Cephalalgia最新文献

BackgroundMany patients with medically-refractory trigeminal neuralgia (TN) fail to achieve lasting pain relief following surgery targeting the trigeminal nerve (cranial nerve five; CNV). While some studies using MRI diffusion tensor imaging (DTI) suggest that preoperative CNV microstructure may predict surgical response, the findings remain inconsistent. Furthermore, the relationship between post-surgical CNV microstructural changes and long-term pain relief is not well understood. Using a novel CNV-nerve specific DTI protocol, the present study aimed to determine whether: (1) preoperative CNV microstructure differentiates surgical responders from non-responders and (2) sustained pain relief after surgery is associated with distinct postoperative microstructural changes in CNV.MethodsWe conducted a single-centre, prospective, longitudinal study in TN patients undergoing microvascular decompression (MVD) or percutaneous rhizotomy by balloon compression (BC). Patients underwent preoperative and postoperative (one week, one month, six months and one year) high-resolution DTI scanning of CNV using a novel fluid-attenuated inversion recovery DTI protocol. Healthy controls (HC) were scanned at a single timepoint using the same protocol. CNV microstructure was inferred primarily from fractional anisotropy (FA), supplemented with other diffusion metrics. Responders were defined as patients with immediate and complete pain relief (Barrow Neurological Institute facial pain scale I or IIIa) sustained for at least two years.ResultsThirty-five TN patients (22 MVD and 13 BC) and 19 HC were studied. There was no difference in FA between HC CNV and affected ipsilateral or unaffected contralateral CNV in TN patients. However, CNV ipsilateral to the painful side of the face showed microstructural alteration in the form of reduced FA compared to the contralateral, unaffected CNV (0.45 vs. 0.49, p = 0.0017). This was largely driven by eventual surgical responders (n = 18, FA ipsilateral 0.45 vs. contralateral 0.49, p = 0.049), whereas non-responders (n = 17) showed no such difference (p = 0.15). Following surgery, responders showed early reduction in ipsilateral CNV FA by one month (0.45 vs. 0.38, p = 0.013), sustained at six months (0.38, p = 0.021) and one year (0.37, p = 0.006). The same pattern was observed for MVD and BC responders. Conversely, non-responders exhibited no significant postoperative CNV FA change. Postoperative pain-free timepoints were associated with significantly lower ipsilateral CNV FA compared to painful states or HC on average (0.39 vs. 0.45 or 0.47, p < 0.0001) and in individual patients experiencing multiple pain recurrences after repeat operations.ConclusionsLong-term pain relief after TN surgery requires the induction of specific and sustained microstructural changes in the treated CNV, irrespective of surgical modality.

Visual snow syndrome (VSS) manifests as continuous, fine-grained visual static that is often accompanied by other visual symptoms. Its frequent association with migraine, particularly migraine with aura (MwA), has prompted debate regarding a shared pathogenic substrate. To interrogate this relationship, we performed a narrative review of clinical, neuroimaging and electrophysiological studies on VSS and MwA. The clinical picture of VSS is a persistent phenomenon that does not fluctuate with the migraine cycle and shows no response to therapeutics established to be useful in migraine. Moreover, structural and functional neuroimaging in VSS consistently demonstrates selective abnormalities within primary visual, salience and attentional networks, paralleled by distinctive evidence of glutamatergic dysregulation and impaired top-down suppression in electrophysiological recordings. Collectively, the available evidence supports VSS as a discrete disorder marked by aberrant salience assignment and impaired sensory gating, with clinical features and pathophysiology that are separate from those of MwA. While features such as shared serotonergic dysregulation, involvement of comparable cortical territories and high comorbidity suggest overlap between MwA and VSS, these similarities are likely better attributed to a shared predisposition for increased cortical excitability than to a single nosological entity. Future research aiming to characterize further network abnormalities in VSS will be pivotal for guiding the development of targeted therapies.

