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Spatial orientation is based on a complex cortical network with input from multiple sensory systems. It is affected by training, sex and age as well as cultural and psychological factors, resulting in different individual skill levels in healthy subjects. Various neurological disorders can lead to different patterns or specific deficits of spatial orientation and navigation. Accordingly, numerous tests have been proposed to assess these abilities. Here, we compare the results of (1) a validated questionnaire-based self-estimate of orientation/navigation ability (Santa Barbara Sense of Direction Scale, SBSODS) and (2) a validated pen-and-paper two-dimensional perspective test (Perspective Taking Spatial Orientation Test, SOT) with (3) a newly developed test of finger-arm pointing performance in a 3D real-world (3D-RWPT) paradigm using a recently established pointing device. A heterogeneous group of 121 participants (mean age 56.5 ± 17.7 years, 52 females), including 16 healthy volunteers and 105 patients with different vestibular, ocular motor and degenerative brain disorders, was included in this study. A high correlation was found between 2D perspective task and 3D pointing along the horizontal (azimuth) but not along the vertical (polar) plane. Self-estimated navigation ability (SBSODS) could not reliably predict actual performance in either 2D- or 3D-tests. Clinical assessment of spatial orientation and memory should therefore include measurements of actual performance, based on a 2D pen-and-paper test or a 3D pointing task, rather than memory-based questionnaires, since solely relying on the patient's history of self-estimated navigation ability results in misjudgments. The 3D finger-arm pointing test (3D-RWPT) reveals additional information on vertical (polar) spatial performance which goes undetected in conventional 2D pen-and-paper tests. Diseases or age-specific changes of spatial orientation in the vertical plane should not be clinically neglected. The major aim of this pilot study was to compare the practicability and capability of the three tests but not yet to prove their use for differential diagnosis. The next step will be to establish a suitable clinical bedside test for spatial memory and orientation., (© 2022. The Author(s).)

Background: Neurological disorders remain a worldwide concern due to their increasing prevalence and mortality, combined with the lack of available treatment, in most cases. Exploring protective and risk factors associated with the development of neurological disorders will allow for improving prevention strategies. However, ascertaining neurological outcomes in population-based studies can be both complex and costly. The application of eHealth tools in research may contribute to lowering the costs and increase accessibility. The aim of this systematic review is to map existing eHealth tools assessing neurological signs and/or symptoms for epidemiological research., Methods: Four search engines (PubMed, Web of Science, Scopus & EBSCOHost) were used to retrieve articles on the development, validation, or implementation of eHealth tools to assess neurological signs and/or symptoms. The clinical and technical properties of the software tools were summarised. Due to high numbers, only software tools are presented here., Findings: A total of 42 tools were retrieved. These captured signs and/or symptoms belonging to four neurological domains: cognitive function, motor function, cranial nerves, and gait and coordination. An additional fifth category of composite tools was added. Most of the tools were available in English and were developed for smartphone device, with the remaining tools being available as web-based platforms. Less than half of the captured tools were fully validated, and only approximately half were still active at the time of data collection., Interpretation: The identified tools often presented limitations either due to language barriers or lack of proper validation. Maintenance and durability of most tools were low. The present mapping exercise offers a detailed guide for epidemiologists to identify the most appropriate eHealth tool for their research., Funding: The current study was funded by a PhD position at the University of Groningen. No additional funding was acquired., (© 2023. The Author(s).)

Background: Autonomic dysfunctions are prevalent in several cerebellar disorders, but they have not been systematically investigated in spinocerebellar ataxias (SCAs). Studies investigating autonomic deficits in SCAs are fragmented, with each one focusing on different autonomic dysfunctions and different SCA subtypes., Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we conducted a systematic review of the literature to assess the presence of autonomic dysfunctions in various SCAs. PubMed served as the primary database, and the Rayyan web application was employed for study screening., Results: We identified 46 articles investigating at least one autonomic function in patients with SCA. The results were analyzed and categorized based on the genetic subtype of SCA, thereby characterizing the specific autonomic deficits associated with each subtype., Conclusion: This review confirms the presence of autonomic dysfunctions in various genetic subtypes of SCA, underscoring the cerebellum's role in the autonomic nervous system (ANS). It also emphasizes the importance of investigating these functions in clinical practice., (© 2023. The Author(s).)

In 2017, one of us reviewed advances in epilepsy (Manford in J Neurol 264:1811-1824, 2017). The current paper brings that review up to date and gives a slight change in emphasis. Once again, the story is of evolution rather than revolution. In recognition that most of our current medications act on neurotransmitters or ion channels, and not on the underlying changes in connectivity and pathways, they have been renamed as antiseizure (ASM) medications rather than antiepileptic drugs. Cenobamate is the one newly licensed medication for broader use in focal epilepsy but there have been a number of developments for specific disorders. We review new players and look forward to new developments in the light of evolving underlying science. We look at teratogenicity; old villains and new concerns in which clinicians play a vital role in explaining and balancing the risks. Medical treatment of status epilepticus, long without evidence, has benefitted from high-quality trials to inform practice; like buses, several arriving at once. Surgical treatment continues to be refined with improvements in the pre-surgical evaluation of patients, especially with new imaging techniques. Alternatives including stereotactic radiotherapy have received further focus and targets for palliative stimulation techniques have grown in number. Individuals' autonomy and quality of life continue to be the subject of research with refinement of what clinicians can do to help persons with epilepsy (PWE) achieve control. This includes seizure management but extends to broader considerations of human empowerment, needs and desires, which may be aided by emerging technologies such as seizure detection devices. The role of specialist nurses in improving that quality has been reinforced by specific endorsement from the International League against Epilepsy (ILAE)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-DL-leucine (AL) by means of resting-state [ 18 F]-FDG-PET brain imaging., Methods: Retrospective analyses of [ 18 F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated., Results: Prior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas., Conclusions: Central compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms., (© 2022. The Author(s).)

