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The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Neuro-oncology education in American neurology departments is highly variable, with no clear guidelines on appropriate practices. To better understand its current state, we focus on the perspective of departmental Grand Rounds (GR), views of adult neurology residency program directors (ANRPD), neuro-oncologists, and residents. First, we obtained GR series from academic years 2017-2018 and 2018-2019 via an online search and direct emails to neurology residency programs. Second, two online surveys were dispensed to ANRPD and neuro-oncologists. Third, a cohort of neurology residents completed surveys with pre/post-didactic tests. Neuro-oncology consisted of 7% (28/ 411) GR in 2017-2018 and 6% (29/463) in 2018-2019; approximately 20% of institutions had no neuro-oncology GR. Twenty neuro-oncologists and 25 of the 175 ANRPDs completed the surveys. Respondents thought 1-to-4 GR annually was adequate. Thirty-five residents completed the survey. Residents might consider neuro-oncology with more exposure (77%, 27/35) and a stronger knowledge base (57%, 20/35). After 8-hours of didactics, residents demonstrated significant (P = .019) pre-/post-test improvement. Here, we begin to define the status of several aspects of neuro-oncology education: 1 in 5 academic institutions do not have any neuro-oncology GR lectures annually, and both ANRPDs and neuro-oncologists agree that 1-to-4 lectures annually are adequate. Residents overwhelmingly stated they would be more interested in neuro-oncology with more exposure, and a pilot study of 8 hours of didactic did show knowledge improvement. While these initial datasets require confirmation in larger studies, it suggests that small changes to the current state at some institutions could have a meaningful impact.
To gather (almost) all (reasonable) theories of phenomenal consciousness, describe them neutrally (largely in the words of their authors), and organize them in a comprehensive, cross-disciplinary taxonomy of categories-"Landscape of Consciousness." Perhaps the process can encourage novel ways of thinking among medical (psychiatry/neurology) practitioners and neuroscientists. Landscape organizes more than 350 explanations of phenomenal consciousness across physicalist and non-physicalist traditions. There are 10 primary categories: Materialism. Non-Reductive Physicalism. Quantum & Dimensions. Information. Panpsychisms. Monisms. Dualisms. Idealisms. Anomalous & Altered States. Materialism, with the largest number of theories by far, has 12 subcategories: Philosophical. Eliminative/Illusionism. Neurobiological. Electromagnetic Field. Computational & Functionalism. Homeostatic & Affective. Embodied & Enactive. Relational. First-order. Higher-order. Language. Phylogenetic/Evolutionary. Representative theories are here summarized as (non-exhaustive) examples. The Landscape of Consciousness is a work-in-process-permanently. Two central theses: (i) understanding phenomenal consciousness at this point should not be restricted to selected ways of thinking or constrained by approved modes of knowing, but should rather seek expansive yet rational diversity, and (ii) issues of sentience, such as AI consciousness, virtual immortality, meaning/purpose, free will, life after death, etc., cannot be understood except in the light of particular theories of consciousness. Implications for psychiatry/neurology and neuroscience may be considered.
