontrollen als sinnvoll erachtet bzw. empfohlen werden. Schlussfolgerung Die Entwicklung dieses Vorsorgebogens stellt einen bedeutenden Schritt in der Standardisierung der Versorgung von Kindern und Jugendlichen mit NF1 in Österreich dar. Durch die einfache Strukturierung und praxisorientierte Empfehlungen sollen eine effektivere Betreuung und Früherkennung von relevanten Gesundheitsaspekten ermöglicht werden.

BackgroundAnti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance.MethodsIgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method.ResultsThe median age at onset was 66 years (range: 54–75), disease duration 10 years (range: 15–156 months), and follow-up 25 months (range: 0–83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab.ConclusionOur findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

Summary Background Neurofibromatosis type 1 (NF1) is a rare autosomal dominant tumor predisposition syndrome with a birth prevalence of approximately 1 in 2000–3000 individuals. Management of both benign and malignant tumors arising in individuals with NF1 is demanding and tumors may be difficult to treat. Both standardized and individual surveillance programs are therefore highly important to prevent morbidity and mortality in patients with NF1. Methods The guidelines for the clinical management of NF1 recently proposed by the European Reference Network for Genetic Tumor Risk Syndromes provide the cornerstone of the present surveillance form and were discussed through three rounds of voting and a final consensus meeting involving experts from five Austrian and one German clinical NF1 centers for adults and one patient organization representative. Subsequently, 31 items within 4 categories were integrated into the proposed surveillance form for Austria. All recommendations, unless otherwise specified, pertain to primarily asymptomatic patients in routine follow-up. Recommendations At healthcare transition from pediatric to adult surveillance or the initial visit in adulthood, we suggest a thorough clinical, laboratory and radiological examination to obtain a baseline for future diagnostics. To comply with the general screening recommendations in Austria, we suggest extending the frequency of clinical visits from annual to biennial at 50 years of age. In cases of clinical dynamics, early follow-up is recommended to facilitate early detection of potential complications. Particular emphasis should be placed on preventive patient education.

Background: Neurofibromatosis type 1 (NF1) manifests in childhood with a variety of potential symptoms. Besides the development of tumours (primarily but not exclusively in the nervous system), orthopaedic, neurocognitive/educational and psychosocial aspects are particularly important. Objective: In Austria clear guidelines for the care of children and adolescents with NF1 were lacking. The development of a form for prevention and care should facilitate a standardised approach. Methodology: The Austrian NF network was established in 2021 and is comprised of experts as well as members of the patient association NF Kinder, reached a consensus through repeated discussions regarding the optimal preventive care for children and adolescents with NF1. The form is designed for healthcare professionals who provide care and treatment for individuals with NF1. Results: The paediatric prevention and care form is divided into the sections clinical examination/laboratory/radiology and referral. It precisely indicates when and which investigations or controls are considered advisable or recommended. Conclusion: The development of this form for paediatric prevention and care in NF1 represents a significant step in standardising the care for children and adolescents with NF1 in Austria. With its clear structure and practical recommendations, it aims to facilitate more effective management and early detection of relevant health aspects.

Abstract BACKGROUND Unified strategies for the care of children and adolescents affected by Neurofibromatosis type 1 (NF1) are lacking in Europe. While ERN GENTURIS developed guidelines for the tumour surveillance and management in NF1, these recommendations do not cover all other aspects of the disease. This holds not only true on an international level, but also on the national level in Austria. Despite being a small country with a uniform health and social security system, approaches to patient care may be comparable but not identical. AIM In order to standardise and improve patient care for children with NF1 in Austria, a care and prevention sheet was developed. METHODS In close cooperation with the Austrian patient organisation NF Kinder the Austrian NF network was established. This network is composed of dedicated health-care providers (medical as well as psychosocial) involved in the care of patients with NF1 in ten Austrian centres as well as patient representatives, some of whom were also involved in drafting the novel ERN GENTURIS recommendations. This network undertook the task of reviewing existing guidelines and incorporate the national healthcare structure and best practice guidelines into a consensus document. RESULTS The recommendations were condensed into a single sheet that is divided in four sections: clinical examination, lab investigations, imaging, additional consultations. For each parameter, the document advises on the age specific intervals for screening. Furthermore, it indicates the appropriate time points during follow-up (e.g. at initial presentation, at transition, if clinically indicated, …). The recommendations thereby focus not only on the inherent tumour risk but address the broad spectrum of possible symptoms (such as orthopaedic or surgical), specifically emphasising also psychosocial and neurocognitive issues. CONCLUSION The novel Austrian care and prevention guide for children and adolescents with NF1 will facilitate uniform best practice care for affected kids on a national level

Supplementary Data from HER3 Is a Determinant for Poor Prognosis in Melanoma

Krebserkrankungen sind im mittleren und höheren Lebensalter häufig. Die Lebenszeitprävalenz beträgt knapp 50