Migraine is a complex neurological disorder involving multiple neuropeptides that modulate nociceptive and sensory pathways. The most studied peptide is calcitonin gene-related peptide (CGRP), which is a well-established migraine trigger and therapeutic target. Recently, another peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has emerged as an alternative target for migraine therapeutics. This review compares the roles of PACAP and CGRP in preclinical mouse models of migraine. PACAP shares similarities with CGRP, and both are expressed in peripheral and central migraine-relevant regions. However, CGRP is more abundant in the trigeminal pain system, whereas PACAP is more prominent in parasympathetic ganglia that may contribute to autonomic aspects of migraine. PACAP and CGRP act on receptors that can activate overlapping but distinct intracellular signaling pathways. While both peptides elevate cAMP levels to activate protein kinase A, PACAP is more effective than CGRP at engaging an alternative cAMP pathway involving small G proteins, as well as Gq-mediated calcium pathways. Moreover, PACAP and CGRP induce similar migraine-like behaviors in mice, including cephalic and plantar mechanical allodynia, photophobia and non-evoked pain, but they do so by largely independent pathways. Notably, PACAP-mediated photophobia and mechanical allodynia symptoms are not blocked by CGRP-targeted therapies in mice. Finally, we discuss how preclinical PACAP and CGRP studies have translated to the clinic, with the exception of a PACAP type I receptor monoclonal antibody. Overall, CGRP and PACAP are likely to act by parallel and non-redundant roles in migraine pathophysiology, which suggests that a combined targeting of CGRP and PACAP may offer a more effective strategy for treating migraine.

AimPrimary headache disorders such as migraine and tension-type headache are highly prevalent in military populations and may severely impact operational performance and readiness. Despite this, data from many European armed forces are lacking. This study investigates headache phenotypes, diagnosis, treatment and functional impairment in active-duty personnel of a major European military organization.MethodsThis cross-sectional cohort study utilized an anonymous 33-item online questionnaire distributed across military medical centers in Germany between May and July 2023. The survey assessed demographics, headache types according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), diagnostic awareness, treatment history and headache-related disability using the Migraine Disability Assessment Score (MIDAS).ResultsOf the 1189 participants, 914 (77%) completed the survey. Among them, 839 (94.9%) reported experiencing headaches in the past 12 months. Based on ICHD-3 criteria, 227 individuals (27.1%) met the complete set of criteria for migraine, while 246 (29.2%) were classified as probable migraine. Tension-type headache was reported by 222 respondents (26.5%), and cluster headache was resported by 34 (4.1%). Notably, 61.4% of participants had never received a formal diagnosis and only 38.6% had ever sought medical care for their headaches. Functional impairment was substantial: 63.8% reported losing at least one workday in the past three months due to headache. Among those with migraine, an average of 3.9 workdays per month were lost. Despite this burden, only 27.3% of individuals with migraine had ever used preventive medication.ConclusionsPrimary headache disorders are common, underdiagnosed and inadequately treated in this military population, leading to significant functional and operational impairment. Our findings underscore the urgent need for improved screening, diagnosis and evidence-based treatment strategies in uniformed health systems. The results may inform similar efforts in other military and high-demand occupational settings.

Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silentlyWe propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0-20 minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.

AimDespite its frequency in tertiary headache centers, the International Classification of Headache Disorders, 3rd edition (ICHD-3) does not include refractory migraine. Multiple definitions have been proposed with a recent 2020 proposal for both refractory migraine and resistant migraine by the European Headache Federation (EHF). The aim is to reach an international consensus on the definition of refractory migraine.MethodsThis study is a Delphi consensus carried out by a group of international experts in headache medicine. Following a focus group, a panel of 20 experts and one facilitator reviewed the EHF proposed criteria to build upon their definitions. The Delphi consensus was conducted across five rounds. Questions with >70% consensus were deemed to have strong agreement, 60-70% consensus was deemed minor agreement, and <60% deemed no agreement. A final meeting was held to discuss any concerns and specific wording.ResultsThe Delphi consensus led to the development of four key categories: refractory migraine, probable refractory migraine, resistant migraine, and treatment-responsive migraine. Similar to the EHF 2020 definitions, refractory migraine requires treatment failure of all evidence-based classes, and resistant migraine requires failure of at least three classes. Probable refractory migraine criteria were designed to account for situations where treatment access barriers may prevent trials of certain medication classes (e.g. pediatrics, low to middle-income countries, lack of insurance coverage). Finally, treatment-responsive migraine criteria were developed to allow for standardization in research studies comparing refractory or resistant migraine to migraine that is treatment-responsive.ConclusionsThese four categories may aid in enrollment for studies on pathophysiology, biomarkers, and new treatment targets. Clinically, the criteria for refractory and resistant migraine will help with clinical decision-making by reinforcing the need to try evidence-based treatments and by providing guidance regarding when to try more aggressive treatment approaches. These criteria may also increase attention to this population's disease burden to help advocate for them as a specific migraine subgroup. Field testing in diverse clinical settings will be needed, but it is recommended that ICHD-3 considers inclusion of these four categories in their appendix.