Patients with extensive ischaemic change are often excluded from endovascular thrombectomy. We aimed to synthesise the evidence from recent trials in these patients by performing a systematic review and individual patient data meta-analysis to estimate treatment benefit, including within clinical and imaging subgroups. In this systematic review and meta-analysis, we searched PubMed and Embase for randomised trials published between March 1, 2018, and March 1, 2025, that evaluated efficacy and safety of endovascular thrombectomy compared with medical management in patients with large-core ischaemic stroke (based on an Alberta Stroke Program Early CT Score [ASPECTS] of ≤5 or estimated ischaemic core ≥50 mL) presenting within 24 h of onset. Individual patient-level data from all eligible trials were obtained. A central imaging core laboratory readjudicated ASPECTS and reanalysed ischaemic core volume. A two-stage meta-analysis with random-effects model was used to evaluate the distribution of 90-day modified Rankin Scale (mRS) scores (the primary outcome) using adjusted pooled generalised odds ratios (aGenORs). Missing data were handled by multiple imputation. Safety outcomes were all-cause mortality within 90-day follow-up and neurological worsening within 24-48 h of randomisation, reported as adjusted pooled relative risk (aRR); and symptomatic intracerebral haemorrhage within 36 h of randomisation (reported as risk difference). Subgroup analyses based on clinical and imaging characteristics were done, including subgroups defined by ischaemic core volume, ASPECTS, and time window from onset to randomisation. The meta-analysis was registered with PROSPERO (CRD420251058584). We included 1886 patients (944 assigned to endovascular thrombectomy and 942 assigned to medical management) from six trials. Baseline characteristics were similar between treatment groups. At day 90, the distribution of mRS scores was improved in patients in the endovascular thrombectomy group (median score 4 [IQR 3-6]; n=940) versus those in the medical management group (5 [4-6]; n=931; aGenOR 1·63 [95% CI 1·42-1·88], p<0·0001). The endovascular thrombectomy group also had reduced mortality (292 [31·1%]) compared with the medical management group (347 [37·3%]; aRR 0·82 [95% CI 0·70-0·97], p=0·022). No significant differences were observed in symptomatic intracranial haemorrhage (ten [1·1%] of 944 vs nine [1·0%] of 942 patients; pooled unadjusted risk difference -0·17 percentage points [95% CI -1·01 to 0·67], p=0·69) or neurological worsening (197 [22·0%] of 896 patients vs 161 [17·9%] of 899; aRR 1·19 [0·87-1·62], p=0·27). Improved functional outcomes with endovascular thrombectomy were consistent across clinical and imaging subgroups, except for those with an estimated ischaemic core volume of 150 mL or greater, in whom point estimates favoured endovascular thrombectomy, particularly in the early time window (0-6 h), but wide 95% CIs limited interpretation. Endovascular thrombectomy was associated with improved functional outcomes and reduced mortality versus medical management in patients with large-core ischaemic stroke presenting within 24 h of onset. With the exception of very extensive ischaemic changes (core volume ≥150 mL) presenting beyond 6 h, where evidence remains limited, benefit was sustained across ASPECTS and ischaemic core strata for patients presenting up to 24 h after onset. None.
Conventional methods of functional assessment include subjective self- or informant report, which may be biased by personal characteristics, cognitive abilities, and lack of standardization (eg, influence of idiosyncratic task demands). Traditional performance-based assessments offer some advantages over self- or informant reports but are time-consuming to administer and score. This study aims to evaluate the validity and reliability of the Virtual Kitchen Challenge-Version 2 (VKC-2), an objective, standardized, and highly efficient alternative to current functional assessments for older adults across the spectrum of cognitive aging, from preclinical to mild dementia. A total of 236 community-dwelling, diverse older adults completed a comprehensive neuropsychological evaluation to classify cognitive status as healthy, mild cognitive impairment, or mild dementia, after adjustment for demographic variables (age, education, sex, and estimated IQ). Participants completed 2 everyday tasks (breakfast and lunch) in a virtual kitchen (VKC-2) using a touchscreen interface to select objects and sequence steps. Automated scoring reflected completion time and performance efficiency (eg, number of screen interactions, percentage of time spent off-screen, interactions with distractor objects). Participants also completed the VKC-2 tasks using real objects (Real Kitchen). All participants and informants for 219 participants completed questionnaires regarding everyday function. A subsample of participants (n=143) performed the VKC-2 again in a second session, 4-6 weeks after the baseline, for retest analyses. Analyses evaluated construct and convergent validity, as well as retest and internal reliability, of VKC-2 automated scores. A principal component analysis showed that the primary VKC-2 automated scores captured a single dimension and could be combined into a composite score reflecting task efficiency. Construct validity was supported by analyses of covariance results showing that participants with healthy cognition obtained significantly better VKC-2 scores than participants with cognitive impairment (all Ps<.001), even after controlling for demographics and general computer visuomotor dexterity. Convergent validity was supported by significant correlations between VKC-2 scores and performance on the Real Kitchen (r=-0.58 to 0.64, Ps<.001), conventional cognitive test scores (r=-0.50 to -0.22, Ps<.001), and self- and informant report questionnaires evaluating everyday function (r=0.25 to 0.43, Ps<.001). Intraclass correlation coefficients (ICCs) indicated moderate to excellent retest reliability (ICC=0.70-0.90) for VKC-2 scores after 4-6 weeks. Reliability improved in analyses including only participants who reported no change in cognitive status between time 1 and time 2 (n=123). Spearman-Brown correlations showed acceptable to good internal consistency between the VKC-2 tasks (breakfast and lunch) for all scores (0.77-0.84), supporting the use of total scores. The VKC-2 is an efficient, valid, and sensitive measure of everyday function for diverse older adults and holds promise to improve the status quo of functional assessment in aging, particularly when informants are unavailable or unreliable.