Background: A brief bedside test has recently been introduced by Hoche et al. (Brain, 2018) to screen for the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with cerebellar disease., Objective: This multicenter study tested the ability of the CCAS-Scale to diagnose CCAS in individual patients with common forms of hereditary ataxia., Methods: A German version of the CCAS-Scale was applied in 30 SCA3, 14 SCA6 and 20 FRDA patients, and 64 healthy participants matched for age, sex, and level of education. Based on original cut-off values, the number of failed test items was assessed, and CCAS was considered possible (one failed item), probable (two failed items) or definite (three failed items). In addition a total sum raw score was calculated., Results: On a group level, failed items were significantly higher and total sum scores were significantly lower in SCA3 patients compared to matched controls. SCA6 and FRDA patients performed numerically below controls, but respective group differences failed to reach significance. The ability of the CCAS-Scale to diagnose CCAS in individual patients was limited to severe cases failing three or more items. Milder cases failing one or two items showed a great overlap with the performance of controls exhibiting a substantial number of false-positive test results. The word fluency test items differentiated best between patients and controls., Conclusions: As a group, SCA3 patients performed below the level of SCA6 and FRDA patients, possibly reflecting additional cerebral involvement. Moreover, the application of the CCAS-Scale in its present form results in a high number of false-positive test results, that is identifying controls as patients, reducing its usefulness as a screening tool for CCAS in individual patients., (© 2022. The Author(s).)

Background: The COVID-19 pandemic outbreak has dramatically disrupted healthcare systems. Two rapid WHO pulse surveys studied disruptions in mental health services, but did not particularly focus on neurology. Here, a global survey was conducted and addresses the impact of the pandemic on neurology services., Methods: A cross-sectional study was carried out in which 34 international neurological associations were asked to distribute the survey to national associations. The responses represented the national situation, in November-December 2020, with regard to the main disrupted neurological services, reasons and the mitigation strategies implemented as well as the disruption on training of residents and on neurological research. A comparison with the situation in February-April 2020, first pandemic wave, was also requested., Findings: 54 completed surveys came from 43 countries covering all the 6 WHO regions. Overall, neurological services disruption was reported as mild by 26%, moderate by 30%, complete by 13% of associations. The most affected services were cross-sectoral neurological services (57%) and neurorehabilitation (56%). The second wave of the pandemic, however, was associated with the improvement of service provision for diagnostics services (44%) and for neurorehabilitation (41%). Governmental directives were the major cause of services' disruption (56%). Mitigation strategies were mostly established through telemedicine (48%). Almost half of respondents reported a significant impact on neurological research (48%) and educational activities (60%). Most associations (67%) were not involved in decision making for neurological patients' issues by their national government., Interpretation: The COVID-19 pandemic affects neurological services and raises the universal need for the development of neurological health care at the policy, systems and services levels. A global national plan on mitigation strategies for disruption of neurological services during pandemic situations should be established and neurological scientific and patients associations should get involved in decision making., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Multiverse analysis provides an ideal tool for understanding how inherent, yet ultimately arbitrary methodological choices impact the conclusions of individual studies. With this investigation, we aimed to demonstrate the utility of multiverse analysis for evaluating generalisability and identifying potential sources of bias within studies employing neurological populations., Methods: Multiverse analysis was used to evaluate the robustness of the relationship between post-stroke visuospatial neglect and poor long-term recovery outcome within a sample of 1113 (age = 72.5, 45.1% female) stroke survivors. A total of 25,600 t-test comparisons were run across 400 different patient groups defined using various combinations of valid inclusion criteria based on lesion location, stroke type, assessment time, neglect impairment definition, and scoring criteria across 16 standardised outcome measures., Results: Overall, 33.9% of conducted comparisons yielded significant results. 99.9% of these significant results fell below the null specification curve, indicating a highly robust relationship between neglect and poor recovery outcome. However, the strength of this effect was not constant across all comparison groups. Comparisons which included < 100 participants, pre-selected patients based on lesion type, or failed to account for allocentric neglect impairment were found to yield average effect sizes which differed substantially. Similarly, average effect sizes differed across various outcome measures with the strongest average effect in comparisons involving an activities of daily living measure and the weakest in comparisons employing a depression subscale., Conclusions: This investigation demonstrates the utility of multiverse analysis techniques for evaluating effect robustness and identifying potential sources of bias within neurological research., (© 2021. The Author(s).)

Multiple sclerosis (MS) is characterized by progressive neuroinflammation and neurodegeneration from disease onset that, if left untreated, can result in the accumulation of irreversible neurological disability. Early intervention with high-efficacy therapies (HETs) is increasingly recognized as the best strategy to delay or mitigate disease progression from the earliest stages of the disease and to prevent long-term neurodegeneration. Although there is growing clinical and real-world evidence supporting early HET intervention, foregoing this strategy in favor of a traditional escalation approach prioritizing lower-efficacy disease-modifying therapies remains a common approach in clinical practice. This review explores potential health care professional- and patient-related barriers to the early use of HETs in patients with MS in the United States. Barriers can include regulatory and reimbursement restrictions; knowledge gaps and long-term safety concerns among health care professionals; and various individual, cultural, and societal factors affecting patients. Potential strategies for overcoming these barriers and encouraging early HET use are proposed., (© 2024. The Author(s).)

Background: Physical activity (PA) represents a promising behavioral approach for managing cognitive dysfunction in multiple sclerosis (MS). However, there is a lack of information on the pattern of free-living PA intensity (e.g., step rate) and its unique association with cognition. Such information is essential for informing clinical trials in MS., Objective: We examined associations among PA volume and intensity with cognitive function in persons with MS, and intensity was derived from steps-based metrics (peak 30-min cadence [Peak-30 CAD ], and time spent in incremental cadence bands)., Methods: We included data from 147 persons with MS who underwent assessments of cognitive function (via Brief International Cognitive Assessment in MS) and wore an ActiGraph GT3X + accelerometer for 7 days. We performed bivariate and partial correlations and regression analyses examining associations among PA metrics and cognitive outcomes., Results: Higher Peak-30 CAD was significantly associated with better performance in cognitive processing speed and verbal learning and memory (r s  = 0.19-0.38), and the associations remained significant when controlling for daily steps, age, sex, and years of education (p < 0.05). By comparison, daily steps was only correlated with cognitive processing speed (r s  = 0.26), and the association was non-significant when controlling for Peak-30 CAD and covariates. There were stronger correlations among time spent in higher intensity cadence bands with cognitive performance (r s  = 0.18-0.38)., Conclusion: Our results highlight the important role of PA intensity for cognition in MS, and may inform future development of focal PA interventions that focusing on step rate patterns for improving cognition in persons with MS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

