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Abstract Background and aim Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features. Main results The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities. Conclusions Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

Abstract Background Headache disorders are among the most prevalent neurological disorders worldwide. However, whether groups differing in socioeconomic position (SEP) are disproportionately affected by headache disorders has not yet been adequately clarified. Our aim was to analyse (1) the headache prevalence by socioeconomic position (SEP) and (2) the attack frequency by SEP in a German population-based adult sample. Methods Cross-sectional data from a random general population were used. The sample included N = 2,189 participants aged ≥ 18 years. SEP was measured using net equivalised income (NEI) and education. A binary logistic regression model tested the effect of SEP in predicting the prevalence of headache in general. Ordinal logistic regressions were modeled to predict the effect of SEP on the likelihood of attack frequency. Attack frequency was categorized in low frequency episodic headache (LFEH: 0–3 days per month), moderate frequency episodic headache (MFEH: 4–14 days per month) and chronic headache (CH: ≥ 15 days per month). Results Of the 2,189 participants, 891 reported headache in the last six months. Neither income nor education was associated with headache prevalence. However, significant differences between income groups were found for attack frequency. Compared to participants with NEI > 150%, those with NEI

Abstract Background Cluster headache (CH) is associated with high disability. The Cluster Headache Impact Questionnaire (CHIQ) is a short, disease-specific disability questionnaire first developed and validated in German. Here, we validated the English version of this questionnaire. Methods The CHIQ was assessed together with nonspecific headache-related disability questionnaires in CH patients from a tertiary headache center and an American self-help group. Results 155 active episodic and chronic CH patients were included. The CHIQ showed good internal consistency (Cronbach’s α = 0.91) and test-retest reliability (ICC = 0.93, n = 44). Factor analysis identified a single factor. Convergent validity was shown by significant correlations with the Headache Impact Test™ (HIT-6™, ρ = 0.72, p < 0.001), the Hospital Anxiety and Depression Scale (HADS depression: ρ = 0.53, HADS anxiety: ρ = 0.61, both p < 0.001), the Perceived Stress Scale (PSS-10, ρ = 0.61, p < 0.001) and with CH attack frequency (ρ = 0.29, p < 0.001). Chronic CH patients showed the highest CHIQ scores (25.4 ± 7.9, n = 76), followed by active episodic CH and episodic CH patients in remission (active eCH: 22.2 ± 8.7, n = 79; eCH in remission: 14.1 ± 13.1, n = 127; p < 0.001). Furthermore, the CHIQ was graded into 5 levels from “no to low impact” to “extreme impact” based on the patients’ perception. Higher CHIQ grading was associated with higher attack and acute medication frequency, HIT-6™, HADS and PSS scores. Conclusion The English version of the CHIQ is a reliable, valid, and disease-specific patient-reported outcome measure to assess the impact of headaches on CH patients.

Abstract Background The adverse events (AEs) after a Coronavirus disease 2019 (Covid-19) Pfizer-Biotech mRNA vaccination present a medical and epidemiological issue of increasing interest. Headache is the most frequent neurological adverse effect and generally the third most common adverse event after a Covid-19 vaccination, but only a few studies focus on the link between headache and other AEs after vaccination. This study aims to investigate the correlation between headaches and Covid-19 vaccination, as well as the possible links between headaches and other AEs after Covid-19 vaccination, thereby helping the management of AEs and avoiding further occurrences. Methods This study is based on a published questionnaire survey of 1,402 healthcare workers. Our study focused on the 5 questions including 12 AEs and headaches extracted from the questionnaire post the first and second Covid-19 vaccination. The severity of the 12 AEs and headaches could be classified by the participants on a five-step scale: “Not at all”, “Little”, “Average”, “Quite”, and “Very” (abbreviated as “N”, “L”, “A”, “Q”, “V”). We used the Bowker test to study the comparison of headache severity, indicated on a 5-point Likert scale between the first and second vaccinations. We applied an ordinal logistic regression to the 5 categories with headache severity serving as the dependent variable and the ratings of the other 12 AEs serving as the independent variable to further explore to what extent the severity of the 12 AEs is associated with the severity of headaches. Receiver Operating Characteristic (ROC) analysis was conducted to evaluate the predictive value of the ratings of the 12 AEs to headache severity. Results We found that participants rated their headaches as more severe after the second vaccination, and participants who reported experiencing fatigue, flu-like symptoms, pain at the injection site, known tension-type headache, fever, dizziness/balance problems and known migraine are associated with headache symptoms. Conclusions There are clusters of headache-associated AEs post Covid-19 vaccination. The association of various AEs with headaches may be due to similar causative mechanisms.

Abstract Background Migraine is a brain disorder with recurrent headache attacks and altered sensory processing. Introvision is a self-regulation method based on mindfulness-like perception techniques, developed at the University of Hamburg. Here, we examined the effect of Introvision in migraine prevention. Methods Migraineurs with at least five headache days per month were block-randomized to the experimental group (EG) or waiting list group (WL), the latter starting Introvision training six weeks after the EG. Participants learned Introvision in six weekly on-site group sessions with video-conference support followed by three individual video-conference sessions. Headache diaries and questionnaires were obtained before Introvision training and three months after the last individual Introvision session. Results Fifty-one patients completed the study. The primary outcome, headache days of the EG after Introvision training compared to those of the WL before the training, showed no significant effect (10.6 ± 7.7, n = 22; vs. 10.9 ± 6.3, n = 29, p = 0.63; Mann–Whitney-U-Test). The secondary outcome, comparing pooled EG and WL data before and after Introvision training, revealed a significant reduction of headache days (from 11.7 ± 6.5 to 9.8 ± 7.0; p = 0.003; Wilcoxon-paired-Test) as well as of acute medication intake and Headache-Impact-Test 6 (HIT-6) scores and increased self-efficacy as quantified by increased FKMS-scores (FKMS: german short form of the Headache Management Self-Efficacy Scale (HMSE)). Conclusion Although the study did not reach its primary endpoint, several secondary outcome parameters in the pooled (non-controlled) pre-post analysis showed an improvement with a decrease in monthly headache days by 1.9 days/ month. A larger randomized controlled trial has to corroborate these preliminary findings. Trial registration NCT03507400, Registration date 09.03.2018.