Cathodal transcranial direct current stimulation (C-tDCS) is a potential neuroprotective method in the hyperacute phase of ischemic stroke. We aimed to assess safety, tolerability, feasibility, and potential efficacy of C-tDCS in stroke patients with salvageable penumbra. DICAST-SF was a double-blind, randomized, sham-controlled (3 active: 1 sham), 3 + 3 dose-escalation trial. Inclusion criteria were stroke due to occlusion of the internal carotid or middle cerebral artery, last known well time within 24 h, substantial penumbra on CT perfusion, and ineligibility for mechanical thrombectomy. We applied C-tDCS at six dose tiers over the affected primary motor cortex. The primary safety outcome was the symptomatic intracranial hemorrhage (SICH) rate at 24 h post-stimulation. Secondary outcomes included the rates of asymptomatic intracranial hemorrhage (AICH), early neurological deterioration, serious adverse events, and 90-day mortality. Tolerability was assessed by completion rate and questionnaires. Feasibility threshold was defined as median randomization-to-C-tDCS start time within 10 min in the last ten patients. Twenty five patients were enrolled (19 active, 6 sham), mean age 81 (SD 12) years, 16 women, median NIHSS 8 (IQR 6-16). Ten active and 4 sham patients were treated with thrombolysis. No SICH occurred. Three AICH (2 post-thrombolysis) occurred in the active arm. Rates of early deterioration, serious adverse events, and mortality (4 active vs. 2 sham) were comparable. C-tDCS was well tolerated and feasible, median randomization-to-C-tDCS start time was 8 (7-9) min. C-tDCS in hyperacute stroke was safe, well tolerated, and feasible. Findings support further evaluation in larger efficacy trials. TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801446.
This exploratory pilot double-blind, placebo-controlled trial evaluated the effectiveness and safety of combining transcranial direct current stimulation (tDCS) with antidepressants for late-life depression (LLD), and examined whether baseline hippocampal subfield volumes moderated treatment response. Thirty-three elderly patients with LLD receiving antidepressant treatment were enrolled in this pilot RCT and randomly assigned to active-tDCS (n = 18) or sham stimulation (n = 15). Of these, 23 completed the intervention and baseline MRI scans (active-tDCS, n = 13; sham, n = 10). Participants underwent 12 tDCS sessions over 4 weeks, with psychiatric symptoms assessed at baseline, weeks 2, 4, and 6. Baseline hippocampal volumes were measured using FreeSurfer 7.1.1. Active-tDCS participants showed significant reductions in depression and anxiety scores at weeks 4 and 6, while the sham group exhibited no significant changes. No differences in hippocampal volumes were observed between active-tDCS and sham groups. Within the active-tDCS group, hippocampal subfield volumes did not differ between responders (clinical response is defined as a >50 % reduction in total HAMD scores from baseline) and non-responders. However, reductions in depressive severity were positively associated with volumes of the right presubiculum head, right presubiculum body, right subiculum head, right subiculum body, right GC-ML-DG body, right fimbria, right hippocampal tail, and right whole hippocampal body. tDCS appears to be an effective adjunctive intervention for reducing depression in elderly LLD patients. Baseline hippocampal volume may serve as a predictive marker for tDCS outcomes. Larger-scale studies are warranted to confirm these findings.