This study aimed to investigate clinical features, influencing factors and neurobiochemical mechanisms of olfactory dysfunction (OD) in Parkinson disease (PD). Total 39 patients were divided into the PD with OD (PD-OD) and PD with no OD (PD-nOD) groups according to overall olfactory function, including threshold, discrimination and identification, assessed by Sniffin' Sticks test. Motor function and non-motor symptoms were rated by multiple scales. Dopamine, acetylcholine, norepinephrine and 5-hydroxytryptamine levels in cerebrospinal fluid (CSF) were measured. We found that the PD-OD group showed significantly lower score of Montreal Cognitive Assessment Scale, higher scores of rapid eye movement sleep behavior disorder (RBD) Screening Questionnaire and Epworth Sleepiness Scale than the PD-nOD group (p < 0.05). RBD Screening Questionnaire score was independently associated with the scores of overall olfactory function and discrimination (p < 0.05). Dopamine and acetylcholine levels in CSF from the PD-OD group was significantly lower than that from the PD-nOD group (p < 0.05). Dopamine and acetylcholine levels in CSF were significantly and positively correlated with the scores of overall olfactory function, threshold, discrimination and identification in PD patients (p < 0.05). RBD Screening Questionnaire score was significantly and negatively correlated with acetylcholine level in CSF in PD patients with poor olfactory detection (p < 0.05). This investigation reveals that PD-OD is associated with cognitive impairment, probable RBD and excessive daytime sleepiness. PD-OD is correlated with the decreased levels of dopamine and acetylcholine in CSF. RBD is an independent influencing factor of overall olfactory function and discrimination, and the decreased acetylcholine level in CSF may be the common neurobiochemical basis of RBD and OD in PD patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS)., Objective: To identify sex-related differences in DMT strategies over the past decades in a real-world setting., Methods: In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing-remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined., Results: A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5-18) clinical visits over an observation period of 3.5 (IQR 1.5-6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS., Conclusions: Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care., (© 2024. The Author(s).)

Background: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease., Methods: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS., Results: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured., Conclusions: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect., (© 2024. The Author(s).)

Objective: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies., Methods: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE])., Results: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively., Conclusions: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE., (© 2024. The Author(s).)

Objectives: To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS)., Materials and Methods: The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study., Results: Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort., Conclusions: ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course., (© 2024. The Author(s).)

Secondary progressive multiple sclerosis (SPMS) is the second most common form of multiple sclerosis (MS). One in two relapse remitting multiple sclerosis (RRMS) patients will develop SPMS within 15 years and up to two-thirds after 30 years, leading to a progressive decrease of neurological function and limitation of daily activities. Nevertheless, the SPMS diagnosis is often established retrospectively and delayed up to 3 years due to several patient- and clinician-related factors. Definitive clinical diagnostic criteria are lacking and research is currently ongoing to identify imaging and biochemical biomarkers. As new therapies are introduced, early SPMS diagnosis may represent a window of opportunity for intervention. New approaches, endpoints or technologies could help physicians establishing a diagnosis. Here, we review SPMS in relation to its diagnostic and definition challenges and current screening techniques and tools.

Background: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce., Objective: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS., Methods: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose., Results: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%., Conclusions: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS., (© 2023. The Author(s).)

Background: Multiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression., Objective: To study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing-remitting (RR) MS in relation to clinical progression., Methods: Healthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners., Results: We included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups., Discussion: Lower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely., (© 2023. The Author(s).)

Background: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA., Methods: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses., Results: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia., Conclusion: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA without effective treatment. This study aimed to evaluate the comparative efficacy of low-frequency repetitive transcranial magnetic stimulation (rTMS) and intermittent Theta Burst Stimulation (iTBS) in a larger cohort of SCA3 patients., Methods: One hundred and twenty patients with SCA3 were randomly assigned to the 3 groups: 40 patients in the 1 Hz rTMS, 40 in the iTBS and 40 in the sham group. Patients underwent 10 sessions of rTMS targeting the cerebellum delivering for 5 consecutive days per week for 2 weeks (a total of 1200 pulses per session). Primary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Secondary outcomes included 10-m walking test (10MWT), nine-hole peg test (9-HPT), and PATA Rate Test (PRT). Outcome assessments were performed at baseline and on the last day of rTMS intervention., Results: This study revealed that active rTMS outperformed sham in reducing the SARA and ICARS scores in SCA3 patients, but with no difference between the 1 Hz rTMS and iTBS protocol. Moreover, no significant differences were observed in SARA and ICARS scores between the mild and moderate to severe groups after the 1 Hz rTMS/iTBS therapy. Additionally, no severe adverse events were recorded in this study., Conclusions: The study concluded that both 1 Hz rTMS and iTBS interventions targeting the cerebellum are effective to improve the symptoms of ataxia in patients with SCA3., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Pre-existing or enhanced cognitive abilities influence symptom onset and severity in neurodegenerative diseases, which improve an individual's ability to deal with neurodegeneration. This process is named cognitive reserve (CR), and it has acquired high visibility in the field of neurodegeneration. However, the investigation of CR has been neglected in the context of cerebellar neurodegenerative disorders. The present study assessed CR and its impact on cognitive abilities in spinocerebellar ataxia type 2 (SCA2), which is a rare cerebellar neurodegenerative disease. We investigated the existence of CR networks in terms of compensatory mechanisms and neural reserve driven by increased cerebello-cerebral functional connectivity. The CR of 12 SCA2 patients was assessed using the Cognitive Reserve Index Questionnaire (CRIq), which was developed for appraising life-span CR. Patients underwent several neuropsychological tests to evaluate cognitive functioning and a functional MRI examination. Network based statistics analysis was used to assess functional brain networks. The results revealed significant correlations of CRIq measures with cognitive domains and patterns of increased connectivity in specific cerebellar and cerebral regions, which likely indicated CR networks. This study showed that CR may influence disease-related cognitive deficits, and it was related to the effective use of specific cerebello-cerebral networks that reflect a CR biomarker., (© 2023. The Author(s).)

Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are common neurological and neuropsychiatric disorders, respectively, that can exist as comorbidities. However, the degree of comorbidity between both disorders has never been quantified based on a systematic review with meta-analysis. We performed a systematic search of the literature in Embase, PubMed, PsychINFO and the Cochrane Library on June 20, 2022. In a meta-analysis of 63 studies with a total sample size of 1,073,188 individuals (172,206 with epilepsy and 900,982 with ADHD) from 17 countries, the pooled prevalence of ADHD in epilepsy was 22.3% (95% CI 20.3-24.4%). The highest pooled prevalence was 12.7% (95% CI 9-17.1%) for ADHD-I subtype, whereas the pooled prevalence of epilepsy in ADHD was 3.4% (95% CI 2.53-4.21%). However, substantial heterogeneity in comorbidity rates was observed and partially attributed to the following factors: sample size, sample specification, geographical variations and diagnostic methods. Our study highlights the need for increased awareness of this diagnostic co-occurrence, and research is warranted to elucidate the underlying pathophysiological mechanisms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study., Method: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA 2 DS 2 -VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF., Results: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7., Conclusion: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units., (© 2023. The Author(s).)

Writing training has shown clinical benefits in Parkinson's disease (PD), albeit with limited retention and insufficient transfer effects. It is still unknown whether anodal transcranial direct current stimulation (atDCS) can boost consolidation in PD and how this interacts with medication. To investigate the effects of training + atDCS versus training + sham stimulation on consolidation of writing skills when ON and OFF medication. Second, to examine the intervention effects on cortical excitability. In this randomized sham-controlled double-blind study, patients underwent writing training (one session) with atDCS (N = 20) or sham (N = 19) over the primary motor cortex. Training was aimed at optimizing amplitude and assessed during online practice, pre- and post-training, after 24-h retention and after continued learning (second session) when ON and OFF medication (interspersed by 2 months). The primary outcome was writing amplitude at retention. Cortical excitability and inhibition were assessed pre- and post-training. Training + atDCS but not training + sham improved writing amplitudes at retention in the ON state (p = 0.017, g = 0.75). Transfer to other writing tasks was enhanced by atDCS in both medication states (g between 0.72 and 0.87). Also, training + atDCS improved continued learning. However, no online effects were found during practice and when writing with a dual task. A post-training increase in cortical inhibition was found in the training + atDCS group (p = 0.039) but not in the sham group, irrespective of medication. We showed that applying atDCS during writing training boosted most but not all consolidation outcomes in PD. We speculate that atDCS together with medication modulates motor learning consolidation via inhibitory processes ( https://osf.io/gk5q8/ , 2018-07-17)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Individuals with Friedreich's ataxia (FRDA) display significantly lower performances in many cognitive domains with a pattern of impairment that falls within the cerebellar cognitive affective syndrome (CCAS)., Objective: To assess in a large cohort of individuals with FRDA, the main determinant of the CCAS using multiple variable regression models., Methods: This is a monocentric observational study that included 39 individuals with FRDA. Ataxic motor symptoms were evaluated with the SARA and cognitive functions with the CCAS-Scale (CCAS-S). Age, SARA, GAA1, Age of symptoms onset (ASO), Age and disease duration (DD) were chosen as covariates in a linear regression model to predict CCAS-S failed items and covariates in a logistic regression model to predict definite CCAS., Results: Patients mean age, SARA score, ASO, DD and GAA1 were respectively of 29 ± 14, 22 ± 10, 14 ± 11, 15 ± 9 and 712 ± 238 (4 point-mutations). Mean CCAS-S raw score was of 86 ± 16, mean number of failed items was 2.9 ± 1.6. Twenty-three individuals had definite CCAS. The multiple linear regression model with age, SARA, ASO, DD & GAA1 as covariates was statistically significant to predict CCAS-S failed items. The SARA was the only significant coefficient in regression models for predicting CCAS-S failed items number and the definite CCAS occurrence., Conclusions: CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background and Objective: Cognitive and physical functions correlate and delineate aging and disease trajectories. Whereas cognitive reserve (CR) is well-established, physical reserve (PR) is poorly understood. We, therefore, developed and evaluated a novel and more comprehensive construct, individual reserve (IR), comprised of residual-derived CR and PR in older adults with and without multiple sclerosis (MS). We hypothesized that: (a) CR and PR would be positively correlated; (b) low CR, PR, and IR would be associated with worse study outcomes; (c) associations of brain atrophy with study outcomes would be stronger in lower compared to higher IR due to compensatory mechanisms conferred by the latter., Methods: Older adults with MS (n = 66, mean age = 64.48 ± 3.84 years) and controls (n = 66, mean age = 68.20 ± 6.09 years), underwent brain MRI, cognitive assessment, and motoric testing. We regressed the repeatable battery for the assessment of neuropsychological status and short physical performance battery on brain pathology and socio-demographic confounders to derive independent residual CR and PR measures, respectively. We combined CR and PR to define a 4-level IR variable. The oral symbol digit modalities test (SDMT) and timed-25-foot-walk-test (T25FW) served as outcome measures., Results: CR and PR were positively correlated. Low CR, PR and IR were associated with worse SDMT and T25FW performances. Reduced left thalamic volume, a marker of brain atrophy, was associated with poor SDMT and T25FW performances only in individuals with low IR. The presence of MS moderated associations between IR and T25FW performance., Conclusion: IR is a novel construct comprised of cognitive and physical dimensions representing collective within-person reserve capacities., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The association between traumatic brain injury (TBI) and dementia is controversial, and of growing importance considering the ageing demography of TBI., Objective: To review the scope and quality of the existing literature investigating the relationship between TBI and dementia., Methods: We conducted a systematic review following PRISMA guidelines. Studies that compared TBI exposure and dementia risk were included. Studies were formally assessed for quality with a validated quality-assessment tool., Results: 44 studies were included in the final analysis. 75% (n = 33) were cohort studies and data collection was predominantly retrospective (n = 30, 66.7%). 25 studies (56.8%) found a positive relationship between TBI and dementia. Clearly defined and valid measures of assessing TBI history were lacking (case-control studies-88.9%, cohort studies-52.9%). Most studies failed to justify a sample size (case-control studies-77.8%, cohort studies-91.2%), blind assessors to exposure (case-control-66.7%) or blind assessors to exposure status (cohort-3.00%). Studies that identified a relationship between TBI and dementia had a longer median follow-up time (120 months vs 48 months, p = 0.022) and were more likely to use validated TBI definitions (p = 0.01). Studies which clearly defined TBI exposure (p = 0.013) and accounted for TBI severity (p = 0.036) were also more likely to identify an association between TBI and dementia. There was no consensus method by which studies diagnosed dementia and neuropathological confirmation was only available in 15.5% of studies., Conclusions: Our review suggests a relationship between TBI and dementia, but we are unable to predict the risk of dementia for an individual following TBI. Our conclusions are limited by heterogeneity in both exposure and outcome reporting and by poor study quality. Future studies should; (a) use validated methods to define TBI, accounting for TBI severity; (b) follow consensus agreement on criteria for dementia diagnosis; and (c) undertake follow-up that is both longitudinal, to determine if there is a progressive neurodegenerative change or static post-traumatic deficit, and of sufficient duration., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Huntington's disease (HD) is a genetic, neurodegenerative disease. Due to the progressive nature of HD and the absence of a cure, (health-related) quality of life ((HR)QoL) is an important topic. Several studies have investigated (HR)QoL in HD, yet a clear synthesis of the existing literature is lacking to date. We performed a systematic review on self-reported (HR)QoL, and factors and intervention effects associated with (HR)QoL in premanifest and manifest HD gene expansion carriers (pHDGECs and mHDGECs, respectively)., Methods: PubMed, EMBASE, Web of Science, and PsycINFO were searched systematically from September 17th, 2021, up to August 11th, 2022. Methodological and conceptual quality of the included studies was assessed with two appraisal tools., Results: 30 out of 70 eligible articles were included. mHDGECs experienced lower (HR)QoL compared to pHDGECs and controls, whereas mixed findings were reported when compared to other neurological diseases. Several factors were associated with (HR)QoL that might contribute to lower (HR)QoL in mHDGECs, including depressive symptoms, physical and psychological symptoms, lower functional capacity, lower support, and unmet needs. Multidisciplinary rehabilitation programs and a respiratory muscle training were beneficial for (HR)QoL in mHDGECs., Discussion: (HR)QoL is experienced differently across the course of the disease. Although (HR)QoL is key for understanding the impact of HD and the effect of symptomatic treatment, there is a need to improve the methodological and conceptual shortcomings that were found in most studies, especially regarding the conceptual clarity when reporting on QoL and HRQoL. Suggestions for strengthening these shortcomings are provided in this review., (© 2023. The Author(s).)

