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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 pose a substantial burden worldwide in healthcare and health research. eHealth has emerged as a promising field given its potential to aid research, with lower resources. With a changing eHealth landscape, identifying available tools is instrumental for informing future research. A systematic review aimed to map existing software and hardware eHealth assessing neurological signs and/or symptoms for research was conducted. In this second part, the results on hardware are presented., Methods: We searched for relevant literature using four search engines (PubMed, Web of Science, Scopus, & EBSCOHost). eHealth software tools have been described elsewhere, and this paper reports hardware tools only. Data extraction focused on collecting the main characteristics of each tool, including the device type and size, the tool setup, and the neurological components assessed. The data were then summarised in tables., Findings: This review captured and described 45 relevant hardware tools. They assessed signs and/or symptoms of five neurological domains: cognitive function, cranial nerves, motor function, posture, gait & coordination, and sensation. Heterogeneity among tool types and setups was high, with most tools assessing posture, gait, & coordination. Over time, there has been an increase in the simplification and versatility of tools, with a preference for commercially available and easily accessible hardware., Interpretation: There is already a considerable number of hardware eHealth assessing neurological function that can be used for research purposes. Furthermore, commercially available tools, such as sensors, appear to be preferred due to their reduced costs, easy setup, and high portability. This opens new opportunities to extend neuroepidemiological research cost-effectively, efficiently, and adaptively., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to this article’s content., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The high incidence of stroke recurrence necessitates effective post-stroke care. This study investigates the effectiveness of a case management-based post-stroke care program in patients with acute stroke and TIA., Methods: In this prospective cohort study, patients with TIA, ischemic stroke or intracerebral hemorrhage were enrolled into a 12-month case management-based program (SOS-Care) along with conventional care. Control patients received only conventional care. The program included home and phone consultations by case managers, focusing on education, medical and social needs and guideline-based secondary prevention. The primary outcome was the composite of stroke recurrence and vascular death after 12 months. Secondary outcomes included vascular risk factor control at 12 months., Results: From 11/2011 to 12/2020, 1109 patients (17.9% TIA, 77.5% ischemic stroke, 4.6% intracerebral hemorrhage) were enrolled. After 85 (7.7%) dropouts, 925 SOS-Care patients remained for comparative analysis with 99 controls. Baseline characteristics were similar, except for fewer males and less frequent history of dyslipidemia in post-stroke care. At 12 months, post-stroke care was associated with a reduction in the composite endpoint compared to controls (4.9 vs. 14.1%; HR 0.30, 95% CI 0.16-0.56, p < 0.001), with consistent results in ischemic stroke patients alone (HR 0.32, 95% CI 0.17-0.61, p < 0.001). Post-stroke care more frequently achieved treatment goals for hypertension, dyslipidemia, diabetes, BMI and adherence to secondary prevention medication (p < 0.05)., Conclusions: Case management-based post-stroke care may effectively mitigate the risk of vascular events in unselected stroke patients. These findings could guide future randomized trials investigating the efficacy of case management-based models in post-stroke care., (© 2024. The Author(s).)

Stroke can lead to cardiac complications such as arrhythmia, myocardial injury, and cardiac dysfunction, collectively termed stroke-heart syndrome (SHS). These cardiac alterations typically peak within 72 h of stroke onset and can have long-term effects on cardiac function. Post-stroke cardiac complications seriously affect prognosis and are the second most frequent cause of death in patients with stroke. Although traditional vascular risk factors contribute to SHS, other potential mechanisms indirectly induced by stroke have also been recognized. Accumulating clinical and experimental evidence has emphasized the role of central autonomic network disorders and inflammation as key pathophysiological mechanisms of SHS. Therefore, an assessment of post-stroke cardiac dysautonomia is necessary. Currently, the development of treatment strategies for SHS is a vital but challenging task. Identifying potential key mediators and signaling pathways of SHS is essential for developing therapeutic targets. Therapies targeting pathophysiological mechanisms may be promising. Remote ischemic conditioning exerts protective effects through humoral, nerve, and immune-inflammatory regulatory mechanisms, potentially preventing the development of SHS. In the future, well-designed trials are required to verify its clinical efficacy. This comprehensive review provides valuable insights for future research., (© 2024. The Author(s).)