Abstract Background Triptans are effective for many migraine patients, but some do not experience adequate efficacy and tolerability. The European Headache Federation (EHF) has proposed that patients with lack of efficacy and/or tolerability of ≥ 2 triptans (‘triptan resistance’) could be considered eligible for treatment with the novel medications from the ditan and gepant groups. There is little data on the frequency of ‘triptan resistance’. Methods We used patient self-report data from the German Migraine and Headache Society (DMKG) Headache Registry to assess triptan response and triptan efficacy and/or tolerability failure. Results A total of 2284 adult migraine patients (females: 85.4%, age: 39.4 ± 12.8 years) were included. 42.5% (n = 970) had failed ≥ 1 triptan, 13.1% (n = 300) had failed ≥ 2 triptans (meeting the EHF definition of ‘triptan resistance’), and 3.9% (n = 88) had failed ≥ 3 triptans. Compared to triptan responders (current use, no failure, n = 597), triptan non-responders had significantly more severe migraine (higher frequency (p

Background: Idiopathic intracranial hypertension (IIH) is typically characterized by headaches and vision loss. However, neurocognitive deficits are also described. Our study aimed to test the influence of therapeutic lumbar puncture on the latter. Methods: A total of 15 patients with IIH were tested with a battery of neurocognitive tests at baseline and after therapeutic lumbar drainage. Hereby, Logical Memory of the Wechsler Memory Scale—Revised Edition (WMS-R), the California Verbal Learning Test Short Version (CVLT), alertness, selective attention, and word fluency were used. Changes in cognitive functioning in the course of CSF pressure lowering were analysed and compared with age, sex, and education-matched healthy controls. Results: Before intervention, scores of Logical Memory, the RWT, and the HADS-D were significantly lower in IIH patients compared to matched controls. After short-term normalization of CSF pressure, the RWT improved significantly. Additionally, significant positive correlations were found between headache intensity and subjective impairment, as well as between BMI and CSF opening pressure. Conclusions: Our findings confirm lower performance in terms of long-term verbal memory and word fluency compared to controls, as well as depressive symptoms in IIH patients. Significant improvement after short-term normalization of intracranial pressure by means of CSF drainage was seen only for word fluency. This indicates that short-term normalization of CSF pressure is not sufficient to normalize observed neurocognitive deficits.

ABSTRACTLung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and EpCAM-directed CAR T-cells were injected either intravenously or into the adjacent brain parenchyma. In mice receiving EpCAM-directed CAR T-cells intravenously, we neither observed substantial CAR T-cell accumulation within the tumor nor relevant anti-tumor effects. Local CAR T-cell injection, however, resulted in intratumoral CAR T-cell accumulation compared to controls treated with T-cells lacking a CAR. This finding was accompanied by reduced tumorous growth as determined per in vivo-microscopy and immunofluorescence of excised brains and also translated into prolonged survival. However, the intratumoral number of EpCAM-directed CAR T-cells decreased during the observation period, pointing toward insufficient persistence. No CNS-specific or systemic toxicities of EpCAM-directed CAR T-cells were observed in our fully immunocompetent model. Collectively, our findings indicate that locally (but not intravenously) injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the intratumoral CAR T-cell persistence may further boost the therapeutic success.

Abstract Background Monoclonal antibodies targeting the CGRP pathway are effective and safe for prophylactic treatment of episodic (EM) and chronic migraine (CM). In case of treatment failure of a CGRP pathway targeting mAb, physician has to decide whether using another anti-CGRP pathway mAb is useful. This interim analysis of Finesse Study evaluates effectiveness of the anti-CGRP mAb fremanezumab in patients with a history of other prior anti-CGRP pathway mAb treatments (switch patients). Methods Finesse, a non-interventional, prospective, multicentre, two-country (Germany-Austria) study observing migraine patients receiving fremanezumab in clinical routine. This subgroup analysis presents data on documented effectiveness over 3 months after the first dose of fremanezumab in switch patients. Effectiveness was evaluated based on reduction in average number of migraine days per month (MMDs), MIDAS and HIT-6 scores changes as well as in number of monthly days with acute migraine medication use. Results One hundred fifty-three out of 867 patients with a history of anti-CGRP pathway mAb treatment prior to initiation of fremanezumab were analysed. Switch to fremanezumab led to ≥ 50% MMD reduction in 42.8% of migraine patients, with higher response rate in EM (48.0%) than in CM patients (36.5%). A ≥ 30% MMD reduction was achieved by 58.7% in CM patients. After three months, monthly number of migraine days decreased by 6.4 ± 5.87 (baseline: 13.6 ± 6.5; p

Abstract Backgound Headache disorders are not only among the most prevalent, they are also among the most disabling disorders worldwide. This paper investigates the association between headache impact on daily life and the socioeconomic status (SES) of headache sufferers. Methods Data stem from a random general population sample in Germany. Respondents who reported having headache for at least a year and were aged ≥ 18 years were included in the study. A standardized questionnaire addressing headache and headache treatment was filled in during the face-to-face survey. The impact of headache on daily life was measured using the German version of the Headache Impact Test (HIT-6). Results Higher headache impact was found in low and medium SES compared to high SES. After adjustment for sociodemographics, headache-related factors (analgesic use, headache duration, headache frequency, migraine diagnosis), depressive symptoms, physical inactivity and obesity, an increased odds ratio of having higher headache impact in low SES compared to high SES was found: OR = 1.83, 95% CI [1.43, 2.23], p = .014. When the interactions "SES*obesity", "SES*depressive symptoms", and "SES*physical inactivity" were added, the results showed a significant interaction effect of “SES*obesity”. Obese persons with low SES were 3.64 times more likely to have higher headache impact than non-obese persons with low SES. No significant differences between obese and non-obese persons were found in the medium and high SES groups. Conclusions SES is an important factor that should not be neglected in headache awareness campaigns and headache treatment. Longitudinal studies are needed in the future to investigate whether lifestyle interventions, such as weight reduction, can help to reduce headache impact in people in lower SES.

ObjectivesAnti-septin-5 encephalitis is a rare disease with only few published cases, mainly based on retrospective CSF and serum analyses. Predominant symptoms are cerebellar ataxia and oculomotor abnormalities. Due to the rareness of the disease, treatment recommendations are scarce. Herein, we prospectively describe the clinical course of a female patient with anti-septin-5 encephalitis.MethodsWe describe diagnostic workup, treatment and follow-up of a 54-year-old patient presenting with vertigo, unsteady gait, lack of drive and behavioral changes.ResultsClinical examination revealed severe cerebellar ataxia, saccadic smooth pursuit, upbeat-nystagmus, and dysarthria. Additionally, the patient presented with a depressive syndrome. MRI of the brain and spinal cord were normal. CSF analysis showed lymphocytic pleocytosis (11 cells/μl). Extensive antibody testing revealed anti septin-5 IgG in both CSF and serum without coexisting anti-neuronal antibodies. PET/CT detected no signs of malignancy. Corticosteroids, plasma exchange, and rituximab led to transient clinical improvement followed by relapse. Re-applied treatment with plasma exchange followed by bortezomib resulted in moderate but sustained clinical improvement.DiscussionAnti septin-5 encephalitis represents a rare but treatable and therefore relevant differential diagnosis in patients with cerebellar ataxia. Psychiatric symptoms can be observed in anti septin-5 encephalitis. Immunosuppressive treatment including bortezomib is moderately effective.

