Cephalalgia最新文献

Background: The anti-calcitonin gene-related peptide (CGRP), or its receptor (CGRP/R) monoclonal antibodies (mAbs), offer targeted, effective, and tolerated drugs for migraine. However, about 25% of patients fail to achieve a clinically meaningful response, usually leading to discontinuation. These patients often have a lengthy migraine history and multiple prior preventive treatment failures, resulting in limited therapeutic options. Herein, we describe the cause for and outcome of withdrawal of anti-CGRP/R mAb and evaluate the treatment course until discontinuation.

Methods: We conducted a prospective analysis on migraine patients attending the Florence Headache Center in Italy, who discontinued treatment with anti-CGRP/R mAbs. The primary objectives were to describe the reasons for anti-CGRP mAbs discontinuation and the treatment course. Secondary objectives were the evaluation of the absolute change from baseline in monthly headache days, response rates, persistence in medication overuse, absolute change from baseline of the overall number and days of analgesics use per month, change of MIDAS and HIT-6 at three, six, and 12 months, and the last month of treatment.

Results: Among 472 patients, 136 (28.8%) discontinued mAb treatment after an average of 9.0 ± 6.1 (mean ± SD) months. The majority (96/136, 70.6%) discontinued due to ineffectiveness, followed by lost to follow-up during treatment (18/136, 13.1%) and adverse events (10/136, 7.3%). In total, 77.9% of the 136 patients ceased treatment within the first year. Following discontinuation, 48.5% initiated new pharmacological treatment, 39.7% were lost to follow-up, and 11.8% opted not to start another treatment. The majority of patients that started a new pharmacology treatment switched to another anti-CGRP/R (46/68, 67.6%). The second most-used treatment was onabotulinumtoxinA (7/68, 10.2%; all patients in this subgroup were naïve to this treatment), followed by an anticonvulsive medication (7/68, 10.2%). The response status (≥50% reduction in monthly headache days) was achieved by 30.5%, 34.6%, and 40.0% of patients at month 3, 6, and 12 of treatment, respectively. Considering only the comprehensive last month of treatment before withdrawn the percentage of responders was 16.9%.

Conclusion: Although anti-CGRP/R mAbs have provided a substantial amelioration of migraine management, a relevant proportion of patients remains unresponsive and requires additional therapeutic support. Further research is required to identify non-responder features and address unmet needs in migraine treatment.

The migraine treatment landscape has seen significant advancements in recent years, including the introduction of novel preventive agents specifically targeting the disease. These new treatments offer improved efficacy and tolerability, potentially addressing the issue of poor treatment adherence commonly observed with conventional preventatives. In this context, pragmatic trials emerge as a critical tool for advancing migraine care, offering a real-world approach to evaluating open clinical questions at the same time as avoiding the biases of real-world observational evidence. By prioritizing external validity and patient-centered outcomes, pragmatic trials provide valuable insights into the advantages of new treatments in improving migraine care. Possible applications of pragmatic trials in migraine research include head-to-head comparisons, evaluation of combination therapies, assessment of treatment sequences and switch, testing the added value of patient-reported outcomes, investigation of long-term effectiveness and on optimal treatment duration, understanding the role of preventive treatments in altering the course of migraine and preventing progression, and cost-effectiveness analyses. Pragmatic trials allow for the assessment of interventions in diverse patient populations and healthcare settings, enhancing the generalizability of findings and informing evidence-based clinical practice. As such, pragmatic trials represent an excellent tool to bridge the gap between placebo-controlled trials and real-world practice and should receive consideration for funding, especially by public institutions such as universities, national health services, and charities.

Background: Medication overuse headache is a prevalent secondary headache due to the overuse of analgesics, mainly over-the-counter analgesics. Over-the-counter analgesics have been associated with disrupted male endocrinology, while the effects on female endocrinology remain nearly unknown. The aim was to understand the effect of long-term analgesic exposure in females with medication overuse headache on Anti-Müllerian hormone, a surrogate measure of female fertility.

Methods: Using a translational approach, an observational prospective clinical study was conducted to determine the effect of withdrawal therapy in females with medication overuse headache on Anti-Müllerian hormone levels, in combination with pre-clinical investigation of primary granulosa cells to understand the effects of analgesics on granulosa cell function.