BackgroundPeople with high-frequency episodic migraine or chronic migraine may have resistant or refractory forms. The lack of efficacy of pharmacologic therapies is a major clinical challenge that requires alternative strategies, including neuromodulation and exploration of new targets to improve disease management. The present study aimed to test the effectiveness of an accelerated protocol of theta burst stimulation (iTBS) via the dorso lateral prefrontal cortex (DLPFC) in a group of chronic migraine individuals who did not respond to monoclonal antibodies against calcitonin gene-related peptide (CGRP). The co-primary outcomes were the reduction in monthly headache frequency, use of symptomatic medication and perceived pain intensity. In parallel we wanted to understand the possible role of the prefrontal cortex in the emotional and cognitive functions likely responsible for treatment failure and to offer a possible non-pharmacologic option to individuals with difficult-to-treat migraine. To this end, we measured clinical outcomes along with an electroencephalogram (EEG) and behavioral responses to cognitive and emotional tests related to prefrontal functions.MethodsThis study was conducted in a controlled, single-blind design in 12 people with chronic refractory migraine. An accelerated protocol of iTBS on DLPFC was preceded by a sham session and followed by a two-month follow-up. Clinical data were collected and a neuropsychological assessment including anxiety, depression and cognitive profile was performed. Cognitive and emotional Stroop testing was performed at baseline, after sham and real stimulation, and at follow-up during high-density EEG recording to obtain event-related potentials (N2, N400 and late sustained potential (LP)). Stroop data from an age- and sex-matched control group were compared with those of migraine individuals.ResultsMonthly headache days, monthly medication days and headache intensity improved after real stimulation. A similar trend emerged for anxiety, depression, and cognitive performance. The Stroop test was impaired in the baseline, as evidenced by an increase in reaction time and a decrease in N2 and LP in the cognitive task, which returned to normal after real iTBS and at follow-up.ConclusionsThe results support the efficacy of iTBS as a non-invasive neuromodulation approach for the treatment of chronic, refractory migraine. They tentatively point to the role of cognitive fog and psychopathological symptoms in refractoriness to anti-CGRP drugs, which should be confirmed in larger multicenter studies, and suggest this non-pharmacological approach as another promising therapeutic option for people with difficult-to-treat migraine.

BackgroundAtogepant is an oral calcitonin gene-related peptide receptor antagonist approved in the US and EU for the preventive treatment of migraine in adults. We evaluated the efficacy, safety, and tolerability of atogepant for the preventive treatment of episodic migraine (EM) in Japanese participants.MethodsRELEASE was a phase 2/3, multicenter, randomized, double-blind, placebo-controlled study enrolling adult participants with a ≥1-year history of migraine, <50 years of age at time of migraine onset, history of 4-14 monthly migraine days (MMDs), and <15 monthly headache days in the three months prior to screening and during the screening/baseline period. The study included a four-week screening/baseline period, 12-week double-blind treatment period (DBTP), 12-week active treatment extension period, and 30-day safety follow-up. Participants were randomized 1:1:1:1 to placebo, atogepant 10 mg once daily (QD), 30 mg QD, or 60 mg QD for the 12-week DBTP. Completers of the DBTP could continue to the 12-week active treatment extension period where the placebo group was rerandomized 1:1:1 to atogepant 10 mg, 30 mg, or 60 mg; atogepant groups continued the same dose. The primary endpoint was the change from baseline in mean MMDs across the 12-week DBTP.ResultsOf 807 participants screened, 523 were treated in the 12-week DBTP (Safety Population 1 [placebo, N = 134; atogepant 10 mg, N = 126; 30 mg, N = 131; 60 mg, N = 132]; modified intent-to-treat population [placebo, N = 133; atogepant 10 mg, N = 127; 30 mg, N = 130; 60 mg, N = 131]). The least square mean difference (95% confidence interval) from placebo in mean MMDs across 12 weeks was -1.57 (-2.24, -0.89) for atogepant 10 mg, -1.90 (-2.57, -1.22) for 30 mg, and -2.10 (-2.78, -1.43) for 60 mg (all p < 0.0001). Treatment-emergent adverse events (TEAEs) in the DBTP occurred in 46.3%, 45.2%, 38.9%, and 43.2% of participants receiving placebo, atogepant 10 mg, 30 mg and 60 mg, respectively. During the DBTP, TEAEs occurring ≥5% were constipation and nasopharyngitis, and there was one serious TEAE in the atogepant 10 mg group considered not related to treatment. TEAEs resulting in treatment discontinuation were infrequent in all treatment groups in the DBTP. Safety was consistent in the 12-week active treatment extension period.ConclusionsAtogepant treatment demonstrated statistically significant and clinically meaningful reductions in mean MMDs compared with placebo across the 12-week DBTP in Japanese participants with EM. The safety profile of atogepant in Japanese participants was consistent with the known safety profile in the global population. No new safety signals were identified.Trial registrationClinicalTrials.gov NCT05861427; https://clinicaltrials.gov/study/NCT05861427.