Background: Few studies interrogated the involvement of cerebellum in modulating gait in Parkinson's disease (PD) patients with postural instability and gait disorders (PD-PIGD). This study aimed at assessing cerebellar atrophy and activity alterations during functional MRI (fMRI) gait-simulating motor- and dual-tasks in PD-PIGD., Methods: Twenty-one PD-PIGD and 23 healthy controls underwent clinical assessment, structural MRI, and fMRI including a motor-task (foot anti-phase movements) and a dual-task (foot anti-phase movements while counting backwards by threes). Grey matter cerebellar volumes were assessed using SUIT atlas. FMRI activations were extracted from each cerebellar lobule, and we correlated cerebellar and basal ganglia activity., Results: PD-PIGD patients had reduced volumes of cerebellar motor and non-motor areas relative to controls. During fMRI motor-task, patients showed greater activation of cognitive cerebellar areas (VI and Crus I-II) vs controls. During fMRI dual-task, PD-PIGD patients showed increased activity of cognitive areas (Crus II) and reduced activity of motor areas (I-IV). Cerebellar structural alterations correlated with increased fMRI activity of cerebellar cognitive areas and with lower executive-attentive performance. The increased activity of Crus I during the motor-task correlated with a better motor performance in PD-PIGD. Moreover, the increased activity of cerebellum correlated with a reduced activity of putamen., Conclusions: In PD-PIGD, the increased activity of non-motor cerebellar areas during gait-simulating tasks may be a consequence of grey matter atrophy or an attempt to compensate the functional failure of cerebellar motor areas and basal ganglia. Cerebellar MRI metrics are useful to characterize brain correlates of motor and dual-task abilities in PD-PIGD patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Little is known about incidence, time of onset, clinical presentation, and risk factors of epileptic seizure following brain arteriovenous malformation (bAVM) rupture., Methods: We performed a monocentric retrospective cohort study from January 2003 to March 2021. The main objective of this study was to determine the incidence of seizures after spontaneous bAVM rupture in nonepileptic adult patients and describe the corresponding clinical features. The secondary objective was to identify clinical, radiological, or biological predictors for the occurrence of de novo seizures after bAVM rupture., Results: Of the 296 cases of bAVM rupture registered during the study period, 247 nonepileptic patients (male 53%, median age 40) were included in the study. Fifty-nine patients (23.9%) had at least one seizure after bAVM rupture. The use of preventive antiepileptic drugs (10.3 [1.5-74.1]; P = 0.02) and decompressive craniectomy (15.4 [2.0-125]; P < 0.009) were independently associated with the occurrence of epilepsy after the bAVM rupture. The factors independently associated with the absence of any seizure after the rupture were isolated intraventricular hemorrhage (0.3 [0.1-0.99]; P = 0.04) and infratentorial location of the bAVM (0.2 [0.1-0.5]; P = 0.09). The first seizure occurred within the first year or within 5 years in, respectively, 83.1% and 98.3% of the patients., Conclusions: Epilepsy affects nearly a quarter of patients after bAVM rupture. Decompressive craniectomy represents an independent risk factor significantly associated with the occurrence of epilepsy after bAVM rupture. The introduction of preventive AEDs after rupture could be considered in these most severe patients who have a decompressive craniectomy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Cognitive impairment is a disabling non-motor symptom of Parkinson's disease (PD). It remains uncertain whether declines in specific cognitive domains relate to imaging or plasma biomarkers across the disease continuum., Objective: We investigated whether neuroimaging and plasma biomarkers correlate with individual task-specific cognitive domain declines evidenced by computerized neuropsychological tests in PD patients., Methods: A total of 107 participants, including 87 PD patients (30 with normal cognition [PD-NC], 30 with mild cognitive impairment [PD-MCI], 27 with dementia [PDD]), and 20 healthy controls, were recruited. All received the Cambridge Neuropsychological Test Automatic Battery (CANTAB) test, brain MRI, and assays of plasma biomarkers, including α-synuclein, tau, Aβ42, and Aβ40., Results: PD patients had generally poorer cognitive performance than controls. Patients with PD-MCI and PDD had worse performance in visual, verbal, and working memory and executive function than those with PD-NC. After adjusting for covariates, PDD patients had global cortical thinning, especially in the temporal and parietal lobes, and higher plasma α-synuclein levels and tau:Aβ42 ratios than PD-NC group. Plasma α-synuclein level was associated with frontal lobe-mediated tasks, while the tau:Aβ42 ratio was associated with posterior cortical-mediated tasks. Facial emotion recognition tasks and visual pattern recognition associated with frontotemporal cortical thinning. The accuracy of predicting PDD using age alone (area under the curve [AUC] 0.756) increased by incorporating plasma biomarkers (AUC = 0.851, p = 0.025)., Conclusions: Cognitive decline in PD patients has a task-specific correlation with neuroimaging and plasma biomarkers, which may implicate the underlying neuropathological process of PDD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The main objective of this study was to investigate the efficacy of a directed rhythmic-melodic voice training (SIPARI) compared to language therapy with the focus on improvement in expressive linguistic performance. 20 patients suffering from chronic non-fluent aphasia, allocated by coin tossing to either of the groups, participated in 32 single therapy sessions over a period of 4 months. Before and after therapy, independent testers performed a standardized language test (Aachener Aphasie Test). Behavioral assessments revealed that improvements of patients of the experimental group were clinically significant compared to those of the control group. These improvements concerned the description level articulation and prosody for spontaneous speech and the subtests repetition, naming, and comprehension. Based on these improvements, a significant increase in profile level (effect size (ES) = 2.028, p < 0.001) was assessed, an overall and clinically relevant measure of the severity of aphasia. Additional fMRI examinations yielded activation in the left superior frontal gyrus for the post-minus pre- therapy assessments only for participants of the experimental group. Since this brain region is reported to be particularly involved in executive processing, we assume that the directed procedure of the SIPARI treatment with regard to musical, linguistic, and cognitive function potentially holds the key for successful language rehabilitation. While our imaging results hint at a possible explanation for its efficacy, our behavioral results corroborate the efficacy of this therapy in the treatment of chronic non-fluent aphasia patients. DRKS00026730, 19.10.21, retrospectively registered https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00026730., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: We aimed to determine school performance and psychiatric comorbidity in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures (GTCS) alone., Methods: All children (< 18 years) fulfilled International League Against Epilepsy criteria after review of their medical records. Control groups were the pediatric background population or children with non-neurological chronic disease. Outcomes were on school performance and psychiatric comorbidity. We compared mean grade point averages using linear regression and estimated hazard ratios using Cox regression in the remaining analyses. We adjusted for the child's sex, age, and year