Background: Understanding the increasing trends in Italy may inform new prevention strategies and better treatments. We investigated trends and risk factors of dementia, stroke, and ischemic heart disease (IHD) in Italy with the second-oldest population globally, compared to European and high-income countries and the world., Methods: We analyzed the Global Burden of Disease Study (GBD) 2019 estimates on incidence and burden (i.e., disability and death combined) of the three conditions in both sexes. We also analyzed the burden attributable to 12 modifiable risk factors and their changes during 1990-2019., Results: In 2019, Italy had 186,108 new dementias (123,885 women) and 94,074 new strokes (53,572 women). Women had 98% higher crude dementia and 24% higher crude stroke burdens than men. The average age-standardized new dementia rate was 114.7 per 100,000 women and 88.4 per 100,000 men, both higher than Western Europe, the European Union, high-income countries, and the world. During 1990-2019, this rate increased in both sexes (4%), despite a decline in stroke (- 45%) and IHD (- 17%) in Italy. Dementia burden attributable to tobacco decreased in both sexes (- 12.7%) during 1990-2019, while high blood glucose and high body mass index combined burden increased (25.4%). Stroke and IHD had similar trends., Conclusions: While decreases in new strokes and IHDs are encouraging, new approaches to their joint prevention are required to reverse the rising dementia trends, especially among women. Life course approaches to promoting holistic brain health should be implemented at the community, national, and international levels before the growing trends become overwhelming., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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: Temporal lobe epilepsy with isolated amygdala enlargement (TLE-AE) still lacks a definite characterization and controversies exist., Methods: We conducted a retrospective study identifying brain MRI scans with isolated AE between 2015 and 2021. We collected clinical and paraclinical data of patients with TLE-AE and evaluated the outcome., Results: Forty-one subjects were included (20 males; AE: right 13; left 24; bilateral 4). A strong correlation was found between AE and MRI T2-hyperintensity (right: p < 0.005; left: p < 0.003). There was no history of febrile seizures; 85,4% had focal seizures with impaired awareness, 78,1% reported auras (epigastric sensation, déjà-vu, anxiety), 37% had psychiatric disturbances, 48,6% presented with cognitive impairment. We report that AE correlates with FDG-PET temporomesial hypometabolism (right: p = 0.022; left: p = 0.053), temporal interictal activity on EEG (n = 41), and temporal ictal findings during long-term video-EEG monitoring (n = 23). Epilepsy surgery (n = 17) revealed gliosis (n = 4), inflammatory infiltrates (n = 4), or low-grade epilepsy-associated neuroepithelial tumors (n = 5) in the amygdala. Other treatments were immunotherapy (n = 6) and only antiseizure medications (n = 17), with good prognosis (58,1% seizure-free and 17,1% only with auras at last follow-up). There was no correlation between longitudinal changes in seizure frequency and amygdala size (p = 0.848) and T2-hyperintensity (p = 0.909)., Conclusions: AE should be searched in TLE patients with typical aura, psychiatric and/or neurocognitive disturbances. The strong correlations found between AE lateralization and neurophysiological, FDG-PET, and MRI data support involvement of AE in the epileptogenic network. Drug resistance should prompt presurgical study. Inflammation in amygdala specimens and response after immunotherapy suggest an immune-mediated etiology in some TLE-AE cases., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: This study was done in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration. Informed consent: Patients signed an informed consent, accepting the anonymous collection of their clinical data., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aims to evaluate the methodological quality of guidelines concerning the prophylactic use of antiseizure medications (ASMs) in neurosurgery and to summarize relevant recommendations., Methods: PubMed, Embase, MEDLINE, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, China Science and Technology Journal Database (VIP), National Guideline Clearinghouse (NGC), Guidelines International Network (GIN), and other guideline repositories and official organizations were searched from 2004 to 2023 (20 years). The extracted information consisted of the guideline characteristics, relevant recommendations, levels of evidence, and strength of recommendations. Using the Guideline Research and Evaluation Tool II (AGREE II), five reviewers assessed the methodological quality of the guidelines, and the intraclass correlation coefficient (ICC) is used to assess the inter-reviewer consistency., Results: Of 27 eligible guidelines, AGREE II scores varied with higher scores in Clarity of Presentation (88.89%), Scope and Purpose (83.33%), and Editorial Independence (72.92%), but lower in Rigor of Development (59.17%), Stakeholder Involvement (46.67%), and Applicability (41.67%). ICC ranged from 0.51 to 0.92. Nine guidelines were recommended, eight with modifications, and ten not recommended. ASMs prophylaxis are recommended for patients with a seizure history, which means secondary prophylaxis, and specific high-risk groups, but not recommended for primary prophylaxis routinely for those without a history of seizure., Conclusions: Guidelines in neurosurgical perioperative prophylactic use of ASMs are of moderate quality with domains for enhancement. Guidelines lack detailed guidance on medication initiation, dosage, and duration, highlighting the need for more high-quality clinical trials comparing newer and classical ASMs., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethical statement: This study does not contain clinical studies or patient data., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Editors of scientific journals play a key role in the health-related research process. Our study aims to characterize the demographics, work habits, decision-making processes, and ethical challenges faced by editors of neurological journals and to evaluate associations between editor or journal characteristics and editorial decisions, as well as sources of conflict of interest., Methods: Cross-sectional study involving editors from neurological journals that fell above the 50th percentile in the Scimago rankings. Editors were invited to complete a 16-item anonymous online survey. Data on demographics, editorial processes, decision-making, and ethical issues were collected and analysed., Results: 64 editors completed the survey (35.94% were aged 55-65 years, 68.75% had over 7 years of experience); journals' impact factors(IF) ranged from 1 to 10 (mean 3.412 ± 0.260). When reviewers were blinded to authors, editors relied more on reviewers' decisions (p = < 0.007). Editors with more years of experience relied less on reviewers' decisions (p = 0.009). Higher IF journals were associated with more frequent conflicts of interest between authors (p = 0.019) and reviewers (p = 0.033). Younger editors faced more ethical dilemmas related to scientific conduct and plagiarism (p = 0.008 and p = 0.016). Younger editors and those working for journals with higher IF were more likely to face ethical dilemmas related to editorial decisions (p = 0.016 and p = 0.042)., Discussion: The study highlights relevant aspects of the editorial process in neurological journals, emphasizing the influence of blinding procedures and the inconsistent handling of decision-making and ethical challenges. Addressing these issues through collaboration and standardized guidelines can promote the integrity of the process, ensuring high-quality and trustworthy scientific research., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: The Ethical Committee of the University of Campania "Luigi Vanvitelli" approved the study (protocol number 0014460/i)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), and neurofilament light (NfL) to distinguish biomarker-defined Alzheimer disease (AD) from non-AD conditions, in a heterogenous clinical cohort of younger people., Methods: Plasma biomarkers were analysed using ultrasensitive technology, and compared in patients with CSF Alzheimer disease profiles (A+T+) to other CSF profiles (Other)., Results: Seventy-nine patients were included, median age 60.8 years: 16 A+T+, 63 Other. Ptau217, ptau181, GFAP were significantly elevated in A+T+ compared to Other (3.67 vs 1.12 pg/mL, 3.87 vs 1.79 pg/mL, 189 vs 80 pg/mL, respectively). ptau217 distinguished AD from Other with 90% accuracy (88% specificity, 100% sensitivity). ptau217 also demonstrated strong diagnostic performance for clinically diagnosed AD., Conclusions: Plasma ptau217 has strong diagnostic performance in distinguishing CSF biomarker-defined AD in a clinically relevant, younger cohort of people with symptoms, adding further weight for a simple diagnostic blood test for AD as a cause of a patient's symptoms., Competing Interests: Declaration of interests and financial disclosures: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). SL has received honorarium from Lundbeck and Otsuka. AHE has received honoraria from Abbvie, STADA, Seqirus, and Ipsen. KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. All the other authors have nothing to disclose. Statistical analysis conducted by: Dr Dhamidhu Eratne. Consent statement: All human subjects provided informed consent., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Declarations. Conflicts of interest: The author declares no conflicts of interest. Ethical approval: This study was performed in accordance with ethical standards.