We performed a narrative review of the literature of amyloid and tau co-pathology in Parkinson Disease and atypical parkinsonism in Pubmed database, including articles published between January 2020 to July 2025. In the last decade, different multicenter research efforts have worked to improve the accuracy of clinical-pathological diagnosis in neurogenerative disease. In this search, growing evidence from neuropathology, neuroimaging and fluid biomarkers have highlighted the role of Alzheimer's disease (AD) co-pathology in Parkinson's disease (PD) and atypical parkinsonism (AP) disorders potentially affecting progression, motor phenotype and cognitive status. Regarding studies of structural and functional imaging evidencing the presence of Amyloid-β (Aβ), tau, as co-pathologies contribute to α-synuclein-related profile of cortical atrophy, network disruption, as well as clinical heterogeneity in PD and AP disorders. In AP fluid biomarkers have shown limited diagnostic accuracy. Neuropathological evidence from systematic post-mortem surveys confirmed that diffuse and neuritic Aβ plaques are uncommon in non-demented PD (10%), intermediate in PD-dementia (30-40%), and frequent in Dementia with Lewy Bodies (60-80%). The evidence in PD and DLB showed that Aß fluid biomarkers may predict clinical trajectory and cognitive decline, while Aβ-imaging would help stratifying patients and directing therapeutic pipeline designs. In AP disorders, including progressive supranuclear palsy and corticobasal degeneration, a combined multimodal assessment of molecular imaging, structural and functional magnetic resonance with fluid biomarkers shall guarantee future differential diagnosis and prediction of clinical outcomes. Although there are no currently accepted biomarkers for PD or AP, the recent design of plasma tau biomarkers and seed-amplification assays are promising approaches which are also reviewed here.
This review aims to collate takeaways from the most recent and relevant literature related to tics, from genetic studies to case studies elucidating Functional tic like behaviors (FTLBs) and clinical trials of novel drugs in development. Recent genome-wide association studies (GWAS) and functional neuroimaging studies have enhanced the understanding of genetic and structural links to Tourette Syndrome (TS). The rise of FTLBs during the Covid-19 pandemic heightened our understanding of this phenomenon and led to the identification of social media’s influence on tics. New studies have identified sex-related difference in TS and common psychiatric co-morbidities. Tic treatment is evolving away from traditional anti-psychotics toward newer compounds including VMAT-2 inhibitors, Ecopipam, and cannabinoid formulations, as well as novel transcranial stimulation approaches. Our understanding of tic etiology and pathophysiology as well tics’ functional counterpart FTLBs and social media impact is expanding along with our ability to manage tics with novel treatments in development.
Temperature is a key determinant of cerebral vulnerability after acute brain injury and a physiological variable that can be continuously monitored and actively controlled in the intensive care unit. Its therapeutic role has evolved from hypothermia-centred strategies toward early recognition of fever and controlled normothermia. This review examines the physiological rationale, clinical evidence, and contemporary practice of temperature management in neurocritical care. We synthesised evidence from major randomised trials, observational studies, and international consensus recommendations across traumatic brain injury, acute vascular brain injury, and post-cardiac arrest encephalopathy, together with current monitoring and implementation approaches. Fever is consistently associated with worse neurological outcomes. In traumatic brain injury, hypothermia reduces intracranial pressure but does not improve functional outcome when used prophylactically and is reserved for refractory intracranial hypertension. In acute vascular brain injury, neutral trials and feasibility constraints have shifted practice toward early detection and treatment of fever rather than hypothermia. In post-cardiac arrest care, contemporary guidelines recommend protocolised temperature control with selection and maintenance of a constant target between 32°C and 37.5°C and active prevention of fever, rather than mandatory hypothermia. Temperature control is a fundamental component of care aimed at protecting the injured brain through continuous monitoring, early detection of fever, and prevention of temperature-related harm.
