@article{SchuhmannGunrebenKleinschnitzetal.2016, author = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter}, title = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {3}, doi = {10.3390/ijms17030298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206}, pages = {298}, year = {2016}, abstract = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.}, language = {en} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95\% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95\% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.}, language = {en} } @phdthesis{Palmisano2022, author = {Palmisano, Chiara}, title = {Supraspinal Locomotor Network Derangements: A Multimodal Approach}, doi = {10.25972/OPUS-26644}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266442}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56\% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease-related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50-70\% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network. In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control. I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control. By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS). Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.}, language = {en} } @article{ElhfnawyHeuschmannPhametal.2019, author = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix}, title = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {317}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.}, language = {en} } @article{PozziPalmisanoReichetal.2022, author = {Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Reich, Martin M. and Capetian, Philip and Pacchetti, Claudio and Volkmann, Jens and Isaias, Ioannis U.}, title = {Troubleshooting gait disturbances in Parkinson's disease with deep brain stimulation}, series = {Frontiers in Human Neuroscience}, volume = {16}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2022.806513}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274007}, year = {2022}, abstract = {Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson's disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.}, language = {en} } @article{PetzkeKloseWelschetal.2020, author = {Petzke, Frank and Klose, Petra and Welsch, Patrick and Sommer, Claudia and H{\"a}user, Winfried}, title = {Opioids for chronic low back pain: An updated systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks of double-blind duration}, series = {European Journal of Pain}, volume = {24}, journal = {European Journal of Pain}, number = {3}, doi = {10.1002/ejp.1519}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218498}, pages = {497 -- 517}, year = {2020}, abstract = {Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non-malignant chronic low back pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of double-blinded duration were analysed. Primary outcomes were pain relief of 50\% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross-over design: Based on very low to low-quality evidence, opioids provided no clinically relevant pain relief of 50\% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low-quality evidence, opioids provided a clinically relevant pain relief of 50\% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross-over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross-over, but not in studies with EERW design. Conclusions Opioids may provide a safe and clinically relevant pain relief for 4-15 weeks in highly selected patients. Significance Within the context of randomized controlled trials of 4-15 weeks, opioids provided a clinically relevant pain relief of 30\% or greater and a clinically relevant reduction of disability compared to placebo in non-malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95\% confidence interval: 6-33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo.}, language = {en} } @phdthesis{Braun2021, author = {Braun, Alexandra}, title = {Psychosocial and somatic resilience factors of patients with fibromyalgia syndrome (FMS)}, doi = {10.25972/OPUS-24280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242809}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Background: In recent years, health care has increasingly become the focus of public interest, politics, health insurance companies, and research. This includes the development of therapeutic concepts that can respond individually to patients' resources in order to improve coping with chronic diseases. Research into psychosocial and biological resilience factors is very important and the basic objective of the present work. I studied patients with fibromyalgia syndrome (FMS), who suffer among others from chronic pain, fatigue, sleep and gastrointestinal problems. This patient cohort is characterized by a pronounced heterogeneity in terms of clinical outcome, degree in disability and coping. FMS has a prevalence of 3 - 8 \% in the Western population and has a significant socio-economic impact. Validated psychosocial resilience factors include optimism, humor, coherence, self-efficacy, awareness with one's own resources and the ability to apply them profitably (coping), and a healthy social environment with positive relationships. Studies in patients with cancer revealed religiosity as positive and negative factor on the health outcome, but there is little data on religious aspects of pain resilience. Various genetic polymorphisms and anti-inflammatory cytokines are known as biological resilience factors. Various microRNA (miRNA) were detected to contribute to resilience in the context of stress and psychiatric disorders. Objective: The underlying research question of this work is to understand the factors that make some FMS patients resilient and others not, even though they suffer from the same disease. The long-term aim was to understand mechanisms and influencing factors of resilience to design preventive and resource-oriented therapies for FMS patients. Material and Methods: Three studies examined religious, physiological, biological, and psychosocial factors which may contribute to resilience in FMS patients. Study one combined data of questionnaires, a psychosocial interview, and regression analyses to investigate the relevance of religiosity for coping and resilience. Study two examined variance explaining factors and defined clusters among FMS patients by their differences in coping, pain phenotype and disability. The factor analysis used variables derived from questionnaires and qPCR of cytokines in white blood samples (WBC) of patients and healthy controls. Study three assessed cluster-wise miRNA signatures which may underly differences in behaviour, emotional and physiological disability, and resilience among patient clusters. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed and its potential targets verified by an online tool. Results: The data from the first study revealed a not very religious patient cohort, which was rather ambivalent towards the institution church, but described itself as a believer. The degree of religiosity played a role in the choice of coping strategy but had no effect on psychological parameters or health outcomes. The coping strategy "reinterpretation", which is closely related iv to the religious coping "reappraisal", had the highest influence on FMS related disability. Cognitive active coping strategies such as reappraisal which belongs to religious coping had the highest effect on FMS related disability (resilience) and could be trained by a therapist. Results from the second study showed high variances of all measured cytokines within the patient group and no difference between patient and control group. The high dispersion indicated cluster among patients. Factor analysis extracted four variance-explaining factors named as affective load, coping, pain, and pro-inflammatory cytokines. Psychological factors such as depression were the most decisive factors of everyday stress in life and represented the greatest influence on the variance of the data. Study two identified four clusters with respective differences in the factors and characterized them as poorly adapted (maladaptive), well adapted (adaptive), vulnerable and resilient. Their naming was based on characteristics of both resilience concepts, indicated by patients who were less stress-sensitive and impaired as a personal characteristic and by patients who emerged as more resilient from a learning and adaptive process. The data from the variance analysis suggests that problem- and emotion-focused coping strategies and a more anti-inflammatory cytokine pattern are associated with low impairment and contribute to resilience. Additional favorable factors include low anxiety, acceptance, and persistence. Some cluster-specific intervention proposals were created that combine existing concepts of behavioral and mindfulness therapies with alternative therapies such as vitamin D supplementation and a healthy intestinal flora. The results of the third study revealed lower relative gene expression of miR103a-3p, miR107, and miR130a-3p in the FMS cohort compared to the healthy controls with a large effect size. The adaptive cluster had the highest gene expression of miR103a-3p and tendentially of miR107, which was correlated with the subscale score "physical abuse" of the trauma questionnaire. Further correlations were found in particular with pain catastrophizing and FMS-related disability. MiR103a-3p and miR107 form a miRNA-family. Based on this, we proposed a miR103a/107 regulated model of an adaptive process to stress, inflammation and pain by targeting genetic factors which are included in different anti-inflammatory and stress-regulating pathways. Conclusion: All three studies provide new insights into resilience in FMS patients. Cognitive coping (reappraisal/reinterpretation) plays a central role and thus offers therapeutic targets (reframing in the context of behavioral therapy). Religosity as a resilience factor was only partially valid for our patient cohort. Basically, the use of resource-oriented therapy in large institutions still requires research and interdisciplinary cooperation to create a consensus between the humanities, natural sciences and humanism.}, subject = {Resilienz}, language = {en} } @article{StengelVuralBrunderetal.2019, author = {Stengel, Helena and Vural, Atay and Brunder, Anna-Michelle and Heinius, Annika and Appeltshauser, Luise and Fiebig, Bianca and Giese, Florian and Dresel, Christian and Papagianni, Aikaterini and Birklein, Frank and Weis, Joachim and Huchtemann, Tessa and Schmidt, Christian and K{\"o}rtvelyessy, Peter and Villmann, Carmen and Meinl, Edgar and Sommer, Claudia and Leypoldt, Frank and Doppler, Kathrin}, title = {Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {6}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {5}, doi = {10.1212/NXI.0000000000000603}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202462}, year = {2019}, abstract = {Objective To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti-NF-155 IgG4 were directed against the NF-155-specific Fn3Fn4 domain. The description of a second phenotype of anti-NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions Our results indicate that anti-pan-NF-associated neuropathy differs from anti-NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti-NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.}, language = {en} } @phdthesis{Rost2021, author = {Rost, Anna-Lena}, title = {Akute erregerbedingte Meningoenzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2015}, doi = {10.25972/OPUS-24084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240846}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Am Universit{\"a}tsklinikum W{\"u}rzburg wurden zwischen 2006-2015 447 F{\"a}lle einer akuten erregerbedingten Meningoenzephalitis in den Kliniken der Neurologie, Kinderklinik, Neurochirurgie und Psychiatrie behandelt. Es konnten sowohl F{\"a}lle durch Bakterien als auch F{\"a}lle durch Viren, Parasiten und Pilze gesichert werden. Diese Arbeit beschreibt die lokale Epidemiologie akuter erregerbedingter Meningoenzephalitiden.}, subject = {Meningoenzephalitis}, language = {de} } @article{EvdokimovFrankKlitschetal.2019, author = {Evdokimov, Dimitar and Frank, Johanna and Klitsch, Alexander and Unterecker, Stefan and Warrings, Bodo and Serra, Jordi and Papagianni, Aikaterini and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}ceyler, Nurcan}, title = {Reduction of skin innervation is associated with a severe fibromyalgia phenotype}, series = {Annals of Neurology}, volume = {86}, journal = {Annals of Neurology}, number = {4}, doi = {10.1002/ana.25565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206168}, pages = {504-516}, year = {2019}, abstract = {Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63\% of FMS patients (MDP: 10\%, controls: 18\%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS.}, language = {en} } @article{KlitschEvdokimovFranketal.2020, author = {Klitsch, Alexander and Evdokimov, Dimitar and Frank, Johanna and Thomas, Dominique and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Sisignano, Marco and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome}, series = {Journal of the Peripheral Nervous System}, volume = {25}, journal = {Journal of the Peripheral Nervous System}, number = {1}, doi = {10.1111/jns.12360}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214150}, pages = {9-18}, year = {2020}, abstract = {In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17\%) and SFN (28\%) patients than in controls (5\%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.}, language = {en} } @article{WirschingOrtUeceyler2020, author = {Wirsching, Isabelle and Ort, Nora and {\"U}{\c{c}}eyler, Nurcan}, title = {ALS or ALS mimic by neuroborreliosis — A case report}, series = {Clinical Case Reports}, volume = {8}, journal = {Clinical Case Reports}, doi = {10.1002/ccr3.2569}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201308}, pages = {86-91}, year = {2020}, abstract = {Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work-up. However, false-positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results.}, language = {en} } @phdthesis{Frank2019, author = {Frank, Johanna}, title = {Untersuchung der Kleinfaserpathologie beim Fibromyalgie-Syndrom}, publisher = {Annals of Neurology, The Journal of Rheumatology}, doi = {10.25972/OPUS-19265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192653}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Die Studienergebnisse st{\"u}tzen das Konzept, dass das periphere Nervensystem zu Schmerzen beim Fibromyalgie-Syndrom (FMS) beitr{\"a}gt. An der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg wurden 53 FMS Patientinnen und 35 gesunde Kontrollen rekrutiert, ausf{\"u}hrlich anamnestiziert inklusive spezieller Schmerzfrageb{\"o}gen, neurologisch und mittels spezieller Tests auf eine St{\"o}rung der kleinkalibrigen A-delta- und C-Nervenfasern untersucht. Hierzu geh{\"o}rte eine quantitative sensorische Testung mit Pleasant touch Untersuchung und die schmerz-assoziierten elektrisch-evoziierten Potentiale f{\"u}r die Kleinfaserfunktion und die corneale confocale Mikroskopie, sowie die Analyse von Hautstanbiopsien f{\"u}r die Kleinfasermorphologie. Im Unterschied zu gesunden Kontrollen wiesen die FMS Patientinnen eine Reduktion, als auch eine Funktions{\"a}nderung der kleinkalibrigen Nervenfasern auf. Des Weiteren konnten wir aus der heterogenen Patientenpopulation anhand von unterschiedlichen Nervenfaserdichten der Haut eine Subgruppe mit generalisierter Reduktion der Hautinnervation identifizieren, die besonders schwer betroffen ist. Diese Subgruppenanalysen k{\"o}nnen k{\"u}nftig von großer Bedeutung f{\"u}r die Therapiewahl sein.}, subject = {Fibromyalgie}, language = {de} } @phdthesis{Kuzkina2020, author = {Kuzkina, Anastasia}, title = {Dermal α-synuclein oligomers and aggregates in Parkinson's disease}, doi = {10.25972/OPUS-20436}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204369}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson's disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24\% (cohort 1) and 37\% (cohort 2), ASyO5 positive lesions in 17,7\% (cohort 1) and 33\% (cohort 2), syn211 positive lesions after PK digestion in 38,7\% (cohort 1) and 48\% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59\% were also PK resistant, 41\% were 5G4 positive and 45\% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy.}, subject = {Parkinson-Krankheit}, language = {en} } @phdthesis{Toeppner2020, author = {T{\"o}ppner, Verena}, title = {Therapie und Outcome von Patienten mit aneurysmatischer Subarachnoidalblutung am Universit{\"a}tsklinikum W{\"u}rzburg}, doi = {10.25972/OPUS-20912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalit{\"a}t. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universit{\"a}tsklinikum W{\"u}rzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren f{\"u}r ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.}, subject = {Subarachnoidalblutung}, language = {de} } @phdthesis{Buchwald2020, author = {Buchwald, Sina}, title = {Autoimmune Enzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2016}, doi = {10.25972/OPUS-20720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In den Jahren von 2006 bis 2016 sind am Universit{\"a}tsklinikum W{\"u}rzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverl{\"a}ufe, Outcome, die gefundenen Antik{\"o}rper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben F{\"a}llen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu k{\"o}nnen.}, subject = {Enzephalitis}, language = {de} } @article{SilwedelSpeerHaarmannetal.2018, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Buttmann, Mathias and Glaser, Kirsten}, title = {Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {156}, doi = {10.1186/s12974-018-1170-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175952}, year = {2018}, abstract = {Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor's ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.}, language = {en} } @article{HofmannKarlSommeretal.2017, author = {Hofmann, Lukas and Karl, Franziska and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0180601}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170745}, pages = {e0180601}, year = {2017}, abstract = {Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the na{\"i}ve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in na{\"i}ve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and na{\"i}ve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.}, language = {en} } @article{PiroEckesKasaragodetal.2021, author = {Piro, Inken and Eckes, Anna-Lena and Kasaragod, Vikram Babu and Sommer, Claudia and Harvey, Robert J. and Schaefer, Natascha and Villmann, Carmen}, title = {Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {14}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.745275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246676}, year = {2021}, abstract = {Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.}, language = {en} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45\%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25\% distribution) in 6/87 (7\%) mouth epithelial cell samples, 31/88 (35\%) blood samples, and 9/27 (33\%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.}, language = {en} }