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).)

Implanted cortical neuroprosthetics (ICNs) are medical devices developed to replace dysfunctional neural pathways by creating information exchange between the brain and a digital system which can facilitate interaction with the external world. Over the last decade, researchers have explored the application of ICNs for diverse conditions including blindness, aphasia, and paralysis. Both transcranial and endovascular approaches have been used to record neural activity in humans, and in a laboratory setting, high-performance decoding of the signals associated with speech intention has been demonstrated. Particular progress towards a device which can move into clinical practice has been made with ICNs focussed on the restoration of speech and movement. This article provides an overview of contemporary ICNs for speech and movement restoration, their mechanisms of action and the unique ethical challenges raised by the field., Competing Interests: Declarations Conflicts of interest ATS has co-founded and holds shares in Paradromics, Inc. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research United Kingdom (UK; Grant FC001153); the UK Medical Research Council (Grant FC001153); the Wellcome Trust (Grant FC001153). JC was supported by a BBSRC Discovery Felllowship (BB/W010623/1). HJM was supported by UCLH/UCL BRC Neuroscience and the Wellcome EPSRC Centre for Interventional and Surgical Sciences (203145/A/16/Z). HA is supported by UCLH Biomedical Research Centre., (© 2024. The Author(s).)

'Active' and 'non-active' secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of 'active' and 'non-active' SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into 'active SPMS' and 'non-active SPMS', based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either 'active' or 'non-active' SPMS. A total of 237 were classified into patients with 'active SPMS' (27.2%) and 635 as 'non-active SPMS' (72.8%). 'Non-active SPMS' patients were older, with a longer disease duration compared to those with 'active SPMS'. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between 'active' and 'non-active' SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the 'active' group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). 'Active' and 'non-active' SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity., (© 2024. The Author(s).)

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs., Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs., Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged., Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy., (© 2024. The Author(s).)

Importance: B-cell-targeting monoclonal antibodies have demonstrated safety and efficacy in multiple sclerosis or anti-aquaporin-4 IgG positive neuromyelitis optica spectrum disorder. However, these therapies do not facilitate drug-free remission, which may become possible with cell-based therapies, including chimeric antigen receptor (CAR) T cells. CAR T-cell therapy holds promise for addressing other antibody-mediated CNS disorders, e.g., MOG-associated disease or autoimmune encephalitis., Objective: To provide an overview of the current clinical knowledge on CAR T-cell therapy in central nervous system autoimmunity., Evidence Review: We searched PubMed, Embase, Google Scholar, PsycINFO, and clinicaltrials.gov using the terms 'CAR T cell' and 'multiple sclerosis/MS' or 'neuromyelitis optica/spectrum diseases/NMOSD' or 'MOG-associated disease/MOGAD 'or' autoimmune encephalitis' or 'neuroimmunology'., Findings: An ongoing phase I clinical trial has indicated the safety and benefits of anti-BCMA CAR T cells in 12 patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder. Case reports involving two individuals with progressive multiple sclerosis and one patient with stiff-person syndrome demonstrated a manageable safety profile following treatment with anti-CD19 CAR T cells. Recruitment has commenced for two larger studies in MS, and a phase I open-label basket study is underway to evaluate BCMA-directed CAR T cells in various antibody-associated inflammatory diseases, including MOG-associated disease. Preclinical research on NMDA receptor antibody autoimmune encephalitis treated with chimeric autoantibody receptor T cells generated promising data., Conclusions and Relevance: There is minimal evidence of the benefits of CAR T-cell therapy in individuals with central nervous system-directed autoimmunity. Nevertheless, multicenter controlled clinical trials with a manageable safety profile appear feasible and are warranted due to very promising case experiences., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a demyelinating neurological disorder with a highly heterogeneous clinical presentation and course of progression. Disease-modifying therapies are the only available treatment, as there is no known cure for the disease. Careful selection of suitable therapies is necessary, as they can be accompanied by serious risks and adverse effects such as infection. Magnetic resonance imaging (MRI) plays a central role in the diagnosis and management of MS, though MRI lesions have displayed only moderate associations with MS clinical outcomes, known as the clinico-radiological paradox. With the advent of machine learning (ML) in healthcare, the predictive power of MRI can be improved by leveraging both traditional and advanced ML algorithms capable of analyzing increasingly complex patterns within neuroimaging data. The purpose of this review was to examine the application of MRI-based ML for prediction of MS disease progression. Studies were divided into five main categories: predicting the conversion of clinically isolated syndrome to MS, cognitive outcome, EDSS-related disability, motor disability and disease activity. The performance of ML models is discussed along with highlighting the influential MRI-derived biomarkers. Overall, MRI-based ML presents a promising avenue for MS prognosis. However, integration of imaging biomarkers with other multimodal patient data shows great potential for advancing personalized healthcare approaches in MS., (© 2024. The Author(s).)

