Monoclonal antibodies targeting the calcitonin gene-related peptide pathway improve the effectiveness of acute medication-a real-world study.

BACKGROUND: One of the aims of migraine prevention is to improve response to acute migraine treatments. The aim of the present study was to assess whether monoclonal antibodies targeting the CGRP pathway (CGRP-mAbs) can improve the perceived efficacy of acute treatments. METHODS: We included and followed up patients with chronic or episodic migraine from the Headache Centers of Avezzano-L'Aquila and Naples treated with CGRP-mAbs from March 2021 to December 2022. All patients filled out the Migraine Treatment Optimization Questionnaire (MTOQ), the Headache Impact Test (HIT-6), and the Migraine Impact and Disability Assessment Scale (MIDAS) at baseline and 3-6 months after the start of treatment with CGRP-mAbs. RESULTS: Sixty-five patients (81.3%) completed the 6-month follow-up. Most patients were female (55, 84.6%), with a median age of 46 years (IQR 39-56). Median MTOQ score increased from 8 (interquartile range [IQR] 4-13) at baseline to 15 (IQR 11-17) at 3 months (p < 0.001) and 16 (IQR 13-17) at the 6-month follow-up (p < 0.001). Median migraine days over 90-day periods decreased from 40 (IQR 24-60) to 24 (IQR 15-30) at 3 months (p < 0.001) and to 20 (IQR 12-24) at 6 months (p < 0.001). Median monthly intake of acute medication decreased from 55 doses (IQR 29-80.5) to 24 doses (IQR 15-40) at 3 months and 18 doses (IQR 11-30) at 6 months (p < 0.001). CONCLUSIONS: We showed that 6 months of preventive treatment with CGRP-mAbs led to a significantly better effectiveness of acute treatments, paralleled by decreased monthly migraine days and acute treatment intake.

Resting-state network connectivity changes in drug-naive Parkinson's disease patients with probable REM sleep behavior disorder.

Epidemiological studies have shown that Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) present an increased risk of worse cognitive progression over the disease course. The aim of this study was to investigate, using resting-state functional MRI (RS-fMRI), the functional connectivity (FC) changes associated with the presence of pRBD in a cohort of newly diagnosed, drug-naive and cognitively unimpaired PD patients compared to healthy controls (HC). Fifty-six drug-naïve patients (25 PD-pRBD+ and 31 PD-pRBD-) and 23 HC underwent both RS-fMRI and clinical assessment. Single-subject and group-level independent component analysis was used to analyze intra- and inter-network FC differences within the major large-scale neurocognitive networks, namely the default mode (DMN), frontoparietal (FPN), salience (SN) and executive-control (ECN) networks. Widespread FC changes were found within the most relevant neurocognitive networks in PD patients compared to HC. Moreover, PD-pRBD+ patients showed abnormal intrinsic FC within the DMN, ECN and SN compared to PD-pRBD-. Finally, PD-pRBD+ patients showed functional decoupling between left and right FPN. In the present study, we revealed that FC changes within the most relevant neurocognitive networks are already detectable in early drug-naïve PD patients, even in the absence of clinical overt cognitive impairment. These changes are even more evident in PD patients with RBD, potentially leading to profound impairment in cognitive processing and cognitive/behavioral integration, as well as to fronto-striatal maladaptive compensatory mechanisms.

Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials.

INTRODUCTION: Migraine is a leading cause of years lived with disability and preventive strategies represent a mainstay to reduce health-related disability and improve quality of life of migraine patients. Until a few years ago, migraine prevention was based on drugs developed for other clinical indications and relocated in the migraine therapeutic armamentarium, characterized by unfavorable tolerability profiles. The advent of monoclonal antibodies against Calcitonin Gene-Related Peptide (CGRP) and gepants, CGRP receptor antagonists, has been a turning point in migraine prevention owing to advantageous efficacy, safety and tolerability profiles.Nevertheless, while in an ideal scenario a drug characterized by significant greater efficacy and tolerability compared to existing therapeutic strategies should be adopted as a first-line treatment, cost-effectiveness analyses available for monoclonal antibodies against CGRP pathway tend to limit their administration to more severe migraine phenotypes. AREAS COVERED: The present narrative review aims to provide a critical appraisal of phase II and III CGRP-mAbs and gepants trials to analyze their use in clinical practice. EXPERT OPINION: Despite monoclonal antibodies against CGRP pathway and gepants can be undoubtedly considered top-of-the-range treatments, there are still issues deserving to be addressed in the coming years as the risk of off-target effects as well as their economic sustainability based on the considerable migraine burden.