Abstract Background Even with high standards of acute care and neurological early rehabilitation (NER) a substantial number of patients with neurological conditions still need mechanical ventilation and/or airway protection by tracheal cannulas when discharged and hence home-based specialised intensive care nursing (HSICN). It may be possible to improve the home care situation with structured specialized long-term neurorehabilitation support and following up patients with neurorehabilitation teams. Consequently, more people might recover over an extended period to a degree that they were no longer dependent on HSICN. Methods This healthcare project and clinical trial implements a new specialised neurorehabilitation outreach service for people being discharged from NER with the need for HSICN. The multicentre, open, parallel-group RCT compares the effects of one year post-discharge specialized outpatient follow-up to usual care in people receiving HSICN. Participants will randomly be assigned to receive the new form of healthcare (intervention) or the standard healthcare (control) on a 2:1 basis. Primary outcome is the rate of weaning from mechanical ventilation and/or decannulation (primary outcome) after one year, secondary outcomes include both clinical and economic measures. 173 participants are required to corroborate a difference of 30 vs. 10% weaning success rate statistically with 80% power at a 5% significance level allowing for 15% attrition. Discussion The OptiNIV-Study will implement a new specialised neurorehabilitation outreach service and will determine its weaning success rates, other clinical outcomes, and cost-effectiveness compared to usual care for people in need for mechanical ventilation and/or tracheal cannula and hence HSICN after discharge from NER. Trial registration The trial OptiNIV has been registered in the German Clinical Trials Register (DRKS) since 18.01.2022 with the ID DRKS00027326 .

Abstract Background Although good treatment options exist for many headache disorders, not all patients benefit and disability continues to be large. To design strategies for improving headache care, real-world data observing standard care is necessary. Therefore, the German Migraine and Headache Society (DMKG) has established the DMKG Headache Registry. Here we present methods and baseline data. Methods Accredited German headache centers (clinic-based or private practice) can offer participation to their patients. Patients provide headache history, current headache load (including a mobile headache diary), medication and comorbidities and answer validated questionnaires, prior to their physician appointment. Physicians use these data as the base of their history taking, and add, change or confirm some central information. Before the next visit, patients are asked to update their data. Patients will continuously be included over the next years. Results The present analysis is based on the first 1,351 patients (1110 females, 39.6 ± 12.9 years) with a completed first visit. Most participants had a migraine diagnosis. Participants had 14.4 ± 8.5 headache days and 7.7 ± 6.1 acute medication days per month and 63.9% had a migraine disability assessment (MIDAS) grade 4 (severe disability). 93.6% used at least one acute headache medication, most frequently a triptan (60.0%) or non-opioid analgesic (58.3%). 45.0% used at least one headache preventive medication, most frequently an antidepressant (11.4%, mostly amitriptyline 8.4%) or a CGRP(receptor) antibody (9.8%). Most common causes for discontinuation of preventive medication were lack of effect (54.2%) and side effects (43.3%). Conclusion The DMKG Headache Registry allows to continuously monitor headache care at German headache centers in both a cross-sectional and a longitudinal approach. Trial registration The DMKG Headache Registry is registered with the German Clinical Trials Register (DRKS 00021081 ).

Abstract Background Cluster headache (CH) is a severe, highly disabling primary headache disorder. However, there is little research on CH-related disability, and most of it is based on non CH-specific questionnaires. The aim of this study was to develop a short, CH-specific disability questionnaire. Methods The 8-item Cluster Headache Impact Questionnaire (CHIQ) was developed based on a literature review and patient and expert interviews. The questionnaire was tested in 254 CH patients (171 males; 47.5 ± 11.4 years; 111 chronic CH, 85 active episodic CH, 52 episodic CH in remission) from our tertiary headache center or from a German support group. Results Reliability and validity of the CHIQ was evaluated in active episodic and chronic CH patients (n = 196). Internal consistency (Cronbach’s α = 0.88) and test-retest reliability (ICC 0.91, n = 41) were good. Factor analysis identified a single factor. Convergent validity was shown by significant correlations with the Headache Impact Test (HIT-6, r = 0.58, p

Abstract Objective Patients with visual snow syndrome (VSS) suffer from a debilitating continuous (“TV noise-like”) visual disturbance. They report problems with vision at night and palinopsia despite normal visual acuity. The underlying pathophysiology of VSS is largely unknown. Currently, it is a clinical diagnosis based on the patient’s history, an objective test is not available. Here, we tested the hypothesis that patients with VSS have an increased threshold for detecting visual contrasts at particular temporal frequencies by measuring dynamic contrast detection-thresholds. Methods Twenty patients with VSS were compared to age-, gender-, migraine- and aura-matched controls in this case-control study. Subjects were shown bars randomly tilted to the left or right, flickering at six different frequencies (15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz). The contrast threshold (CT) for detection of left or right tilt was measured in a two-alternative adaptive forced-choice procedure (QUEST). The threshold was defined as the Michelson contrast necessary to achieve the correct response in 75% of the cases. Results The CT increased for higher flicker frequencies (ANOVA: main effect frequency: F (5,180) = 942; p

Brain metastases frequently occur in lung cancer and dramatically limit prognosis of affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized. We established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intravital 2-photon laser scanning microscopy. This allowed in vivo tracking of fluorescence-expressing tumor cells and TAM/M on a single-cell level over weeks. Intracarotid injection of red tdTomato-fluorescent Lewis lung carcinoma cell was performed in transgenic mice either proficient or deficient for CX3CR1. After intracarotid cell injection, intravascular tumor cells extravasated into the brain parenchyma and formed micro- and mature macrometastases. We observed potential phagocytosis of extravasated tumor cells by TAM/M. However, during later steps of metastasis formation, these anti-tumor effects diminished and were paralleled by TAM/M accumulation and activation. Although CX3CR1 deficiency resulted in a lower number of extravasated tumor cells, progression of these extravasated cells into micro metastases was more efficient. Overall, this resulted in a comparable number of mature macrometastases in CX3CR1-deficient and -proficient mice. Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic option to prevent dissemination of lung cancer cells to the brain. Given the close interaction between TAM/M and tumor cells during metastasis formation, other therapeutic approaches targeting TAM/M function may warrant further evaluation. The herein established orthotopic mouse model may be a useful tool to evaluate such concepts in vivo.

