Not all headaches are fully defined or characterized by the current classification systems. The variability in headache descriptions and presentation may be influenced by individual or group factors, or may even suggest the discovery of a new or an atypical phenotype. This paper aims to describe a novel headache syndrome characterized by a burning sensation on the vertex. Demographic and clinical profiles of 25 patients from a referral headache center in India were analyzed. The syndrome presents as episodic, burning headaches on the vertex (10-20 cm diameter). Most patients were women (16/25), with a mean age of 40.96 years (SD+ 0.75). Episodes occurred 1-3 times weekly or daily, lasting <4 h (range: 1 min to 24 h). Associated symptoms included nausea, vomiting, photophobia, phonophobia, or autonomic features (76%). Common comorbidities were hypertension, diabetes, and polycystic ovarian disease. Neurological exams were normal, except for a slight local temperature rise in 2 patients. Treatment responses varied, though two patients reported reduced frequency and severity after greater occipital nerve (GON) block. This syndrome is not completely compatible with any other primary headache disorders like nummular headache, migraine, cluster, or tension-type headaches. It potentially involves small fiber pathways from the scalp. Further studies are needed to better understand its clinical features, gender predilection, mechanisms, biomarkers, and treatment options.

The purpose of this article is to provide an overview of progression in multiple sclerosis (MS), including definitions, pathological mechanisms, and evidence that progressive biology begins early in the disease course. Definitions of MS clinical course have been refined to acknowledge the presence of both relapse and progression biology throughout the disease. Progression independent of relapse activity represents a significant proportion of disability worsening in relapsing-remitting MS (RRMS) disease. Progression in MS appears to be caused by the complex interplay of multiple processes, including nonresolving inflammation, microglial activation, oxidative stress, mitochondrial dysfunction, energetic failure, and neuro-axonal degeneration. These processes appear to begin in the earliest disease stages and their contribution to clinical phenotypes is dynamic over time. Promising results from clinical trials of tolebrutinib, in particular, underline the utility of targeting both innate and adaptive immune mechanisms to reduce disability accumulation. Pathological processes that underpin MS progression are detectable early in RRMS, evolve throughout the disease course and correlate with disability accumulation. Progression in MS should not be defined dichotomously - the focus instead should be on recognizing progressive components based on clinical measures and biomarkers early in the disease to better individualize treatment strategies.

Neuropathological studies in human brain tissue are indispensable for our understanding of disease mechanisms in multiple sclerosis (MS). They inform concepts of lesion evolution, tissue regeneration and disease progression, and ideally reveal new disease mechanisms and therapeutic targets. Here we review recent neuropathological studies that have advanced our knowledge of MS pathogenesis. Recent cohort studies support the notion that different clinical MS disease phenotypes share underlying pathological features, and that clinical and pathological heterogeneity is derived from a variable combination of innate and adaptive inflammation, demyelinating activity, and neuroaxonal loss. Importantly, emerging technologies for spatial transcriptome analysis enable an unprecedented glimpse into the cellular composition and molecular mechanisms involved in lesion evolution. These promising technologies will help identify the identification of molecular hubs governing tissue damage and regeneration. Recent neuropathological studies helped to identify tissue correlates of disability and disease progression. Substantial progress in molecular brain tissue analysis revealed the complexity of MS-related tissue features. Close collaboration between tissue-based, molecular, bioinformatic, pharmacologic, imaging and clinical experts is needed to continue to advance the field, particularly for the benefit of people with progressive MS.