Results: We included 21 females (mean-age 30.0 years; SD (7.3)) for Anti-Müllerian hormone -measurement. Anti-Müllerian Hormone increased by 21% from baseline (mean 20.1 pmol/L; SD (8.7)) after withdrawal of analgesics ((mean 24.3 pmol/L; SD (12.0)); p = 0.0023). Exposing primary granulosa cells to analgesics (acetaminophen (100 and 200 µM, n = 9-10) and ibuprofen (150 and 200 µM, n = 12-13)) did not reduce Anti-Müllerian hormone levels. In contrast, de novo DNA synthesis in GCs (n = 6) exposed to acetaminophen was reduced by 78% (p = 0.0036) compared to controls, suggesting that cellular proliferation was restricted.

Conclusion: We found that frequent use of over-the-counter analgesics was associated with repressed Anti-Müllerian Hormone levels, likely through disruption of granulosa cell proliferation. Further research is crucial to investigate a potential effect of analgesics on adult female reproductive endocrinology.Trial registration: ClinicalTrials.gov Identifier NCT04090333.

Background: Time in headache disorders is crucial for diagnosis and gives insight into headache pathophysiology.

Objective: To summarize published studies which describe timing processes in both attack presentation (onset, duration) and disease characterization (age of onset, evolution over time) in primary headache disorders and link to pathophysiology.

Methods: A comprehensive search was conducted through Ovid MEDLINE(R) and PubMed, focusing on English-language articles from 1946 to 2023 to write the review. The International Classification of Headache Disorders, 3rd edition provided the framework for the review of primary headache disorders (migraine, tension-type headache and cluster headache).

Results: Attack presentation: Migraine attacks exhibit significant circadian and infradian rhythms, influenced by hormonal levels, light sensitivity, and hypothalamic activation. Tension-type headache lacks clear chronobiological patterns, with limited understanding of its underlying mechanisms. Cluster headache displays a distinct circannual pattern, with attacks often occurring at night and relevant involvement of the hypothalamus. Disease characterization: Age of onset exhibits the earliest peak in migraine; frequency and typical features of primary headache disorders decrease over time.

Conclusion: This comprehensive analysis of time patterns in primary headache disorders underscores their role in phenotyping, understanding and treating primary headache disorders, offering promising avenues for advancing and tailoring headache management.

Background: In this study, we aimed to evaluate the differing global access to acute and preventive medications for migraine and tension-type headache.

Methods: A custom-built questionnaire created by members of the International Headache Society Juniors Group was sent to International Headache Society members worldwide, including a list of acute and preventive treatments for migraine and tension-type headache. This list was based on evidence-based medicine guidelines. For each treatment, participants were asked about availability, type of reimbursement and variability of access within their country.

Results: Eighty-four members completed the questionnaire providing data for 84 countries. The majority were neurologists (88%) and worked at an academic/university hospital (62%). Of participants, 36% were located in high-income economy countries and 13% were located in low-income economies. Common preventive treatments such as propranolol and topiramate were available in most countries (respectively in 99% and 92% of responding countries). Sumatriptan was available in most countries (95%), whereas other triptan availability was lower. Novel migraine treatments such as rimegepant and erenumab were only available in 14% and 46% of the assessed countries, respectively.

Conclusions: Availability of headache medications, ranging from simple analgesics to novel therapies migraine-specific drugs, varied greatly across the world. Actions are needed to improve effective drug availability in many countries to ensure an adequate management of people living with headache.

Background: To evaluate the benefit-risk assessment of atogepant and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) vs. placebo based on the number needed to treat (NNT) and the number needed to harm (NNH) in a blended episodic migraine and chronic migraine (EM + CM) population.

Methods: The NNT was calculated based on achievement of a ≥ 50% reduction in mean monthly migraine days (MMDs) from baseline across 12 weeks. The NNH was calculated using the proportion of participants reporting a discontinuation due to adverse events (AEs). The primary analysis included data from studies of atogepant, erenumab, galcanezumab, eptinezumab and fremanezumab.

Results: In the primary analysis, the calculated NNT for atogepant 60 mg vs. placebo was 4.2 (95% credible interval (CrI) = 3.1-6.7), which was the lowest relative to the CGRP mAbs in the blended EM + CM population. Participants who received atogepant 60 mg or fremanezumab showed the most favorable NNH values (-1010 (95% Crl = 44 to ∞ to number needed to benefit 80) for atogepant) resulting from lower rates of discontinuation due to AEs compared with those receiving placebo.