Abstract Background Erenumab, the first-in-class fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, was shown to be efficacious and safe for the prophylactic treatment of migraine in adults in randomized clinical trials. Large-scale, real-world evidence in multi-centre settings is still needed to confirm these results. Erenumab patient profiles outside clinical trials and physicians’ treatment patterns, as well as data from patients treated in Germany, a severely impacted population, are not published yet. Methods TELESCOPE was a multi-centre survey gathering real-world data from 45 German headache centres between July 2019 and December 2019. The project consisted of two parts. In the first part, treating physicians shared their experiences on current erenumab treatment with regard to patient profiles, treatment patterns and treatment responses. In the second part, a retrospective chart review was conducted of 542 migraine patients treated with erenumab for at least three months. Treatment responses focused on various aspects of patients’ quality of life. Results The analysis of 542 patients’ charts revealed that three-month treatment with erenumab significantly reduced monthly headaches, migraine and acute medication days. Furthermore, headache intensity and frequency were reduced in over 75 % and accompanying aura in 35 % of patients. The clinical global impression scale revealed a general improvement in 91 % of patients. According to the treating physicians’ professional judgement, 83 % of patients responded to erenumab and 80 % were satisfied with the treatment. Physicians evaluated restricted quality of life, the number of monthly migraine days and previous, prophylactic treatments as the main components of the current patient profile for monoclonal antibody recipients. Based on the assessment of physicians, erenumab reduced migraine symptoms in 65 % and increased quality of life in more than 75 % of their patients. Conclusions TELESCOPE confirms positive treatment responses with erenumab shown in clinical trials in a real-world multi-centre setting. The results show consistently positive experiences of physicians utilizing erenumab in clinical practice and underline that therapy with this monoclonal antibody is effective in migraine patients, particular in those, who have failed several prophylactic therapies.

Abstract Background Health care costs of migraine constitute a major issue in health economics. Several publications analyzed health care costs for adult migraine patients, based on questionnaires or secondary (health insurance) data. Although migraine often starts already in primary school age, data on migraine related costs in children is scarce. In this paper we aimed to assess the migraine-related health care costs in 6 to 11 year old children in Germany. Methods Using claims data of a large German health insurer (BARMER), overall annual health care costs of 6 to 11 year old children with a diagnosis of migraine in 2017 (n = 2597) were compared to a control group of 6 to 11 year old children without a headache diagnosis between 2013 and 2017 (n = 306,926). The association of migraine and costs was modeled by generalized linear regression (Gamma regression) with adjustment for sex, age and comorbidities. Results Children with migraine caused considerably higher annual per capita health care costs than children without a headache diagnosis (migraine group: € 1018, control group: € 618). Excess costs directly related to migraine amounted to € 115. The remaining excess costs were related to comorbidities, which were more frequent in the migraine group. Mental and behavioural disorders constituted the most expensive comorbidity, accounting for € 105 of the € 400 annual excess costs in the migraine group. Conclusion 6 to 11 year old children with a migraine diagnosis cause significant direct and comorbidity related excess costs in the German health care system.

Abstract Background Migraine is common in childhood, peaks in adolescents and persists into adulthood in at least 40% of patients. There is need for early interventions to improve the burden of disease and, if possible, reduce chronification. The aim of the project is to compare two types of ambulatory treatment strategies regarding their effect on headache days and quality of life in 6 to 11 year old children with migraine: 1) the routine care in pediatricians’ practices (intervention group A) and 2) a structured interdisciplinary multimodal intervention administered at social pediatric centers (intervention group B). Methods The study is a nation-wide cluster-randomized study. Based on the postal codes the regions are randomly assigned to the two intervention-strategies. Children with migraine are recruited in the pediatric practices, as common outpatient-care in the German health-care system. Parents rate headache frequency, intensity and acute medication intake at a daily basis via a digital smartphone application specifically designed for the study. Migraine-related disability and quality of life are assessed every 3 months. Study duration is 9 months for every participant: 3 months of baseline at the pediatric practice (both groups); 3 months of intervention at the pediatric practice (intervention group A) or at the social pediatric center (intervention group B), respectively; 3 months of follow-up at the pediatric practice (both groups). Discussion Results of the planned comparison of routine care in pediatric practices and interdisciplinary social pediatric centers will be relevant for treatment of children with migraine, both for the individual and for the health care system. Trial registration The study was approved by the ethics committee at the Ludwig-Maximilians-University Munich (number 18–804) and was retrospectively registered on 27 April 2021 in the WHO approved German Clinical Trials Register (number DRKS00016698 ).

Dupilumab is a new monoclonal antibody inhibiting IL-4 and IL-13 signaling transduction through the blockage of the α-subunit of the IL-4 receptor. It is used to treat type 2 inflammatory disorders including atopic dermatitis, asthma, and chronic rhinosinusitis. Here we describe the case of a 79-year-old male presenting with visual hallucinations, disorientation, cognitive decline, and behavioral changes, evolving over 3 weeks. He had been under treatment with dupilumab for atopic dermatitis for the previous 4 months. Radiology and CSF analysis showed a granulomatous meningoencephalitis suspicious of sarcoidosis. Underlying infectious and antibody-mediated causes for meningoencephalitis were ruled out. Pausing Dupilumab and steroids (i.v. and oral) led to rapid clinical improvement. Inhibition of IL-4 and IL-13, key players in the differentiation and activation of Th2 cells, may shift the Th1/Th2- ratio toward an excessive Th1-mediated response, granuloma formation, and drug-induced (neuro)sarcoidosis reaction. Attention should be raised to this side effect.

Abstract Background With headache experienced by up to 75% of adults worldwide in the last year, primary headache disorders constitute a major public health problem, yet they remain under-diagnosed and under-treated. Headache prevalence and burden is changing as society evolves, with headache now occurring earlier in life. Contributing factors, mostly associated with changing life style, such as stress, bad posture, physical inactivity, sleep disturbance, poor diet and excess use of digital technology may be associated with the phenomenon that could be labelled as ‘21st century headache’. This is especially notable in workplace and learning environments where headache impacts mental clarity and therefore cognitive performance. The headache-related impact on productivity and absenteeism negatively influences an individual’s behaviour and quality of life, and is also associated with a high economic cost. Since the majority of sufferers opt to self-treat rather than seek medical advice, substantial knowledge on headache prevalence, causation and burden is unknown globally. Mapping the entire population of headache sufferers can close this knowledge gap, leading to better headache management. The broad use of digital technology to gather real world data on headache triggers, burden and management strategies, in self-treated population will allow these sufferers to access appropriate support and medication, and therefore improve quality of life. Conclusion These data can yield important insights into a substantial global healthcare issue and form the basis for improved patient awareness, professional education, clinical study design and drug development.

Abstract Background Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors. Methods Data of a random sample of the general population in Germany aged ≥14 years were analyzed (N = 2461). A multivariate binary logistic regression was conducted to identify a parsimonious model to predict physician consultation. Results 50.7% of the participants with headache reported at least one headache-specific physician consultation during lifetime. Of these, 53.6% had seen one, 26.1% two, and 20.3% more than two physicians because of their headaches. The odds of physician consultation increased with the number of headache days per month (HDM) [(reference HDM

Abstract This study examined saccade adaptation induced by intrasaccadic target steps (ITS). By manipulating the ITS, we investigated potential effects of the consistency of the feedback error on saccade adaptation, which would provide evidence against the linearity of standard models of visuomotor adaptation. Previous studies addressing saccade adaptation arrived at different interpretations, but in these experiments only a single saccade amplitude was trained rather than a variety of saccade amplitudes in random order (mixed training). We extend previous studies by testing for effects of error consistency under additional control conditions described by the factors training protocol (single‐amplitude/mixed), ITS direction (onward/backward), and adaptation phase (training/washout). Adaptation dynamics were assessed using a model of “multi‐gainfield adaptation” developed by tailoring an existing linear model for visuomotor adaptation of movements with multiple target positions to gain adaptation of saccades with multiple amplitudes. The total adaptive change did not depend on the consistency of the ITS in either mixed or single‐amplitude training. The initial adaptation speed was lower with inconsistent ITS. However, the effect on adaptation speed occurred only during amplitude reduction and not during enlargement or washout. These results corroborate the linearity of saccade adaptation in that the mean error is the main factor determining the total adaptive change, independent of error consistency. The multi‐gainfield adaptation model was confirmed in that the retention rate and error sensitivity did not depend on the training protocol. The absence of effects of error consistency on saccade adaptation is relevant in the context of adaptive deficits in movement disorders.