Objectives: The few voxel-wise lesion-symptom mapping (VLSM) studies aimed at identifying the anatomy of executive function are limited by the absence of a model and by small populations. Using Trail Making Test (TMT) and verbal fluency and a model of their architectures, our objective was to identify the key structures underlying two major executive processes, set-shifting and strategic word search., Methods: We applied a validated VLSM analysis to harmonized cognitive and imaging data from 2009 ischemic stroke patients as a part of the Meta VCI Map consortium. All contrast analyses used an adjusted threshold with 2000 Freedman-Lane permutations (p ≤ 0.05)., Results: The TMT parts A and B were associated with structures involved in visual-spatial processing, the motor system, the frontal lobes, and their subcortical connections. Set-shifting depended on the left dorsomedial frontal region. Both semantic and phonemic fluency tests depended on verbal output abilities and processing speed with similar slopes in different languages. The strategic search process depended on Broca's area, F2 and related tracts, temporal and deep regions. Lastly, the lesion map of set-shifting did not overlap with those of strategic word search processes., Interpretation: Our results identify the anatomical substrates of two main executive processes, revealing that they represent only a specific subpart of previously reported structures. Finally, our results indicate that executive functions depend on several specific, anatomically separable executive processes mainly operating in various parts of the frontal lobes., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Lennox-Gastaut Syndrome (LGS) is characterized by the presence of multiple seizure types and encompasses a heterogenous group of etiologies. The aim of our study was to evaluate the etiological profile of LGS and investigate seizure outcomes based on different clinical variables., Methods: The clinical features, neuroimaging findings, genetic testing and other testing results of LGS patients were systematically reviewed. The identifiable etiology was categorized as either acquired or nonacquired. Univariate and multivariate regression analyses were performed to explore the association between clinical variables and seizure outcome at the last follow-up., Results: We enrolled 156 patients diagnosed with LGS, of whom 66% were male. The mean age of patients was 34.2 months and the median follow-up duration was 29.5 months (interquartile range = 14-56.25 months). The initial seizure type was epileptic spasm in 61 patients, among which 33 of them met the criteria for infantile epileptic spasm syndrome. All patients underwent neuroimaging test, with 25% falling into the acquired structural category. Etiology could be identified in 84 individuals, including pathogenetic variants found in 34 out of 117 patients with nonacquired etiology. CHD2 mutations were most frequently observed among these pathogenetic variants. At the last follow-up, favorable outcomes were observed in 27 patients. The identification of etiology emerged as a significant determinant influencing LGS outcome; specifically, patients with unknown etiology had a higher likelihood of experiencing favorable outcomes compared to those with known cause (p = 0.041). Early onset age and longer epilepsy duration significantly increased the odds of an unfavorable outcome (p = 0.006 and 0.024)., Significance: We present novel data on the clinical and etiological spectrum of LGS, with determined etiology observed in over half of the patients. Epileptic spasms were found to be more prevalent than tonic seizures as seizure onset types in LGS. The presence of a known etiology, earlier age at onset, and longer duration of epilepsy were associated with a poorer long-term epileptological outcome., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Essential tremor (ET) stands as the most prevalent movement disorder, characterized by rhythmic and involuntary shaking of body parts. Achieving an accurate and comprehensive assessment of tremor severity is crucial for effectively diagnosing and managing ET. Traditional methods rely on clinical observation and rating scales, which may introduce subjective biases and hinder continuous evaluation of disease progression. Recent research has explored new approaches to quantifying ET. A promising method involves the use of intelligent devices to facilitate objective and quantitative measurements. These devices include inertial measurement units, electromyography, video equipment, and electronic handwriting boards, and more. Their deployment enables real-time monitoring of human activity data, featuring portability and efficiency. This capability allows for more extensive research in this field and supports the shift from in-lab/clinic to in-home monitoring of ET symptoms. Therefore, this review provides an in-depth analysis of the application, current development, potential characteristics, and roles of intelligent devices in assessing ET., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE., (© 2024. The Author(s).)