Glioblastoma is the most common malignant brain tumor in adults. Since 2005, state-of-the-art treatment consists of maximal safe resection followed by combined radio- and TMZ chemotherapy. A number of population-based outcome and pattern of care studies have documented its successful translation to community practice as well as the associated survival benefit in the general population. However, whether this holds true for Austria has not yet been systematically addressed. To assess real-world patterns of care for glioblastoma in the Austrian population. A close cooperation between the Austrian Brain Tumor Registry and the Society of Austrian Neuro-Oncology is the platform for the conduct of this study. Consensus parameters are abstracted from medical records across all Austrian neurooncology units. All data are entered and stored in a dedicated IT database referred to as ABTR-SANOnet. So far, all patients with newly diagnosed glioblastomas from 01-12/2014 have been recorded (n=310, median age=63 ys) with a last follow-up at 12/2015. Median time from onset of symptoms to diagnostic scan was 7 days (range 0–163 days) and another 8 days to surgical intervention. Total or subtotal resections were achieved in 68.7%. The majority of patients (84.5%) started on a combined treatment schedule with a considerable drop-out rate of 23.4% due to treatment toxicity or early tumor progression. Among elderly patients monotherapies stratified by MGMT promoter methylation status were more prevalent. Herein, we report on the first successful real-world pattern of care study on glioblastoma in Austria. Initial data are in line with internationally reported findings and confirm that the current standard of care has been widely adopted across Austrian neurooncology units. Future multivariate survival analyses will provide important insights in prognostic and therapy-associated factors, which act in Austrian patients.

The isocitrate dehydrogenase (IDH) mutation status is an indispensable prerequisite for diagnosis of glioma (astrocytoma and oligodendroglioma) according to the WHO classification of brain tumors 2021 and is a potential therapeutic target. Usually, immunohistochemistry followed by sequencing of tumor tissue is performed for this purpose. In clinical routine, however, non-invasive determination of IDH mutation status is desirable in cases where tumor biopsy is not possible and for monitoring neuro-oncological therapies. In a previous publication, we presented reliable prediction of IDH mutation status employing proton magnetic resonance spectroscopy (1H-MRS) on a 3.0 Tesla (T) scanner and machine learning in a prospective cohort of 34 glioma patients. Here, we validated this approach in an independent cohort of 67 patients, for which 1H-MR spectra were acquired at 1.5 T between 2002 and 2007, using the same data analysis approach. Despite different technical conditions, a sensitivity of 82.6% (95% CI, 61.2–95.1%) and a specificity of 72.7% (95% CI, 57.2–85.0%) could be achieved. We concluded that our 1H-MRS based approach can be established in a routine clinical setting with affordable effort and time, independent of technical conditions employed. Therefore, the method provides a non-invasive tool for determining IDH status that is well-applicable in an everyday clinical setting.

Abstract Background The Austrian ABTR-SANO Glioblastoma Registry is the first population-based assessment of patterns of care for patients with Glioblastoma across Austrian healthcare institutions. The primary aim is to assess the real world effectiveness of administered therapies. Material and Methods Clinical data are collected via a common web-based IT platform “ABTR-SANO Net” since 2014. The database and the ongoing evaluation of clinical parameters, as well as interims analysis are provided in cooperation with a review board. First Outcome analysis, including patients from 2014-2020, was performed at the end of 2021. Results Eleven centers across Austria are involved, and the data of 1416 patients (m/f ratio: 1,35, median age: 66 years) were recently analyzed in detail. Age, extent of resection, as well as ECOG was associated with improved survival. Methylated MGMT Status also showed a moderate survival benefit. Patients with re-resection and re-radiation also exhibited improved survival, which however may be attributed to a selection bias.Second line treatment manly comprised of antiangiogenic treatment, followed by alkylated agents, re-radiation and re-surgery. Median overall survival of all patients was 344 days and clearly age dependent (best for <50 years, worse for>80 years). Conclusion This is the first population based outcome analysis of Glioblastoma in Austria. Results regarding prognostic markers and outcome are mostly comparable with international data. Robust population based data are important in order to monitor quality of health care, and to match the data with results from clinical studies.