This study investigates visuospatial memory in patients with unilateral lesions of the temporal lobe and the hippocampus resulting from surgery to treat drug-resistant epilepsy. To detect impairments of visuospatial memory in these individuals, a memory test should be specific to episodic memory, the type of memory in which the hippocampus is crucially involved. However, most known visuospatial memory tests do not focus on episodic memory. We hypothesized that a new sequential visuospatial memory test, which has been previously developed and applied only in healthy subjects, might be suitable to fill this gap. The test requires the subject to reproduce a memorized sequence of target locations in ordered recall by typing on a blank graphics tablet. The length of the memorized sequence extended successively after repeated presentation of a sequence of 20 target positions. The test was done twice on day one and again after one week. Visual working memory was tested with the Corsi block-tapping task. The performance in the new test was also related to the performance of the patients in the standard test battery of the neuropsychological examination in the clinical context. Thirteen patients and 14 controls participated. Patients showed reduced learning speed in the new sequential visuospatial memory task. Right-sided lesions induced stronger impairments than left-sided lesions. After one week, retention was reduced in the patients with left-sided lesions. The performance of the patients in commonly used tests of the neuropsychological standard battery did not differ compared to healthy subjects, whereas the new test allowed discrimination between patients and controls at a high correct-decision rate of 0.89. The Corsi block-span of the patients was slightly shorter than that of the controls. The results suggest that the new test provides a specific investigation of episodic visuospatial memory. Hemispheric asymmetries were consistent with the general hypothesis of right hemispheric dominance in visuospatial processing.

Increased intracranial pressure in cerebral venous sinus thrombosis or metabolic disease has been reported. We present a case of new-onset chronic headache and bilateral papilledema in the setting of elevated intracranial pressure in strong temporal association to vaccination against COVID-19 with AstraZeneca. After repeated drainage of cerebrospinal fluid and conservative drug therapy, pathological findings were regredient. Even in absence of typical risk factors, increased intracranial pressure should be considered in case of clinical suspicion after COVID-19 vaccination.

Objectives: We describe two new cases of acute hemorrhagic leucoencephalitis (AHLE), who survived with minimal sequelae due to early measures against increased intracranial pressure, particularly craniotomy. The recently published literature review on treatment and outcome of AHLE was further examined for the effect of craniotomy.Methods: We present two cases from our institution. The outcome of 44 cases from the literature was defined either as good (no deficit, minimal deficit/no daily help) or poor outcome (severe deficit/disabled, death). Patients with purely infratentorial lesions (n = 9) were excluded. Fisher's exact test was applied.Results: Two cases are presented: A 43-year-old woman with rapidly progressive aphasia and right hemiparesis due to a huge left frontal white matter lesion with rim contrast enhancement. Pathology was consistent with AHLE. The second case was a 56-year-old woman with rapidly progressive aphasia and right hemiparesis. Cranial MRI showed a huge left temporo-occipital white matter lesion with typical morphology for AHLE. Both patients received craniotomy within the first 24 h and consequent immunosuppressive-immunomodulatory treatment and survived with minimal deficits. Out of 35 supratentorial reported AHLE cases, seven patients received decompressive craniotomy. Comparing all supratentorial cases, patients who received craniotomy were more likely to have a good outcome (71 vs. 29%).Conclusion: Due to early control of the intracranial pressure, particularly due to early craniotomy; diagnosis per biopsy; and immediate start of immunosuppressive-immunomodulatory therapies (cortisone pulse, plasma exchanges), both patients survived with minimal sequelae. Craniotomy plays an important role and should be considered early on in patients with probable AHLE.

Abstract Background Early diagnosis of CNS lymphoma (CNSL) is essential for successful therapy of this rapidly progressing brain tumor. However, in patients presenting with focal brain lesions, fast and reliable diagnosis of PCNSL remains a challenge. A proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) are important factors in the pathophysiology, diagnosis, and prognosis of systemic B cell malignancies. However, their utility as biomarkers for the diagnosis of CNSL and their effects on CNSL cells remain unclear. Methods In this prospective study, we analyzed the levels of APRIL and BAFF in the cerebrospinal fluid (CSF) of 116 patients with suspected focal brain lesions, including 53 CNSL patients. Additionally, we serially measured their levels during chemotherapy and relapse. Furthermore, we analyzed the effect of APRIL and BAFF on two B cell lymphoma cell lines using proliferation, viability, and chemotaxis assays. Results CSF levels of APRIL and BAFF reliably differentiated CNSL from other focal brain lesions (including primary and metastatic brain tumors, autoimmune-inflammatory lesions, and neuroinfectious lesions) with a specificity of 93.7% (APRIL, BAFF) and a sensitivity of 62.3% (APRIL) and 47.1% (BAFF). Serial CSF analysis of CNSL patients during chemotherapy and relapse demonstrates a close correlation of APRIL CSF levels and the course of this disease. In vitro, APRIL and BAFF showed anti-apoptotic effects during MTX treatment and mediated chemotaxis of malignant B cells. Conclusion This study extends the spectrum of valuable diagnostic biomarkers in CNSL. In patients with focal brain lesions, measurement of APRIL in CSF could help accelerating the diagnosis of CNSL. Moreover, our results highlight an important role of APRIL and BAFF in the pathophysiology of CNSL.

Abstract Primary headaches are one of the most prevalent neurological disorders and can occur during a wide range of lifespan. Primary headaches, especially migraine, are cyclic disorders with a complex sequence of symptoms within every headache attack. There is no systematic review of whether these symptoms changes during lifespan. Indeed, the clinical presentation of migraine shows an age-dependent change with a significantly shorter duration of the attacks and occurrence of different paroxysmal symptoms, such as vomiting, abdominal pain or vertigo, in childhood and, in contrast, largely an absence of autonomic signs and a more often bilateral headache in the elderly. The age-dependent differences in the clinical presentation are less distinct in cluster headache and, especially, in tension-type headache. The differences in the clinical presentation are in agreement with the idea that the connectivity of hypothalamic areas with different brainstem areas, especially the central parasympathetic areas, is important for the clinical manifestation of migraine, as well as, the change during lifespan.