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder., (© 2024. The Author(s).)

Objective: Cognitive impairment is now recognized as an impending public health crisis. About one-third of adults are concerned about their cognition, and the prevalence of objective cognitive impairment is much higher among those with neurological disorders. Existing screening tools are narrowly focused on detecting dementia in older adults and must be clinician-administered and scored, making them impractical for many neurology practices. This study examined the utility of a brief, self-administered, computerized cognitive screening tool, the Brief Assessment of Cognitive Health (BACH), in identifying cognitive impairment in adults., Methods: 912 adults (ages 18-84) completed BACH and a neuropsychological battery. Multivariable models were developed to provide a BACH index score reflecting the probability of cognitive impairment for individual patients. Predictive accuracy was compared to that of the Montreal Cognitive Assessment (MoCA) in a subset of 160 older adults from a Memory Disorders clinic., Results: The final multivariable model showed good accuracy in identifying cognitively impaired individuals (c = 0·77). Compared to MoCA, BACH had superior predictive accuracy in identifying older patients with cognitive impairment (c = 0·79 vs. 0·67) as well as differentiating those with MCI or dementia from those without cognitive impairment (c = 0·86 vs. c = 0·67)., Conclusions: Results suggest that cognitive impairment can be identified in adults using a brief, self-administered, automated cognitive screening tool, and BACH provides several advantages over existing screeners: self-administered; automatic scoring; immediate results in health record; easily interpretable score; utility in wide range of patients; and flags for treatable factors that may contribute to cognitive complaints (i.e., depression, sleep problems, and stress)., (© 2024. The Author(s).)

Background and Objectives: The diagnostic challenge of myasthenia gravis (MG) is exacerbated by the variable efficacy of current testing methodologies, necessitating innovative approaches to accurately identify the condition. This study aimed to assess ocular muscle fatigue in patients with MG using video-oculography (VOG) by examining repetitive saccadic eye movements and comparing these metrics to those of healthy control participants., Methods: This prospective, cross-sectional study was conducted at a tertiary care center and involved 62 patients diagnosed with MG (48 with ocular MG and 14 with generalized MG) and a control group of 31 healthy individuals, matched for age and sex. The assessment involved recording saccadic eye movements within a ± 15° range, both horizontally and vertically, at a rate of 15 saccades per minute over a 5-min period, resulting in 75 cycles. Participants were afforded a 3-min rest interval between each set to mitigate cumulative fatigue. The primary outcome was the detection of oculomotor fatigue, assessed through changes in saccadic waveforms, range, peak velocity, latency, and the duration from onset to target, with a focus on comparing the second saccade against the average of the last five saccades., Results: In the evaluation of repetitive saccadic movements, patients with MG exhibited a reduced saccadic range and a prolonged duration to reach the target, compared to healthy subjects. Furthermore, a significant elevation in the frequency of multistep saccades was observed among MG patients, with a marked rise observed over consecutive trials. Receiver operating characteristic (ROC) analysis revealed the discriminative performance of multistep saccade frequency, in conjunction with variations in saccadic range and duration from onset to target achievement between the second saccade and the mean of the final five saccades, as effective in distinguishing MG patients from healthy subjects. Although alterations in peak saccadic velocity and latency were less pronounced, they were nevertheless detectable., Discussion: The utilization of VOG for repetitive saccadic testing in the diagnosis of MG has demonstrated considerable diagnostic precision. This methodology affords significant accuracy in evaluating ocular muscle fatigue in MG patients, providing class III evidence supportive of its clinical application., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4 years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, perampanel was initiated at 2 mg/day and up-titrated to 4 mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12 mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8 weeks and 32 (59.3%) patients completed the study. Retention rate at 12 months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy., (© 2024. The Author(s).)