BACKGROUND AND OBJECTIVES:Anti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease.METHODS:In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders.RESULTS:Seventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases.DISCUSSION:Movement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Abstract BACKGROUND Mutation of isocitrate dehydrogenase (IDH) is not only an important landmark in the development of low-grade gliomas, but also has prognostic significance and is a potential therapeutic target. There is a high need to determinate IDH mutation status at diagnosis and during the course of therapy in a non-invasive and reliable manner. We established a machine learning approach based on a support vector machine to detect IDH mutation status in in vivo standard 1H-magnetic resonance spectroscopy (1H-MRS) at 3T with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%), and a specificity of 75% (95% CI, 42.85–94.5%) in a prospective monocentric clinical trial. Here, the same method is applied in a retrospective cohort at 1.5T and tested for transferability. MATERIAL AND METHODS Validation cohort. The validation cohort comprised 100 patients with glioma for which standard in vivo 1H-MRS spectra had been acquired between 2002 and 2007. Standard single voxel spectroscopy had been measured at 1.5T using a PRESS sequence with a TR of 1500ms and a TE of 30ms. One sample had to be excluded due to non-malignant histology and for 15 samples the IDH mutation status was not available. Therefore, the validation cohort comprised 84 samples, of which 35 were bearing an IDH mutation in immunohistochemistry (sequencing for confirmation is outstanding). Machine learning. To transfer our method to an independent validation cohort our previously established machine learning approach was first trained on all samples of the 3T group. The trained algorithm was then applied to the data of the validation cohort. Here, among other factors the different field strengths, with which the spectra were acquired (3T vs. 1.5T) had to be considered. RESULTS 27 samples of the validation cohort had to be excluded due to poor spectra quality. Our approach correctly detected IDH mutation status in 47 of 62 patients (75.8%), although the technical conditions were significantly different from our published prospective cohort. 17 of 30 patients bearing an IDH mutation were correctly identified, while 30 of 32 wild type patients were determined successfully. CONCLUSION Our approach to detect IDH mutation status has promising application in an unselected retrospective cohort, demonstrating transferability across different technical conditions. Further investigations to improve our technique and an advanced neuropathological processing of the samples are planned.

Not required for Clinical Vignette.

Die Neurofibromatosen Typ 1 und Typ 2 sind eine genetisch, klinisch und pathophysiologisch heterogene Gruppe von hereditären Tumorsyndromen. Aufgrund einer Inzidenz von 1:3000 (NF1, 96 %) bzw. 1:33.000 (NF2, 4 %) gehören sie zu den sogenannten „seltenen Erkrankungen“ mit einem chronisch progredienten Krankheitsverlauf. Die Vererbung erfolgt monogen autosomal-dominant von verschiedenen Tumor-Suppressor-Genen (NF1: Neurofibromin, NF2: Schwannomin). Die Spontanmutationsrate ist hoch (ca. 50 %), genetische Mosaike kommen vor. Auch die Genotyp-Phänotyp-Korrelation ist variabel. Dementsprechend sind der Schweregrad und die Prognose der Erkrankungen sehr unterschiedlich. Aus neuropalliativer Sicht leiden Neurofibromatosepatienten mit einem schweren Verlauf unter sehr großen und/oder bösartigen Tumoren des Nervensystems (Gehirn und Rückenmark, Meningen, Hirnnerven, Spinalwurzeln und periphere Nerven) und auch anderen Organsystemen, angeborenen Fehlbildungen, Knochenveränderungen (z. B. Wirbelsäule, Tibia), Pigmentstörungen, chronischen Schmerzsyndromen, kognitiven Beeinträchtigungen und psychiatrischen Störungen (z. B. Aufmerksamkeitsdefizit‑/Hyperaktivitätsstörung [ADHS], depressive und ängstliche Symptome durch multiple psychosoziale Belastungsfaktoren). Patienten mit einer Neurofibromatose bedürfen daher einer individuellen, ganzheitlichen und interdisziplinären Betreuung in spezialisierten neuroonkologischen Zentren. Dabei stehen die Früherkennung von Krankheitsmanifestationen und Symptomen und die Koordination multidisziplinärer Behandlungsstrategien im Vordergrund. Dadurch sollen eine langfristige Steigerung der individuellen Lebensqualität und eine Reduktion der Mortalität erreicht werden.

Cognitive impairment by neurotoxic substances, administered alone or in a multidrug regimen, affects a large number of patients treated for noncentral nervous system cancer during and after chemotherapy with variable onset, severity and duration, but sustainably affecting the patients’ individual health-related quality of life. Depending on the mechanism of action, the ability to cross the blood–brain barrier into the central nervous system and the cumulative total dose of the cytotoxic drugs results in functional and structural brain changes. This neurotoxicity leads to negative effects on neural precursor cells (neurogenesis), microglia (neuroinflammation), neurons (cortical dysfunction with altered brain networks), and astro-/oligodendroglia (white matter tract demyelination) and therefore on patients’ cognitive performance. Memory and executive functions, attention/concentration, and processing speed are the cognitive domains commonly impaired by chemotherapy. Importantly, numerous simultaneously occurring risk factors may also have distinct restrictions on cognitive function. For this reason, the term cancer-related cognitive impairment (CRCI), implicating neurotoxicity in cancer patients with simultaneous consideration of other causes on cognitive performance, should be used. The aim of this review is to provide an update of the most recent clinical and pathophysiological findings, self-reported and neuropsychological testing methods, and the current management strategies of CRCI.

Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard 1H-magnetic resonance spectroscopy (1H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the 1H-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%) and a specificity of 75.0% (95% CI, 42.9–94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo 1H-nuclear magnetic resonance (1H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.