Abstract Background The role of avoidance and endurance behaviour is well established in chronic musculoskeletal pain, but less is known about its significance in migraine. Methods The Avoidance-Endurance Questionnaire behavioural subscales, the Pain Disability Index (PDI), the Migraine Disability Assessment Scale (MIDAS) and the Hospital Anxiety and Depression Scale (HADS) were obtained from 128 migraine patients (90 episodic, 38 chronic). Sixty nine of them were re-evaluated after 3–6 months. Results At baseline, there were positive relations between avoidance (especially social avoidance behaviour) and pain-related disability as assessed by the PDI (Wald χ2 [1] = 32.301, p

Objective: Patients with visual snow syndrome (VSS) suffer from continuous (“TV snow-like”) visual disturbance of unknown pathoetiology. In VSS, changes in cortical excitability in the primary visual cortex and the visual association cortex are discussed, with recent imaging studies tending to point to higher-order visual areas. Migraine, especially migraine with aura, is a common comorbidity. In chronic migraine and episodic migraine with aura but not in episodic migraine without aura, a reduced magnetic suppression of perceptual accuracy (MSPA) reflects a probably reduced inhibition of the primary visual cortex. Here we investigated the inhibition of the primary visual cortex using MSPA in patients with VSS, comparing that with MSPA in controls matched for episodic migraine.Methods: Seventeen patients with VSS were compared to 17 age- and migraine-matched controls. Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals with respect to the letter presentation (40, 100, and 190 ms).Results: Suppression of visual accuracy at the 100-ms interval was present without significant differences between VSS patients and age- and migraine-matched controls (percentage of correctly recognized trigrams, control: 46.4 ± 34.3; VSS: 52.5 ± 25.4, p = 0.56).Conclusions: In contrast to migraine with aura, occipital cortex inhibition, as assessed with MSPA, may not be affected in VSS.

Background: Migraine has been postulated to lead to structural and functional changes of different cortical and subcortical areas, including the frontal lobe, the brainstem, and cerebellum. The (sub-)clinical impact of these changes is a matter of debate. The spectrum of possible clinical differences include domains such as cognition but also coordination. The present study investigated the oculomotor performance of patients with migraine with and without aura compared to control subjects without migraine in reflexive saccades, but also in intentional saccades, which involve cerebellar as well as cortical networks.Methods: In 18 patients with migraine with aura and 21 patients with migraine without aura saccadic eye movements were recorded in two reflexive (gap, overlap) and two intentional (anti, memory) paradigms and compared to 25 controls without migraine.Results: The main finding of the study was an increase of saccade latency in patients with and without aura compared to the control group solely in the anti-task. No deficits were found in the execution of reflexive saccades.Conclusions: Our results suggest a specific deficit in the generation of correct anti-saccades, such as vector inversion. Such processes are considered to need cortical networks to be executed correctly. The parietal cortex has been suggested to be involved in vector inversion processes but is not commonly described to be altered in migraine patients. It could be discussed that the cerebellum, which is recently thought to be involved in the pathophysiology of migraine, might be involved in distinct processes such as spatial re-mapping through known interconnections with parietal and frontal cortical areas.

Background: Diagnostic delay and neurologic deterioration are still a problem for the treatment of rapidly progressing CNS lymphoma (CNSL); there is an unmet need for a diagnostic test with a high diagnostic yield and limited risk, minimizing the time to the initiation of effective treatment.Methods: In this prospective monocentric study, we analyzed the utility of CXCL13 and CXCL9 as diagnostic, therapeutic and prognostic biomarkers for CNSL. Cerebrospinal fluid (CSF) from 155 consecutive patients admitted with brain lesions of various origins was collected. Levels of CXCL13 and CXCL9 were analyzed by ELISA. Additionally, CSF was analyzed during CNSL disease course (relapse, remission, progress) in 17 patients.Results: CXCL13 and CXCL9 CSF levels were significantly increased in patients with CNSL compared to control patients with lesions of other origin. Using logistic regression and a minimal-p-value approach, a cut-off value of 80 pg/ml for CXCL13 shows high sensitivity (90.7%) and specificity (90.1%) for the diagnosis of active CNSL. CXCL9 at a cut-off value of 84 pg/ml is less sensitive (61.5%) and specific (87.1%). Both cytokines correlate with the clinical course and response to therapy.Conclusions: Our results confirm the excellent diagnostic potential of CXCL13 and introduce CXCL9 as a novel albeit less powerful marker for PCNSL.

Primary CNS lymphoma (PCNSL) is an aggressive brain tumor. Despite improvements in therapeutic algorithms, long-term survival remains rare, illustrating an urgent need for novel therapeutic targets. BAFF-R is a pro-survival receptor expressed on most malignant B cells, including PCNSL. To date, its role in PCNSL growth remains elusive. Here, we have created a BAFF-R knockout lymphoma cell line (BAFF-R-KO) using CRISPR-Cas9. In serum-starved conditions, BAFF-R-KO cells exhibit decreased viability in vitro compared to BAFF-R+ cells. Combining an orthotopic mouse model of PCNSL with chronic cranial windows and intravital microscopy, we have demonstrated a significant delay in tumor growth in mice inoculated with BAFF-R-KO cells compared to BAFF-R+ PCNSL. Additionally, median survival of BAFF-R-KO mice was significantly prolonged. Altogether, our results indicate the high potential of BAFF-R as a novel treatment target for PCNSL.

Abstract Background Data on autonomic nervous system (ANS) activations in migraine patients are quite controversial, with previous studies reporting over- and underactivation of the sympathetic as well as parasympathetic nervous system. In the present study, we explicitly aimed to assess the cranial ANS in migraine patients compared to healthy controls by applying the cold pressor test to a cohort of migraine patients in the interictal phase and measuring the pupillary response. Methods In this prospective observational study, a strong sympathetic stimulus was applied to 20 patients with episodic migraine in the interictal phase and 20 matched controls without migraine, whereby each participant dipped the left hand into ice-cold (4 °C) water for a maximum of 5 min (cold pressor test). At baseline, 2, and 5 min during the cold pressor test, infrared monocular pupillometry was applied to quantify pupil diameter and light reflex parameters. Simultaneously, heart rate and blood pressure were measured by the external brachial RR-method at distinct time intervals to look for at least clinically relevant changes of the cardiovascular ANS. Results There were no significant differences between the migraine patients and controls at baseline and after 2 min of sympathetic stimulation in all the measured pupillary and cardio-vascular parameters. However, at 5 min, pupillary light reflex (PLR) constriction velocity was significantly higher in migraineurs than in controls (5.59 ± 0.73 mm/s vs. 5.16 ± 0.53 mm/s; unpaired t-test p