Introduction: Progress in magnetic resonance imaging (MRI) technology and analyses is improving our comprehension of multiple sclerosis (MS) pathophysiology. These advancements, which enable the evaluation of atrophy, microstructural tissue abnormalities, and functional plasticity, are broadening our insights into the effectiveness and working mechanisms of motor and cognitive rehabilitative treatments., Areas Covered: This narrative review with selected studies discusses findings derived from the application of advanced MRI techniques to evaluate structural and functional neuroplasticity modifications underlying the effects of motor and cognitive rehabilitative treatments in people with MS (PwMS). Current applications as outcome measure in longitudinal trials and observational studies, their interpretation and possible pitfalls and limitations in their use are covered. Finally, we examine how the use of these techniques could evolve in the future to improve monitoring of motor and cognitive rehabilitative treatments., Expert Commentary: Despite substantial variability in study design and participant characteristics in rehabilitative studies for PwMS, improvements in motor and cognitive functions accompanied by structural and functional brain modifications induced by rehabilitation can be observed. However, significant enhancements to refine rehabilitation strategies are needed. Future studies in this field should strive to implement standardized methodologies regarding MRI acquisition and processing, possibly integrating multimodal measures. This will help identifying relevant markers of treatment response in PwMS, thus improving the use of rehabilitative interventions at individual level. The combination of motor and cognitive strategies, longer periods of treatment, as well as adequate follow-up assessments will contribute to enhance the quality of evidence in support of their routine use., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

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).)

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).)

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).)

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: A prior small-scale single center study suggested an association between celiac disease (CD)-type immunity and refractory temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). The present study addresses this putative association in a large, well-characterized group of drug-resistant epilepsy (DRE) patients. These patients were grouped based on the spectrum of CD and gluten sensitivity-associated antibodies., Methods: In this cross-sectional study, 253 consecutive adult epilepsy patients (135 females, 118 males; age 16-76 years) were categorized into three groups: (i) CD-positive group with either prior diagnosis of CD or CD-specific TG2/EmA antibodies, (ii) AGA-positive group with antigliadin antibodies (AGA) but without CD, and (iii) CD/AGA-negative group without any gluten sensitivity-associated antibodies or CD. Clinical and immunological findings were then compared among the groups., Results: TLE with HS was more common in the CD-positive group compared to CD/AGA-negative group (31.8% versus 11.9%, P = 0.019). Autoimmune disorders were more common in the AGA-positive group than in the CD/AGA-negative group (P = 0.025). Considering HS lateralization; left lateralization was more common in CD-positive group compared to CD/AGA-negative group (71.4% versus 25%, P = 0.030). TG6 seropositivity did not differ among the groups (P > 0.05)., Conclusions: This study provides further evidence linking TLE with HS and CD-type autoimmunity suggesting that CD-type immune response to gluten can be one potential mechanism as a disease modifier leading to DRE and HS. Understanding these immunological factors is imperative for developing immunomodulatory or dietary treatments for DRE potentially preventing HS progression., (© 2024. The Author(s).)

Neurological conditions are the leading cause of disability and mortality combined, demanding innovative, scalable, and sustainable solutions. Brain health has become a global priority with adoption of the World Health Organization's Intersectoral Global Action Plan in 2022. Simultaneously, rapid advancements in artificial intelligence (AI) are revolutionizing neurological research and practice. This scoping review of 66 original articles explores the value of AI in neurology and brain health, systematizing the landscape for emergent clinical opportunities and future trends across the care trajectory: prevention, risk stratification, early detection, diagnosis, management, and rehabilitation. AI's potential to advance personalized precision neurology and global brain health directives hinges on resolving core challenges across four pillars-models, data, feasibility/equity, and regulation/innovation-through concerted pursuit of targeted recommendations. Paramount actions include swift, ethical, equity-focused integration of novel technologies into clinical workflows, mitigating data-related issues, counteracting digital inequity gaps, and establishing robust governance frameworks balancing safety and innovation., (© 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: 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.)

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: 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: 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.)