Monitoring of disease activity and treatment response in multiple sclerosis (MS) currently relies on the integration of qualitative clinical and radiological data that is of limited predictive value. An array of quantitative digital and fluid biomarkers, many on the cusp of broad clinical translation, is expected to herald a new era of data-driven therapeutic strategy, particularly with respect to the sequencing of disease-modifying therapies (DMTs). Available highly-effective DMTs, which largely abolish acute inflammatory activity in early, relapsing MS, have a limited impact on progressive MS disease biology. However, robust digital and fluid biomarkers of progression independent of relapse activity (PIRA) have emerged as a major unmet need, fuelled by the imminent availability of treatments that target pathomechanisms such as chronic active or smouldering brain inflammation. The criteria for MS diagnosis incorporate both imaging and cerebrospinal fluid (CSF) biomarkers of the disease, which lacks a single diagnostic 'test'. The recent validation of objective and quantitative CSF biomarkers, such as the k-FLC index, promises to improve diagnostic accuracy, particularly in patients with atypical or minor imaging changes. Precision monitoring of disease and is response to therapy is being transformed by the advent of clinically integrated, quantitative digital imaging tools; digital wearables and patient reported outcomes, including cognitive batteries delivered on personal devices; and an array of ultra-sensitive, readily-obtained serum fluid biomarkers that indicate the severity of tissue injury in MS. The promise of data-driven therapeutic strategy is being further explored in multimodal digital/fluid and digital twin biomarker studies that incorporate predictive artificial intelligence algorithms. Here, we review the key near-term biomarkers that will guide individualised therapy for people with MS, targeting no evidence of disease activity (NEDA) in both early relapsing and established disease. In the medium term, composite digital and fluid biomarkers, integrated with clinical outcomes and underpinned by predictive artificial intelligence will have a transformative effect on the management of MS.

Cannabinoids have gained attention as a potential treatment for headache disorders, including migraine and cluster headache. While some studies suggest cannabinoids may provide analgesic and anti-inflammatory effects, concerns remain regarding their potential for overuse headache, cognitive impairment, and psychological dependence. This study critically evaluates the current evidence on cannabinoids in headache treatment, weighing their benefits and risks. With the migraine treatment landscape expanding faster than ever, recent studies explore immune cells as a target for cannabinoids. Immune cells express cannabinoid and CGRP (calcitonin gene-related peptide) receptors. As a result, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Additionally, emerging studies suggest that cannabinoids may enhance neuronal resilience and mitigate central sensitization in chronic migraine. Research into optimal delivery mechanisms, including inhaled, sublingual, and transdermal formulations, is also expanding. Cannabinoids are being studied as a potential treatment for headache disorders, particularly migraine, due to their interaction with the endocannabinoid system, which regulates pain, inflammation, and vascular function. Studies suggest cannabinoids may help reduce headache frequency, alleviate pain, and improve sleep, though concerns remain about dependency, cognitive impairment, and medication overuse headache. While retrospective studies indicate benefits, the lack of standardized dosing, long-term safety data, and controlled trials limits conclusive recommendations. Comparisons with conventional treatments show mixed results, with cannabinoids presenting variable effectiveness and a risk of adverse effects. Further research, including randomized controlled trials, is needed to establish optimal dosing, safety, and efficacy in headache management.

The diagnosis of multiple sclerosis (MS) is often challenging and misdiagnosis remains an important contemporary problem, with considerable consequences for patients. This review aims to specify the appropriate approach in differential diagnosis of MS, highlight the clinical and paraclinical red flags and create a new perspective to the clinicians. The accurate diagnosis of MS is challenged by a broad and heterogeneous spectrum of diseases. The differential diagnosis should be based on the combined evaluation of typical clinical, radiological and laboratory findings. Studies have been recently published reported that 7.1-24.4% of patients have been misdiagnosed with MS. The most frequent correct alternative diagnoses were white matter ischemic disease and migraine. Differential diagnosis of MS requires a holistic approach dependent on the clinical presentation and accompanied by vigilance for clinical and paraclinical red flags suggesting alternative diagnoses. Misdiagnosis could have the potential dangerous consequences for patients, including aggressive immunosuppressive therapies.

