Current Opinion in Neurology最新文献

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: 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 findings: 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.

Summary: 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.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: Paroxysmal hemicrania and hemicrania continua are rare primary headache disorders which are distinguished by an absolute response to indomethacin. As a matter of importance, no guidelines have been proposed for alternative therapeutic options in case of indomethacin intolerance. The purpose of this review is to provide an update on the current findings, especially focusing on the past 18 months, in the treatment of both paroxysmal hemicrania and hemicrania continua and to provide proposed management recommendations based on summarized evidence.

Recent findings: Apart from well recognized gastrolesive effects of indomethacin, a substantial number of patients may suffer from neuropsychiatric adverse reactions. Recent studies demonstrated that melatonin, which has been known for its effectiveness for hemicrania continua, is also useful for paroxysmal hemicrania. Promising nonpharmacological treatment option, which is noninvasive vagus nerve stimulation, has been shown to be beneficial for both indomethacin-responsive headache disorders allowing the reduction of indomethacin dosage. Although the data on substitutive medication choice for indomethacin are currently scarce, the most consistent results have been repeatedly achieved with acemethacin, selective COX-2 inhibitors, and anticonvulsants. However, considering the crucial role of pathophysiology, research investigating the efficacy of drugs targeting the trigemino-vascular system activation, as well as controlled trials assessing the efficacy involving the aforementioned therapeutic options are still vague.

Summary: In spite of numerous reports suggesting reliable alternatives to indomethacin, the consensus on pharmacological therapy guidelines for indomethacin-responsive headache disorders has not yet been reached. Further research and agreement from the experts' standpoint are needed for an establishment of reliable treatment recommendations.

Purpose of review: This review explores the phenomenology, pathogenesis, and nosology of headaches associated with infections, an often-overlooked yet clinically significant symptom. With the increasing recognition of secondary headaches in infections, understanding their clinical patterns, mechanisms, and classifications is crucial for accurate diagnosis and management.

Recent findings: Headaches in infections are ubiquitous but vary in presentation, severity, and underlying mechanisms depending on the causative pathogen. Elevated intracranial pressure, meningeal irritation, and activation of the trigeminovascular system are key contributors to headache generation, which varies depending on each pathogen. Pathogen-specific predilection for one of these mechanisms may subtly alter the clinical phenotype of the headache, which can be used to guide management. Emerging evidence highlights postinfectious headache syndromes, particularly following bacterial meningitis and SARS-CoV-2 infection, underscoring the need for long-term follow-up in these patients.

Summary: The diverse presentations of infection-related headaches necessitate a systematic approach to evaluation and management. While the pathophysiology is complex and multifaceted, understanding these mechanisms aids in differentiating primary headaches from those secondary to infections.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: To summarize recent advancements in understanding multiple sclerosis (MS) pathophysiology, predicting disease course, and monitoring treatment responses using MRI.

Recent findings: 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.

Summary: 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.