of birth; and parental highest education, receipt of cash benefits or early retirement., Results: We included 92 JAE, 190 JME, 27 GTCS alone, 15,084 non-neurological chronic disease controls, and population controls. JAE had two times increased hazard for special needs education compared with age-matched population controls (hazard ratio 2.2, 95% CI = 1.1‒4.6, p = 0.03); this was not seen in JME. Compared with population controls, both JAE and JME had lower grade point average in secondary and high school (JME: 9th grade:  - 0.5 points, 95% CI = -0.9 to -0.06, p = 0.03; high school:  - 0.6 points, 95% CI = -1.3 to -0.1, p = 0.04), and 8% fewer JME and 15% fewer JAE attended high school. Both JME and JAE had higher hazard for redeeming sleep medication compared with non-neurological chronic disease; additionally, JAE had increased hazard for ADHD medicine redemptions., Conclusions: Both JAE and JME had marginally poorer school performance; performance seemed worse in JAE than in JME. Both JAE and JME had increased use of sleep medication., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To investigate the association of chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) with cognitive performance and presence of vascular brain lesions (VBL)., Methods: We determined both cross-sectional and longitudinal association of lung function impairment with cognition, as well as cross-sectional association of lung function impairment with VBL, in the general population. Between 2009 and 2014 we included 3,941 participants from the Rotterdam Study with spirometry tests, brain MRI scans and cognition tests, of whom 1815 had follow-up data on cognition., Results: Our finding indicated that cross-sectionally, participants with PRISm or COPD GOLD2-4 had a worse global cognitive performance. We did not find differences in cognition over time between those with normal spirometry versus those with lung function impairment. In addition, PRISm and COPD GOLD2-4 were associated with a higher prevalence of lacunar infarcts compared to normal spirometry., Conclusions: This study suggests that persons with COPD GOLD2-4 or restrictive lung function, defined as PRISm, are characterized by poorer global cognitive function and a higher prevalence of lacunar infarcts., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Evidence supports that tension-type headache (TTH) involves complex underlying mechanisms. The current study aimed to quantify potential multivariate relationships between headache-related, psychophysical, psychological and health-related variables in patients with TTH using network analysis., Methods: Demographic (age, height, weight), headache-related (intensity, frequency, duration, and headache-related disability), psychological and emotional (Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index), psycho-physical (pressure pain thresholds [PPTs] and myofascial trigger points) and health-related variables (SF-36 questionnaire) were collected in 169 TTH patients. Network connectivity analysis was unsupervised conducted to quantify the adjusted correlations between the modelled variables and to assess their centrality indices (i.e., the connectivity with other symptoms in the network and the importance in the modelled network)., Results: The connectivity network showed local associations between psychophysical and headache-related variables. Multiple significant local positive correlations between PPTs were observed, being the strongest weight between PPTs over the cervical spine and temporalis area ([Formula: see text]: 0.41). The node with the highest strength, closeness and betweenness centrality was depressive levels. Other nodes with high centrality were vitality and headache intensity., Discussion: This is the first study applying a network analysis to understand the connections between headache-related, psychophysical, psychological and health-related variables in TTH. Current findings support a model on how the variables are connected, albeit in separate clusters. The role of emotional aspects, such as depression, is supported by the network. Clinical implications of the findings, such as developing TTH treatments strategies targeting these most important variables, are discussed., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Cerebellar involvement is not comprehensively studied from an MRI point of view in multiple sclerosis (MS). We aimed to quantify cerebellar damage and identify predictors of physical disability and cognitive dysfunction in MS patients, and to characterize patients with cerebellar disability., Methods: In this prospective study, 164 (89 relapsing-remitting and 75 progressive) MS patients and 53 healthy controls were enrolled. Subjects underwent 3T MRI with sequences for assessing lesions and atrophy in cerebellum, supratentorial brain, brainstem and cervical cord. Cerebellar peduncle diffusion-tensor metrics were also derived. Random forest models identified MRI predictors of Expanded Disability Status Scale (EDSS) score and cognition z-score. Hierarchical clustering was applied on MRI metrics in patients with cerebellar disability., Results: In MS patients, predictors of higher EDSS score (out-of-bag-R 2  = 0.83) were: lower cord grey matter (GM) and global areas, brain volume, GM volume (GMV), cortical GMV, cerebellum lobules I-IV and vermis GMV; and higher cord GM and brainstem lesion volume (LV). Predictors of lower cognition z-score (out-of-bag-R 2  = 0.25) were: higher supratentorial and superior cerebellar peduncle LV; and lower brain, thalamus and basal ganglia volumes, GMV, cerebellum lobule VIIIb and Crus II GMV. In patients with cerebellar disability, we found three clusters with homogenous MRI metrics: patients with high brain lesion volumes (including cerebellar peduncles), those with marked cerebellum GM atrophy and patients with severe cord damage., Conclusions: Damage to cerebellum GM and connecting structures has a relevant role in explaining cognitive dysfunction and physical disability in MS. Data-driven MRI clustering might improve our knowledge of MRI-clinical correlations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Convulsive status epilepticus is the most severe form of epilepsy and requires urgent treatment. We synthesised the current evidence on first-line treatments for controlling seizures in adults with convulsive status epilepticus before, or at, arrival at hospital., Methods: We conducted a systematic review of randomised controlled trials (RCTs) assessing antiepileptic drugs offered to adults as first-line treatments. Major electronic databases were searched., Results: Four RCTs (1234 adults) were included. None were conducted in the UK and none assessed the use of buccal or intranasal midazolam. Both intravenous lorazepam and intravenous diazepam administered by paramedics were more effective than placebo and, notably, intramuscular midazolam was non-inferior to intravenous lorazepam. Overall, median time to seizure cessation from drug administration varied from 2 to 15 min. Rates of respiratory depression among participants receiving active treatments ranged from 6.4 to 10.6%. Mortality ranged from 2 to 7.6% in active treatment groups and 6.2 to 15.5% in control groups., Conclusions: Intravenous and intramuscular benzodiazepines are safe and effective in this clinical context. Further research is needed to establish the most clinically and cost-effective first-line treatment and preferable mode of administration. Head-to-head trials comparing buccal versus intranasal midazolam versus rectal diazepam would provide useful information to inform the management of the first stage of convulsive status epilepticus in adults, especially when intravenous or intramuscular access is not feasible. Approaches to improve adherence to clinical guidelines on the use of currently available benzodiazepines for the first-line treatment of convulsive status epilepticus should also be considered., (© 2022. The Author(s).)