A subset of patients with headache disorders presents with a dyscapnic state typically clinically symptomatic chronic respiratory alkalosis (CSCRA). CSCRA is well described as an important factor in increased neuromuscular irritability and reduces tissue oxygen delivery through reduction of cerebral blood flow (vasospasm) and left shift of the oxygen-hemoglobin dissociation curve, as well as increasing metabolic tissue oxygen demand all thought to be important factors in headache disorders. Novel testing paradigms that allow assessment of hypoxemia / orthodeoxia-platypnea include hypoxic echocardiography with bubble contrast to diagnose clinically significant right to left shunts (RLS). RLS (commonly through a patent foramen ovale (PFO)) is associated with migraine, particularly migraine with aura. We evaluate patients with an in-depth acid base analysis (including arterial blood gas analysis, comprehensive metabolic profile and urinalysis) and then pursue diagnostic evaluation of potential causative factors. Common causes of CSCRA include sleep disordered breathing, RLS (anatomic and capillary shunting), post-concussive states as well as post-viral or postoperative derangements of acid base status and associated with altered autonomic function. A focused diagnostic approach to discern the root cause for CSCRA may uncover treatable causes such as hypoxemia secondary to RLS or lung disease, sleep disorders and diaphragmatic dysfunction. The time-limited intervention with carbonic anhydrase to normalize acid base status and tissue carbon dioxide stores, as well as rehabilitation measures to normalize breathing patterns serve to normalize the acid base status, reduce neuromuscular irritability and reduce symptoms including headache.
This article reviews recent literature on the association between migraine and trauma, particularly adverse childhood experiences (ACEs). It makes recommendations for research and clinical practice. ACEs are prevalent and associated with lifetime morbidity and mortality. Observational studies have elucidated the association between migraine and ACEs. Emerging literature highlights a dose-dependent relationship between incident migraine and ACEs. ACEs have been linked with migraine-related outcomes in both children and adolescents as well as adults. However, the mechanisms linking ACEs to migraine remain poorly understood. Principles of, and approaches to, trauma-informed care in other populations can be drawn from, expanded, and extended to the context of migraine. We highlight the need for trauma-informed clinical care. We provide specific suggestions for how clinicians can integrate trauma-informed approaches in their clinical practice to improve patient outcomes. Finally, we make recommendations on how the field can advance research.
To discuss the landscape of immunotherapy trials for central nervous system (CNS) tumors including immune checkpoint inhibitors, vaccine therapies, oncolytic viruses, and chimeric antigen receptor T-cell therapy as well as explore the corresponding spectrum of neurologic toxicities. As more clinical trials are underway in CNS tumors, we are starting to appreciate both the promise of immunotherapy and current limitations. While a subset of patients demonstrate benefit, immunotherapy trials have not transformed CNS tumor outcomes, which prompts the field to consider next generation therapies and combinatorial approaches. In addition, novel toxicities of CNS immunotherapy are being described such as tumor-inflammation associated neurotoxicity. Immunotherapy in CNS tumor is still in its nascent stages and shows early signs of promise. However, immunotherapeutic approaches in CNS tumors need to account for the unique physiology of the CNS and the corresponding neurologic toxicities that are associated with therapies targeting the CNS. Elucidating both will set the stage for advancement of safe and effective immunotherapy for CNS tumors.
To highlight the unique clinical features, risk factors, and management strategies associated with early-onset Parkinson's disease (EOPD), and contrast these with late-onset Parkinson's disease (LOPD). We outline how these differences influence diagnostic and therapeutic approaches and identify key knowledge gaps critical to improving clinical care. Compared to LOPD, EOPD (onset age 21-50) has a higher prevalence of monogenic risk factors, focal dystonia, depression, anxiety; slower motor progression; lower rates of cognitive decline; higher risk for delayed diagnosis. Treatment is complicated by earlier and more frequent dyskinesias, motor fluctuations, and unique considerations such as pregnancy and career impact. Risk factors, clinical presentation, progression, and management needs of EOPD can differ from LOPD. Despite advances in characterizing and diagnosing EOPD, most research remains focused on LOPD. There is a critical need to tailor research and clinical trials to address the distinct needs of people with EOPD.