Background: Reliable population-based data on the prevalence and characteristics of primary headache across the lifespan are essential. However, robust data are lacking.Methods: We utilized questionnaire data from a random general population sample in Germany, that comprised 2,478 participants aged ≥14 years. A standardized questionnaire addressing headache and headache treatment was filled in during the face-to-face survey.Results: The 6-month prevalence of self-reported headache in the total sample amounted to 39.0% (known diagnosis of migraine 7.2%; tension-type headache 12.4%; another diagnosis or unknown diagnosis 23.4%). Age-specific prevalence rates were 37.9% (14–34 years), 44.6% (35–54 years), 38.5% (55–74 years), and 26.9% (≥75 years). Compared to age group 14–34, participants aged 35–54 were more (OR = 1.29, 95%-CI 1.05–1.60, p = 0.018) and those aged ≥75 were less (OR = 0.55, 95%-CI 0.40–0.76, p < 0.001) likely to have any headache. Of the participants with headache, 79.5% reported headache on 14 days per month. The frequency of headache did not differ significantly between age groups in men [χ(3, N = 384)2 = 1.45, p > 0.05], but in women [χ(3, N = 651)2 = 21.57, p < 0.001]: women aged ≥75 years were over-represented in the group reporting 4–14 headache days per month. The analgesic use (days per month) differed significantly between age groups among participants with headache on 14 days per month: 1.8 (14–34 years), 2.5 (35–54 years), 3.2 (55–74 years), and 3.4 (≥75 years), respectively 7.9 (14–34 years), 11.4 (35–54 years), 18.4 (55–74 years), and 22.8 (≥75 years).Conclusions: In general, the prevalence of headache decreases with age. However, older women suffer from more frequent attacks and older participants take analgesics on more days per month than younger participants. This might put them at risk of medication overuse which may lead to medication overuse headache. More research is needed to understand these specifics in headache frequency and treatment behavior in older people.

In within-subject and within-examiner repeated measures designs, measures of heterophoria with the manual prism cover test achieve standard deviations between 0.5 and 0.8 deg. We addressed the question how this total noise is composed of variable errors related to the examiner (measurement noise), to the size of the heterophoria (heterophoria noise), and to the availability of sensory vergence cues (stimulus noise). We developed an automated alternating cover test (based on a combination of VOG and shutter glasses) which minimizes stimulus noise and has a defined measurement noise (sd=0.06 deg). In a within-subject design, 19 measures were taken within 1.5 min and multiple such blocks were repeated either across days or across 45 min. Blocks were separated by periods of binocular viewing. The standard deviation of the heterophoria across blocks from different days or from the same day (sd=0.33 deg) was 6 times larger than expected based on the standard deviation within the block. The results show that about 42% of the inter-block variance with the manual prism cover test was related to variability of the heterophoria and not to measurement noise or stimulus noise. The heterophoria noise across blocks was predominantly induced during the inter-mediate binocular viewing periods.

In recent years, theory-building in motor neuroscience and our understanding of the synergistic control of the redundant human motor system has significantly profited from the emergence of a range of different mathematical approaches to analyze the structure of movement variability. Approaches such as the Uncontrolled Manifold method or the Noise-Tolerance-Covariance decomposition method allow to detect and interpret changes in movement coordination due to e.g., learning, external task constraints or disease, by analyzing the structure of within-subject, inter-trial movement variability. Whereas, for cyclical movements (e.g., locomotion), mathematical approaches exist to investigate the propagation of movement variability in time (e.g., time series analysis), similar approaches are missing for discrete, goal-directed movements, such as reaching. Here, we propose canonical correlation analysis as a suitable method to analyze the propagation of within-subject variability across different time points during the execution of discrete movements. While similar analyses have already been applied for discrete movements with only one degree of freedom (DoF; e.g., Pearson's product-moment correlation), canonical correlation analysis allows to evaluate the coupling of inter-trial variability across different time points along the movement trajectory for multiple DoF-effector systems, such as the arm. The theoretical analysis is illustrated by empirical data from a study on reaching movements under normal and disturbed proprioception. The results show increased movement duration, decreased movement amplitude, as well as altered movement coordination under ischemia, which results in a reduced complexity of movement control. Movement endpoint variability is not increased under ischemia. This suggests that healthy adults are able to immediately and efficiently adjust the control of complex reaching movements to compensate for the loss of proprioceptive information. Further, it is shown that, by using canonical correlation analysis, alterations in movement coordination that indicate changes in the control strategy concerning the use of motor redundancy can be detected, which represents an important methodical advance in the context of neuromechanics.

To assess potential risk factors for vertigo and dizziness in adolescents and to evaluate their variability by different vertigo types. The role of possible risk factors for vertigo and dizziness in adolescents and their population relevance needs to be addressed in order to design preventive strategies.The study population consisted of 1482 school-children between the age of 12 and 19 years, who were instructed to fill out a questionnaire on different vertigo types and related potential risk factors. The questionnaire specifically asked for any vertigo, spinning vertigo, swaying vertigo, orthostatic dizziness, and unspecified dizziness. Further a wide range of potential risk factors were addressed including gender, stress, muscular pain in the neck and shoulder region, sleep duration, migraine, coffee and alcohol consumption, physical activity and smoking.Gender, stress, muscular pain in the neck and shoulder region, sleep duration and migraine were identified as independent risk factors following mutual adjustment: The relative risk was 1.17 [1.10-1.25] for female sex, 1.07 [1.02-1.13] for stress, 1.24 [1.17-1.32] for muscular pain, and 1.09 [1.03-1.14] for migraine. The population attributable risk explained by these risk factors was 26%, with muscular pain, stress, and migraine accounting for 11%, 4%, and 3% respectively.Several established risk factors in adults were also identified in adolescents. Risk factors amenable to prevention accounted for 17% of the total population risk. Therefore, interventions targeting these risk factors may be warranted.

Following publication of the original article [1], we have been notified that one of the author names was incompletely presented.

This study investigates the inter-trial variability of saccade trajectories observed in five rhesus macaques (Macaca mulatta). For each time point during a saccade, the inter-trial variance of eye position and its covariance with eye end position were evaluated. Data were modeled by a superposition of three noise components due to 1) planning noise, 2) signal-dependent motor noise, and 3) signal-dependent premotor noise entering within an internal feedback loop. Both planning noise and signal-dependent motor noise (together called accumulating noise) predict a simple S-shaped variance increase during saccades, which was not sufficient to explain the data. Adding noise within an internal feedback loop enabled the model to mimic variance/covariance structure in each monkey, and to estimate the noise amplitudes and the feedback gain. Feedback noise had little effect on end point noise, which was dominated by accumulating noise. This analysis was further extended to saccades executed during inactivation of the caudal fastigial nucleus (cFN) on one side of the cerebellum. Saccades ipsiversive to an inactivated cFN showed more end point variance than did normal saccades. During cFN inactivation, eye position during saccades was statistically more strongly coupled to eye position at saccade end. The proposed model could fit the variance/covariance structure of ipsiversive and contraversive saccades. Inactivation effects on saccade noise are explained by a decrease of the feedback gain and an increase of planning and/or signal-dependent motor noise. The decrease of the fitted feedback gain is consistent with previous studies suggesting a role for the cerebellum in an internal feedback mechanism. Increased end point variance did not result from impaired feedback but from the increase of accumulating noise. The effects of cFN inactivation on saccade noise indicate that the effects of cFN inactivation cannot be explained entirely with the cFN's direct connections to the saccade-related premotor centers in the brainstem.