IntroductionTypical migraine aura is characterized by transient focal neurologic symptoms, visual, sensory, dysphasic or other higher cortical dysfunctions. Their manifestations are multi-faceted, with inter and intra-variability.ObjectiveTo provide a narrative review describing contributions that assist in achieving a precise phenotypic classification of migraine aura.MethodsWe conducted a comprehensive review of the literature to identify and analyze the full spectrum of migraine aura variables. Based on the findings, we proposed a prospective diary model for systematically recording these elements in clinical or research settings.ResultsVisual symptoms are the most multifaceted with many peculiarities such as quality (26 elementary visual symptoms have been described), colour, intermittence, localization and laterality in visual field and direction of spreading. Sensory and dysphasic symptoms have lower level of complexity. The combinations of symptoms, such as their time relationships or duration, are also extremely variable. Furthermore, headache can have five different patterns of presentation with respect to aura onset/end. Higher cortical dysfunctions need to be further investigated in wider populations. After collecting the full spectrum of migraine aura features, we created a diary which we propose can prospectively record those variables.ConclusionThe findings of this review show that migraine auras present a wide and multi-faceted spectrum of symptoms, generating hundreds of possible scenarios. Therefore, a detailed aura diary to complete during attacks will be of utmost importance to move toward a precise phenotypic classification.

Temporomandibular disorders (TMDs) and migraine are highly prevalent, overlapping pain conditions that cause considerable burden in the population. These two disorders are of different etiology and pathophysiology, but both are mediated by the trigeminal system. Due to the interrelated anatomy and physiology of the craniofacial and cervical structures, shared molecular links and mutual feedback, there is an inherent potential for exacerbation of symptomatology, perpetuation and progression; however, on a positive note, there is good potential for developing integrated, mutually beneficial management protocols when migraine and TMDs are comorbid. Currently, there are no established protocols of management, and the literature is limited in studies exploring dual therapeutic protocols. So, the question is, how can management be optimized with the evidence available? We should start by recognizing the need for multidisciplinary management to improve patient outcomes and we must highlight the importance of the dialogue between headache medicine and dentistry. The meeting point is where the dental discipline and the specialty of orofacial pain reside. The underlying pathophysiology of this comorbidity points to the need to decrease mutual exacerbation inputs. Therefore, it is fundamental to identify contributing factors of potential sensitization, such as the presence of parafunctional behaviors, cervical spine contributors, the presence of other comorbidities and headache hygiene. Current evidence supports management recommendations that should be developed by a multidisciplinary team as an integrated plan with combination therapy including both pharmacological and non-pharmacological approaches to optimize management. This multidisciplinary team should include the medical provider (neurologist/headache medicine expertise), the dentist specialized in orofacial pain, the physical therapist and the behavioral medicine specialist. Research is needed to support evidence-based integrated protocols for the management of comorbid migraine and TMDs. Evidence has shown that calcitonin gene-related peptide (CGRP) is also involved in TMDs. CGRP-targeting therapies may hold future opportunities for pharmacological monotherapy addressing this comorbidity.