Conclusions: Atogepant demonstrated a favorable benefit-risk profile, with NNT and NNH values comparable (not statistically significant) with those of CGRP mAbs across all analyses.

Background: There are currently no intraoperative neurophysiological tools to assess the effectiveness of trigeminal nerve decompression during microvascular decompression surgery for drug-resistant trigeminal neuralgia. In microvascular decompression surgery for hemifacial spasm, an abnormal electromyographic activation of facial muscles after stimulation of the offending vessel was identified and named 'Z-L response'.

Methods: We adapted a neurophysiological protocol to elicit a Z-L response during microvascular decompression surgery for trigeminal neuralgia and applied it to a prospective series of 18 surgical patients.

Results: Patients had suffered from trigeminal neuralgia for a median 9-year timeframe, and median preoperative Barrow Neurological Institute pain score was 4.5. Through monopolar stimulation, using rising amplitudes starting from 0.1 mA, we confirmed intraoperatively the true culprit vessel before decompression. In 4/18 cases, multiple offending vessels were identified (22 conflicts overall). After decompression, a significant increase in activation threshold (p < 0.0001) confirmed the effectiveness of the maneuver; in 10 cases, Z-L response was abolished. Using this technique, we obtained excellent or good outcome (Barrow Neurological Institute 1-3) in all patients, with a significant reduction in postoperative Barrow Neurological Institute score as compared with preoperative one (median Barrow Neurological Institute 1; p = 0.0002).

Conclusion: we provide the first evidence on the applicability and clinical usefulness of Z-L response during microvascular decompression surgery for trigeminal neuralgia.

Background: Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants linked with migraine risk. Surprisingly, some of the most common mutations are associated with transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel that is the primary sensor of cold temperatures in cutaneous primary afferents of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 is relevant in migraine-related tissues, such as the meninges, suggesting other activation mechanisms underly its role in migraine pathogenesis. Thus, to define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor glial cell-line derived neurotrophic factor family receptor alpha-3 (GFRα3), also mediate TRPM8-associated migraine-like pain in the meninges.

Methods: To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in mice lacking GFRα3 we tested the effects of supradural infusions of a mix of inflammatory mediators, as well as tested if dura stimulation with artemin or a TRPM8-specific agonist induce migraine-related pain in mice.

Results: We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway in headaches. Further, we show TRPM8 expression in the meninges, and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, with the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan.

Conclusions: These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to headaches or migraine pathogenesis.

Background: Migraine with aura (MWA) is a risk factor for stroke, but the mechanisms underlying this association remain unclear. Our aim was to assess the association between MWA and cerebral small-vessel disease (CSVD) ischemic stroke after adjustment for vascular risk factors in a population of young patients hospitalized for a first-ever ischemic stroke.

Methods: Patients aged 18-54 years consecutively hospitalized for a first-ever acute ischemic stroke at the neurovascular unit of our university hospital between January 2017 and July 2021 were included in this retrospective cohort study. CSVD lesions were assessed and classified according to ASCOD (Atherosclerosis, Small-Vessel Disease, Cardiac pathology, Others causes, Dissection) classification criteria.

Results: In total, 646 patients were included (median (SD) age, 44.03 (9.01) years; 61.8% male) including 115 patients with MWA and 110 patients with migraine without aura (MWoA). Grade S1, potentially causal, CSVD lesions were significantly less frequent in patients with MWA (odds ratio (OR) = 0.35, 95% cofdence interval (CI)  =  0.13-0.95, p = 0.048) compared to non-migraine patients in univariate analysis. Logistic regression adjusting for vascular risk factors showed no significant association of CSVD of any grade (S1, S2 or S3 vs. S0) with migraine: OR = 0.78, 95% CI = 0.48-1.28, p = 0.34; MWoA: OR = 0.81, 95% CI = 0.42-1.47, p = 0.51; and MWA: OR = 0.84, 95% CI = 0.43-1.56, p = 0.60, as well as no association of grade S1 CSVD lesions with migraine: OR = 0.91, 95% CI = 0.40-1.92, p = 0.81; MWoA: OR = 1.11, 95% CI = 0.42-2.64, p = 0.81; and MWA: OR = 0.72, 95% CI = 0.20-1.98, p = 0.56.

Conclusions: In a retrospective study including almost 650 young adults hospitalized for a first ischemic stroke, MWA was not associated with CSVD cause of stroke after adjustment for vascular risk factors.