Clinical neurology:

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Stroke remains a leading cause of long-term disability and mortality worldwide, necessitating novel therapeutic strategies to enhance recovery. Traditional rehabilitation approaches, including physical therapy and pharmacological interventions, often provide limited functional improvement. Neuromodulation has emerged as a promising strategy to promote post-stroke recovery by enhancing neuroplasticity and functional reorganization. Among various neuromodulatory techniques, chemogenetics, particularly Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers precise, cell-type-specific, and temporally controlled modulation of neuronal and glial activity. This review explores the mechanisms and therapeutic potential of chemogenetic modulation in stroke recovery. Preclinical studies have demonstrated that activation of excitatory DREADDs (hM3Dq) in neurons located within the peri-infarct area or contralateral M1 has been shown to enhance neuroplasticity, facilitate axonal sprouting, and lead to improved behavioral recovery following stroke. Conversely, stimulation of inhibitory DREADDs (hM4Di) suppresses stroke-induced excitotoxicity, mitigates peri-infarct spreading depolarizations (PIDs), and modulates neuroinflammatory responses. By targeting specific neuronal and glial populations, chemogenetics enables phase-specific interventions-early inhibition to minimize damage during the acute phase and late excitation to promote plasticity during the recovery phase. Despite its advantages over traditional neuromodulation techniques, such as optogenetics and deep brain stimulation, several challenges remain before chemogenetics can be translated into clinical applications. These include optimizing viral vector delivery, improving ligand specificity, minimizing off-target effects, and ensuring long-term receptor stability. Furthermore, integrating chemogenetics with existing stroke rehabilitation strategies, including brain-computer interfaces and physical therapy, may enhance functional recovery by facilitating adaptive neuroplasticity. Future research should focus on refining chemogenetic tools to enable clinical application. By offering a highly selective, reversible, and minimally invasive approach, chemogenetics holds great potential for revolutionizing post-stroke therapy and advancing personalized neuromodulation strategies.

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Stroke remains a leading cause of disability and mortality worldwide, primarily due to the complex and multifaceted nature of its pathophysiology. This review aims to provide a comprehensive and mechanistic understanding of the crosstalk between key signaling pathways activated during stroke and the therapeutic potential of specific receptors: PPAR-γ, ROCK, CB1R, and CB2R. We delve into the intricate signaling cascades that occur post-stroke, including excitotoxicity, oxidative stress, and inflammation, highlighting the pivotal molecular players involved. PPAR-γ, known for its neuroprotective and anti-inflammatory properties, emerges as a critical modulator in stroke therapy. ROCK, a central component in the Rho/ROCK pathway, is implicated in vascular and neuronal damage, making its inhibition a promising therapeutic strategy. The roles of CB1R and CB2R within the endocannabinoid system are explored, with a focus on their dualistic nature in neuroprotection and neurotoxicity. The review further examines the interconnectivity of these receptors within the stroke signaling network, proposing that their synergistic modulation could enhance therapeutic outcomes. Current therapeutic approaches, including pharmacological and multi-target strategies, are critically evaluated, addressing the challenges in translating mechanistic insights into clinical practice. Additionally, the identification and utilization of biomarkers for stroke diagnosis and therapy monitoring are discussed, offering a glimpse into future prospects. Emerging therapies, novel drug developments, and personalized medicine approaches are presented as potential game-changers in stroke treatment.

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In the sustainable development goals (SDG) context of seeking universal health coverage, the expanding gap between the supply of specialized and primary health-care providers of headache-related health care and the care needs of the very large number of people affected by headache is a formidable but not insoluble public-health challenge. Structured headache services provide a cost-effective framework wherein controlled patient flows enable the care needs of people with headache to be met at appropriate levels, but these services may still be overwhelmed by inappropriate demand.Community pharmacists are an underutilized resource, potentially well able to provide the solution. To do so, they must, as a profession, be integrated into structured headache services.What remains to be determined is how to achieve this integration in an encouraging climate for change, which recognises the potential for relieving strained health-care systems and meeting a range of health-care needs by expanding pharmacists' scope of practice.This position statement on behalf of the European Headache Federation (EHF) and Lifting The Burden (LTB) is formally endorsed by the International Pharmaceutical Federation (FIP).

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BACKGROUND: The use of monoclonal antibodies targeting Calcitonin Gene-Related Peptide (CGRP) is an established treatment for chronic migraine (CM). However, its efficacy in CM patients with medication overuse headache (MOH) remains underexplored, and data on the safety and patient compliance of standard-to-high doses, especially Eptinezumab and Erenumab, over at least three months are limited.

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Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity.

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and functional loss in older adults. Obstructive sleep apnea (OSA) is common in older adults, can increase cerebrovascular disease risk, and is linked to medial temporal lobe (MTL) degeneration and cognitive impairment. However, the interaction between OSA features and CSVD burden and their combined effect on MTL structure and function are not well understood. This study tested the hypothesis that CSVD burden is a candidate mechanism linking OSA to MTL degeneration and impaired memory in older adults.