Background and Purpose: Seizures represent a core symptom of autoimmune encephalitides with specific therapeutic issues. To date, patients with new-onset seizures or established epilepsy are not systematically tested for autoimmune antibodies. We aimed to identify clinical and paraclinical criterion that could help to select patients requiring additional autoimmune antibodies serum and cerebrospinal fluid (CSF) detection., Methods: In this retrospective single center study from the French Salpêtrière Hospital, data from 286 adult patients with epilepsy who received an autoantibody assay for the first time were analyzed. All patients were evaluated at our institution between January 2007 and December 2018 for assessment of new-onset epilepsy (n = 90) or established epilepsy (n = 196). We only analyzed patients that were screened for autoimmune antibodies. Demographic, clinical and neuroimaging measures were compared between patients with and without autoimmune encephalitis using Fisher's exact test for categorical variables and Welch's t test for continuous variables. Our primary goal was to identify significant factors that differentiated patients with and without autoimmune encephalitis., Results: We identified 27 patients with autoimmune epilepsy (9.4% of the patients who had been tested for autoantibodies). The significant factors differentiating patients with and without autoimmune encephalitis were: (i) the existence of a new-onset focal epilepsy + (e.g., newly diagnosed epilepsy < 6 months associated with additional symptoms, mainly cognitive or psychiatric symptoms), (ii) the presence of faciobrachial dystonic seizures very suggestive of anti- Leucine-rich glioma inactivated 1 (LGI1) encephalitis, and (iii) the presence of magnetic resonance imaging (MRI) abnormalities suggestive of encephalitis., Conclusion: New-onset focal seizures combined with cognitive or psychiatric symptoms support the test for autoimmune antibodies. Further clinical already known red flags for an autoimmune origin are the presence of faciobrachial dystonic seizures and MRI signal changes consistent with encephalitis. On the other hand, isolated new-onset seizures and chronic epilepsy, even with associated symptoms, seem rarely linked to autoimmune encephalitis and should not lead to systematic testing., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Epileptic seizures with insular genesis are often difficult to distinguish from those originating in the temporal lobe due to their complex and variable semiology. Here, we analyzed differentiating characteristics in the clinical spectrum of insulo-opercular seizures., Methods: Ictal semiology in patients with a diagnosis of insulo-opercular epilepsy (IOE) based on imaging of epileptogenic lesions or electrophysiological evidence of an insulo-opercular seizure origin was retrospectively analyzed and compared to age-matched controls with mesial temporal lobe epilepsy (MTE)., Results: Forty-six IOE and 46 matched MTE patients were included. The most prominent ictal features in IOE were focal motor phenomena in 80.4% of these patients. Somatosensory sensations, version, tonic and clonic features, when present, were more frequent contralateral to the SOZ in MTE patients, while they occurred about equally often ipsilateral and contralateral to the SOZ in IOE patients. Ipsilateral manual automatisms were significantly more frequent in MTE patients than in IOE (p = 0.010). Multivariate analysis correctly identified IOE in 78.3% and MTE in 84.8% using five semiologic features (Chi-square = 53.79 with 5 degrees of freedom, p < 0.0001). A subanalysis comparing patients with purely insular lesions with MTE patients using only the earliest ictal signs showed that somatosensory sensations are significantly more frequent in insular epilepsy (p = 0.010), while automatisms were significantly more frequent in MTE patients (p = 0.06)., Significance: Our study represents the first in-depth analysis of ictal semiology in IOE compared to MTE. Use of these differentiating characteristics can serve for a correct syndrome classification and to steer appropriate diagnostic and local therapeutic procedures., (© 2021. The Author(s).)