To review the pathophysiology, clinical presentation, evaluation methods, and current treatment strategies of nocturnal hypokinesia and early morning OFF in Parkinson's disease. A comprehensive literature search was conducted using PubMed, ScienceDirect, and the Cochrane Library for relevant treatment strategies. We identified 31 clinical trials. Pharmacologic treatments include standard and sustained-release levodopa, dopamine agonists (rotigotine, ropinirol, pramipexole, and apomorphine), MAO-B inhibitors (rasagiline, safinamide), COMT inhibitors (opicapone), and rescue therapies like inhaled or dispersible levodopa or apomorphine injection. We propose a tiered treatment algorithm based on disease stage and symptom severity. Non-pharmacological treatment is recommended in all stages. For mild, disturbing symptoms in early PD, inhaled or dispersible levodopa or apomorphine injection are advised. In moderate to advanced stages, treatment options include long-acting dopamine agonists, MAO-B inhibitors, sustained-release levodopa, or COMT inhibitors selected based on factors such as daytime motor symptoms, and non-motor symptoms.
Migraine is one of the most disabling diseases worldwide, especially when it transforms into chronic migraine, which is often associated with medication overuse and can become resistant or even refractory to treatments. Molecular, neuroimaging and neurophysiological changes have been described in chronic migraine, some of which might not be fully reversible with preventive treatment. For these reasons, we should aim to prevent this transition, and initiate preventive treatment before disease becomes refractory and burden increases. Preventive migraine treatments are often delayed because of access to care, stigma leading to undertreatment and patients' reluctance as a result of fear of side effects and, in some cases, fear of being labeled as chronically ill. With the availability of effective and well-tolerated preventive treatments, we must shift our mindset and take advantage of new opportunities to initiate preventive treatment earlier. In this International Headache Society position statement, we propose a migraine preventive strategy under the idea of shifting from reactive treatment once disability is established (prevention of attacks), to proactive, individualized prevention initiated early with safe, effective and tolerable therapies (prevention of disease progression). This approach is based on 1) promoting the early initiation of effective and tolerable preventive therapies, starting from two to four monthly migraine days in line with the majority of current guidelines and recommendations and 2) fostering longitudinal studies to gather more evidence on the potential benefit of early prevention, with the final goal of improving patient outcomes, promoting excellent migraine care, enhancing individual and social well-being, and, ultimately, preventing migraine progression and preserving brain health.
To provide a concise, clinically oriented update on advanced therapies for Parkinson’s disease. Subcutaneous infusion of foscarbidopa/foslevodopa and apomorphine reduce OFF time and improve “good ON time”, though infusion site reactions remain of some concern. Image-guided programming may shorten programming time while matching motor outcomes; while adaptive/closed-loop deep brain stimulation using local field potential signals may improve symptoms and quality of life with a lower energy use. Remote programming accelerates clinical benefit and expands access. Approved magnetic resonance guided high intensity focused ultrasound targets now include the ventralis intermediate nucleus of the thalamus, the globus pallidus pars interna and, recently, the pallidothalamic tract; while research investigates the subthalamic nucleus, each target with distinct benefits and adverse event profiles. Early studies using magnetic resonance guided low intensity focused ultrasound show safe, transient blood brain barrier opening. First-in-human stem cells-derived dopaminergic grafts show safety and graft functioning. The advanced therapeutic landscape for Parkinson’s disease has evolved through innovations in established and novel therapies. Future priorities for the field include standardized biomarkers and protocols for adaptive deep brain stimulation, long-term evaluation of high intensity focused ultrasound outcomes, and rigorously controlled trials of low intensity focused ultrasound and cell-based therapies designed to assess disease-modifying potential.