This article explores the most recent developments in multiple sclerosis (MS), including a selection of advances in diagnostic neuroimaging markers. The proposed revision of diagnostic criteria, new concepts on the prodromal period, and differential diagnosis of MS are included as well. Interesting changes have been introduced to the recently proposed 2024 revisions of MS diagnostic criteria. Optic nerve is proposed as the 5 th CNS topography, additional advanced MRI markers are included, as well as specific cases of "radiologically isolated syndrome" considered at risk of future relapses.The diagnostic power of the central vein sign, paramagnetic rim lesion, and cortical lesions have been demonstrated in recent lines of research in adult and pediatric patients with MS. The contribution of cortical lesions, slowly expanding lesions, choroid plexus enlargement, paramagnetic rim lesions, leptomeningeal enhancement, in addition to measurement of brain and spinal cord atrophy, have expanded our understanding of early disease progression. This review highlights a selection of recent studies that have significantly contributed to increase the accuracy of MS diagnosis in both pediatric and adult patients, and demonstrated the potential to improve the early detection of disease progression.

To review novel multiple sclerosis (MS) therapies currently in clinical trials. Sixty-seven clinical trials were selected and grouped into the following categories: Bruton's tyrosine kinase inhibitors, remyelinating therapies, immunomodulators, B cell therapies, supplements/microbiome influencers, and cell-directed therapies. Important findings include tolebrutinib's successful trial in nonrelapsing secondary progressive MS that slowed CDP compared to placebo and simvastatin's failure to show an effect on disability in its phase 3 trial. Multiple strategies are being investigated in MS to address progressive disability, myelin repair, neural protection and treatment refractory disease. Some of these strategies have successfully completed clinical trials giving hope that some of the most vexing aspects of MS will soon have new treatment options.

This comprehensive overview summarized the latest advances of multiple sclerosis (MS) in China, including the diagnostic and treatment challenges, research and future directions under health policy recommendations. Given the rising prevalence of MS in China during the past decades, it has emerged as a significant public health concern due to the extensive population and pronounced disparities between urban and rural areas. The clinical manifestations of MS patients in China can be various due to the nation's diversity and evolving environmental factors. Advances in diagnostic practices, including the advances under 7T MRI radiological assessments, have enhanced the precision of MS diagnosis. Despite the introduction of disease-modifying therapeutic agents and the support of healthcare policies offering patients a wider range of treatment options, multiple ongoing research efforts and clinical trials will provide additional evidence. The ongoing China National Registry of Neuro-Inflammatory Diseases study (NCT05154370) holds promise for further enhancing the management of MS patients in China. Improved recognition and management of MS in China have been facilitated, encompassing both prompt diagnosis and diverse treatment options. Simultaneously, research efforts and large-scale cohort studies have significantly advanced the overall status in this field.

To summarize recent advancements in understanding multiple sclerosis (MS) pathophysiology, predicting disease course, and monitoring treatment responses using MRI. Paramagnetic rim lesions (PRLs) are highly specific to MS and clinically relevant. Detected from the earliest disease phases, PRLs aid in distinguishing MS from other conditions, improving diagnostic accuracy. Moreover, PRLs are associated with more severe disability and measures of brain damage and may predict disease progression. Similarly, slowly expanding lesions (SELs) are associated with more severe disability and predict a more severe disease course. Disease-modifying therapies have limited effectiveness in reducing PRLs or SELs. Choroid plexus (CP) enlargement is associated with structural brain damage and clinical disability and predicts disease evolution. Enlarged perivascular spaces (ePVS) suggest microangiopathic changes rather than direct MS-related inflammation. Glymphatic dysfunction, evaluated using diffusion tensor image analysis along the perivascular space, emerges early in MS and correlates with disability, cognitive impairment, and structural brain damage. Aging and comorbidities exacerbate MS-related damage, complicating diagnosis and treatment. Emerging technologies, such as brain-age paradigms, aim to disentangle aging from MS-specific neurodegeneration. Advances in MRI have highlighted the clinical significance of chronic inflammation and glymphatic dysfunction as early contributors to MS progression as well as the interplay between aging, comorbidities and MS.