Spinocerebellar ataxias (SCA) comprise a rare, genetic subgroup within the degenerative ataxias and are dominantly inherited, with up to 48 recognized genetic subtypes. While an updated review on the management of degenerative ataxia is published recently, an evidence-based review focussed on the management of SCA is lacking. Here, we reviewed the pharmacological and non-pharmacological management of SCA by conducting a systematic review on Medline Ovid and Scopus. Of 29,284 studies identified, 47 studies (pharmacological: n = 25; non-pharmacological: n = 22) that predominantly involved SCA patients were included. Twenty studies had a high risk of bias based on the Cochrane's Collaboration risk of bias tool. As per the European Federation of Neurological Societies 2004 guideline for therapeutic intervention, the remaining 27 studies were of Class I (n = 4) and Class II (n = 23) evidence. Only two therapies had Level A recommendations for the management of ataxia symptoms: riluzole and immediate in-patient neurorehabilitation. Ten therapies had Level B recommendations for managing ataxia symptoms and require further investigations with better study design. These include high dose valproate acid, branched-chain amino acid, intravenous trehalose; restorative rehabilitation using cycling regimen and videogame; and cerebellar stimulations using transcranial direct current stimulation and transcranial magnetic stimulation. Lithium and coaching on psychological adjustment received Level B recommendation for depressive symptoms and quality of life, respectively. Heterogeneous study designs, different genotypes, and non-standardized clinical measures alongside short duration and small sample sizes may hamper meaningful clinical translation. Therefore, rating of recommendations only serve as points of reference., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Seizures are the most common clinical manifestation of low-grade glioma (LGG). Many papers hypothesized an influence of epilepsy on glioma progression. To our knowledge, no clinical study demonstrated a direct relationship between persistence of epileptic seizures after surgery and overall survival (OS) in LGG patients. The present study aims at investigating the correlation between post-operative seizure outcome and survival in tumor-related epilepsy (TRE) patients., Methods: We performed a retrospective analysis of adult patients affected by TRE who underwent surgery for resection of LGG in a single high-volume neurosurgical center. Seizure outcome was assessed 1 year after surgery and categorized according to Engel classification. Clinical, molecular and radiological features were evaluated in univariate and multivariate analyses to investigate the correlation with OS., Results: A total of 146 patients met the inclusion criteria. Histopathological diagnosis was Diffuse Astrocytoma isocitrate dehydrogenase (IDH) wild type in 16 patients (11%), Diffuse astrocytoma IDH mutated in 89 patients (61%) and oligodendroglioma IDH mutated, 1p 19q codeleted in 41 patients (28%). 1 year after surgery, 103 (70.6%) patients were in Engel class 1. Median duration of follow-up period was 69.5 months. Median OS was 79.3 (72.2-86.4) months in the whole population, while it was 86.8 (78.4-95.2), 63.9 (45.7-82), 63.7 (45.2-82.2) and 47.5 (18.3-76.6) months for patients in Engel class 1, 2, 3 and 4, respectively. In a univariate analysis, Engel class evaluated 1 year after surgery significantly influenced OS (p < 0.01). Multivariate analysis showed that OS was independently associated with extent of resection (p = 0.02), molecular class (p < 0.01) and Engel class (p = 0.04)., Conclusions: Seizure control 1 year after surgery significantly predicted survival of patients affected by LGG-related epilepsy in a large monocentric retrospective series. Future studies are needed to confirm these results and to assess if an epilepsy-surgical therapeutic approach may improve OS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: The diagnosis of psychogenic nonepileptic seizures (PNES) is a common clinical dilemma. We sought to assess the diagnostic value of four ictal signs commonly used in differentiating PNES from epileptic seizures (ES)., Methods: We retrospectively reviewed consecutive adult video-electroencephalogram (VEM) studies conducted at a single tertiary epilepsy center between May 2009 and August 2016. Each event was assessed by a blinded rater for the presence of four signs: fluctuating course, head shaking, hip thrusting, and back arching. The final diagnosis of PNES or ES was established for each event based on clinical and VEM characteristics. All ES were pooled regardless of focal or generalized onset. We analyzed the odds ratio of each sign in PNES in comparison to ES with adjustment for repeated measures using logistic regression. Additionally, we calculated the sensitivity, specificity, predictive values, and likelihood ratios of each sign to diagnose PNES., Results: A total of 742 events from 140 VEM studies were assessed. Fluctuating course (odds ratio (OR) 37.37, 95% confidence interval (CI) 13.56-102.96, P < 0.0001), head shaking (OR 2.95, 95% CI 1.26-6.79, P = 0.012), and hip thrusting (OR 4.28, 95% CI 1.21-15.18, P = 0.02) were each significantly predictive of PNES. Fluctuating course had the highest sensitivity (76.16%). Back arching (OR 1.06, 95% CI 0.35-3.20, P = 0.92) was not significantly associated with PNES., Conclusion: Fluctuating course, head shaking, and hip thrusting are semiological features significantly more common in PNES than ES. Fluctuating course is the most reliable sign. Back arching does not appear to differentiate PNES from ES., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)