Seletracetam (SEL) is a second-generation racetam derivative of the benchmark antiseizure medication (ASM) levetiracetam, discovered in a drug discovery program conducted by UCB Pharma in the early 2000s to optimize binding to synaptic vesicle glycoprotein 2A (SV2A), the main target of levetiracetam. SEL (administered orally) reached phase IIa clinical trials, but its further development was stopped, and its patent expired in 2021. In preclinical studies, SEL showed very potent seizure suppression in several acquired and genetic epilepsy models, with high CNS tolerability. Phase I human studies indicated rapid and extensive oral absorption (> 90% bioavailability), linear pharmacokinetics, and an elimination half-life of about 8 h, with mostly mild to moderate CNS adverse events. Several phase IIa trials found SEL to be effective and to have a good safety profile in patients with photosensitive epilepsy and drug-resistant focal epilepsy. A unique aspect of SEL is its high potency and water solubility that-unlike any other non-benzodiazepine (non-BDZ) ASMs-allows it to be formulated at therapeutic doses in a very low liquid volume suitable for intranasal administration and potential use in acute seizure rescue therapy. The US-based company PrevEp, Inc. (Bethesda, MD) filed a new US patent application in 2024, followed by a worldwide Patent Cooperation Treaty (PCT) application in 2025 on intranasal and orobuccal SEL formulations and new medical uses as the first potential non-BDZ rescue treatment of acute repetitive seizures and rapid epileptic seizure termination (REST). The clinical development of this novel formulation is derisked by the favorable oral SEL administration phase I and phase IIa clinical data. SEL offers several important advantages for rescue treatment in comparison with BZDs. It is only moderately sedative even at the highest doses tested orally, does not cause respiratory depression, and has no addictive potential. Thus, SEL has the potential to become the first non-BDZ acute rescue therapy. Because SEL has never been approved for use in humans, it is a new chemical entity (NCE). In this review, we describe the pharmacology of SEL, its clinical profile after oral administration, and the development of the new intranasal formulation, including first-in-human data.
This review examines the expanding role of genetic factors in cerebral palsy (CP), with a focus on cryptogenic presentations and CP-masquerading conditions. It addresses how genomic insights refine diagnosis, guide management, and influence counseling. Emerging evidence demonstrates that de novo single-nucleotide variants, copy number variants, mitochondrial variants, and, rarely, repeat expansions contribute significantly to CP, particularly when neuroimaging is normal, progression is atypical, or additional neurodevelopmental features are present. Diagnostic yield is highest in these contexts. Trio-based whole-exome sequencing is recommended as first-line testing, supported by chromosomal microarray or whole-genome sequencing. Integration of genomic testing remains limited by inconsistent CP definitions, restricted test access, and under-recognition of genetic etiologies, especially in adults. Standardized CP classification frameworks, such as SCPE (Surveillance of Cerebral Palsy in Europe), combined with early genomic evaluation, can improve diagnostic accuracy, reveal treatable conditions, and enable precision care. This approach has potential to transform management and outcomes across the lifespan.
This systematic review aimed to assess the impact of non-statin lipid-lowering therapies on imaging-defined features of carotid plaque vulnerability. Only studies assessing the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or ezetimibe met inclusion criteria for this review. Recent clinical trials and cohort studies suggest that PCSK9 inhibitors are associated with reductions in lipid-rich necrotic core volume, intraplaque neovascularization, and inflammatory activity. In contrast, ezetimibe has shown neutral or inconsistent effects, particularly when combined with low- or moderate-intensity statins. PCSK9 inhibitors appear to contribute to early and multidimensional stabilization of vulnerable carotid plaques, whereas the evidence supporting ezetimibe remains limited. However, given the heterogeneity of imaging methods, study designs, and outcome definitions, further well-designed clinical studies with standardized imaging protocols are needed to better understand the role of these therapies in carotid plaque remodeling and stroke prevention.