Postpartum cerebral angiopathy (PCA) is a cerebral vasoconstriction syndrome developing shortly after delivery, without signs of preceding eclampsia. The risk for recurrence of PCA is unknown. Here, we report on a closely monitored, uneventful pregnancy of a woman with a previous severe episode of PCA. In summary, this case report demonstrates that PCA does not necessarily recur in following pregnancies, even after previous severe episodes.

To assess the period prevalence and severity of dizziness and vertigo in adolescents.In 1661 students in 8th-10th grade in twelve grammar schools in Munich, Germany information on vertigo/dizziness was assessed by a questionnaire in the class room setting. Three month prevalence of dizziness/vertigo was estimated; symptoms were categorized as orthostatic dizziness, spinning vertigo, swaying vertigo or unspecified dizziness. Duration of symptoms and impact on daily life activities were assessed.72.0% (95%-CI = [69.8-74.2]; N = 1196) of the students (mean age 14.5±1.1) reported to suffer from at least one episode of dizziness or vertigo in the last three months. Most adolescents ticked to have symptoms of orthostatic dizziness (52.0%, 95%-CI = [49.5-54.4], N = 863). The period prevalence for the other types of vertigo were spinning vertigo: 11.6%, 95%-CI = [10.1-13.3], N = 193; swaying vertigo: 12.2%, 95%-CI = [10.6-13.8], N = 202; and unspecified dizziness: 15.2%, 95%-CI = [13.5-17.1], N = 253. About 50% of students with spinning vertigo and swaying vertigo also report to have orthostatic dizziness. Most vertigo/dizziness types were confined to less than one minute on average. The proportion of students with any dizziness/vertigo accounting for failure attending school, leisure activities or obliging them to stay in bed were more pronounced for spinning or swaying vertigo.Dizziness and vertigo in grammar school students appear to be as common as in adults. In face of the high period prevalence and clinical relevance of dizziness/vertigo in adolescents there is a need for prevention strategies. Risk factors for dizziness/vertigo need to be assessed to allow for conception of an intervention programme.

BACKGROUND AND PURPOSE: While penumbra assessment has become an important part of the clinical decision making for acute stroke patients, there is a lack of studies measuring the reliability and reproducibility of defined assessment techniques in the clinical setting. Our aim was to determine reliability and reproducibility of different types of three-dimensional penumbra assessment methods in stroke patients who underwent whole brain CT perfusion imaging (WB-CTP). MATERIALS AND METHODS: We included 29 patients with a confirmed MCA infarction who underwent initial WB-CTP with a scan coverage of 100 mm in the z-axis. Two blinded and experienced readers assessed the flow-volume-mismatch twice and in two quantitative ways: Performing a volumetric mismatch analysis using OsiriX imaging software (MM(VOL)) and visual estimation of mismatch (MM(EST)). Complementarily, the semiquantitative Alberta Stroke Programme Early CT Score for CT perfusion was used to define mismatch (MM(ASPECTS)). A favorable penumbral pattern was defined by a mismatch of ≥ 30% in combination with a cerebral blood flow deficit of ≤ 90 ml and an MM(ASPECTS) score of ≥ 1, respectively. Inter- and intrareader agreement was determined by Kappa-values and ICCs. RESULTS: Overall, MM(VOL) showed considerably higher inter-/intrareader agreement (ICCs: 0.751/0.843) compared to MM(EST) (0.292/0.749). In the subgroup of large (≥ 50 mL) perfusion deficits, inter- and intrareader agreement of MM(VOL) was excellent (ICCs: 0.961/0.942), while MM(EST )interreader agreement was poor (0.415) and intrareader agreement was good (0.919). With respect to penumbra classification, MM(VOL) showed the highest agreement (interreader agreement: 25 agreements/4 non-agreements/κ: 0.595; intrareader agreement 27/2/0.833), followed by MM(EST) (22/7/0.471; 23/6/0.577), and MM(ASPECTS) (18/11/0.133; 21/8/0.340). CONCLUSION: The evaluated approach of volumetric mismatch assessment is superior to pure visual and ASPECTS penumbra pattern assessment in WB-CTP and helps to precisely judge the extent of 3-dimensional mismatch in acute stroke patients.

B-cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferating inducing ligand (APRIL) might play an important role in the pathogenesis of systemic B-cell malignancies. However, the BAFF/APRIL system has not been systematically evaluated in primary central nervous system lymphoma (PCNSL) to date. We assessed the expression of BAFF, APRIL and its receptors BAFF-R (BAFF receptor), BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator cyclophilin ligand interactor) in five PCNSL specimens by immunohistochemical staining. We found extensive expression of BAFF and weak to moderate expression of APRIL, BAFF-R, BCMA, and TACI in all specimens. CD20 positive cells showed expression of both ligands and receptors at the same time. Our results indicate that autocrine stimulation of the BAFF/APRIL system might be involved in the pathogenesis of PCNSL.

To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p

Many patients with heterophoria report on symptoms related to impaired vision. To investigate whether these symptoms are provoked by saccades this study examines whether in heterophoria effects on intrasaccadic and postsaccadic vergence movements are linked to effects on visual performance. Visual acuity was measured in 35 healthy subjects during fixation and immediately after asymmetric diverging saccades. Binocular position traces were recorded by video-oculography. Subjects with exophoria showed larger intrasaccadic divergence amplitudes, which in turn led to smaller postsaccadic divergence amplitudes. Visual acuity did not depend on heterophoria or vergence amplitudes. The results suggest that compensating for exophoria requires increased convergence activity as compared to orthophoria or compensated esophoria. Visual acuity seemed relatively robust with respect to postsaccadic vergence movements.

Bone marrow stromal cells, which normally give rise to bone, cartilage, adipose tissue, and hematopoiesis-supporting cells, have been shown to differentiate in vitro and in vivo into neural-like cells. In this study, we examined the expression of neuronal and glial markers in human marrow stromal cells under culture conditions appropriate for neural stem cells, and compared the unsorted cell population to bone marrow CD133+ stem-like cells using immunofluorescence, Western blot, and functional patch-clamp analysis. Overall, the expression of the early neuronal marker β3-tubulin was most pronounced in the presence of DMEM/F12 and neurotrophin 3 (NT3) or brain-derived neurotrophic factor (BDNF), when marrow stromal cells were cultured onto fibronectin. Electrophysiological examination, however, could not show fast sodium currents or functional neurotransmitter receptors in differentiated marrow stromal cells. CD133+ mesenchymal stem-like cells, but not CD34+/CD133– cells, generally showed a higher expression of neuronal markers than did unsorted marrow stromal cells, and differentiated CD133+ cells more resembled neuron-like cells.