Infodemiology of cluster headache seasonality: A proof of concept by a Google Trends analysis.

BACKGROUND: Cluster headache is commonly reported to follow an annual pattern with a peak in the spring and a second peak in autumn. Patients with headache frequently use search engines, such as Google, to look for terms related to their disease, creating trend data that can be analyzed with Google Trends. Indeed, Google Trends has been used for surveillance studies and can provide indirect estimates of the burden of diseases and symptoms. The present cross-sectional study investigated the seasonality of searches for "cluster headache" in the northern and southern hemispheres using 10 years of Google Trends data. METHODS: The term "cluster headache" or its translation in the 10 most spoken languages in the world was searched on Google Trends to obtain relative search volumes (from 0 to 100), in order to compare variations in searches across periods. Twenty-eight countries were selected according to the following criteria: (1) a relative search volume of >40 for the term for cluster headache; and (2) a population of at least 5 million inhabitants. For statistical purposes, countries were grouped in relation to hemisphere (northern or southern). Relative search volumes were extracted from January 2012 to January 2022 and analyzed according to two subgroups based on meteorological seasons (summer and winter vs. spring and autumn). RESULTS: A seasonal trend for in searches for cluster headache was found worldwide exhibiting higher relative search volumes in spring and autumn compared with summer and winter (17 [0, 39] vs. 13 [0, 37]; p = 0.016). CONCLUSION: Higher search volumes for the term during the meteorological seasons of spring and autumn clearly reflect a circannual pattern of cluster headache occurrence, representing new evidence for its seasonality.

Migraine Treatment: Towards New Pharmacological Targets.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.

Arterial spin labeling MRI applied to migraine: current insights and future perspectives.

INTRODUCTION: Advanced neuroimaging techniques have extensively contributed to elucidate the complex mechanisms underpinning the pathophysiology of migraine, a neurovascular disorder characterized by episodes of headache associated with a constellation of non-pain symptoms. The present manuscript, summarizing the most recent progresses of the arterial spin labelling (ASL) MRI techniques and the most significant findings from ASL studies conducted in migraine, is aimed to clarify how ASL investigations are contributing to the evolving insight on migraine pathophysiology and their putative role in migraine clinical setting. ASL techniques, allowing to quantitatively demonstrate changes in cerebral blood flow (CBF) both during the attacks and in the course of interictal period, could represent the melting point between advanced neuroimaging investigations, conducted with pure scientific purposes, and conventional neuroimaging approaches, employed in the diagnostic decision-making processes. MAIN BODY: Converging ASL evidences have demonstrated that abnormal CBF, exceeding the boundaries of a single vascular territory, with biphasic trend dominated by an initial hypoperfusion (during the aura phenomenon but also in the first part of the headache phase) followed by hyperperfusion, characterizes migraine with aura attack and can represent a valuable clinical tool in the differential diagnosis from acute ischemic strokes and epileptic seizures. Studies conducted during migraine without aura attacks are converging to highlight the involvement of dorsolateral pons and hypothalamus in migraine pathophysiology, albeit not able to disentangle their role as "migraine generators" from mere attack epiphenomenon. Furthermore, ASL findings tend to support the presence of perfusion abnormalities in brain regions known to be involved in aura ignition and propagation as well as in areas involved in multisensory processing, in both patients with migraine with aura and migraine without aura. CONCLUSION: Although ASL studies have dramatically clarified quality and timing of perfusion abnormalities during migraine with aura attacks, the same cannot be said for perfusion changes during migraine attacks without aura and interictal periods. Future studies with more rigorous methodological approaches in terms of study protocol, ASL technique and sample selection and size are mandatory to exploit the possibility of better understanding migraine pathophysiology and identifying neuroimaging biomarkers of each migraine phase in different migraine phenotypes.

Functional connectivity changes in complex migraine aura: beyond the visual network.

BACKGROUND AND PURPOSE: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. METHODS: By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. RESULTS: Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). CONCLUSION: Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.

Validation of new diagnostic criteria for fatigue in patients with Parkinson disease.

BACKGROUND AND PURPOSE: Although disabling fatigue is common in Parkinson disease (PD), available consensus-based diagnostic criteria have not yet been empirically validated. The aim of this study was to evaluate the clinimetric properties of the criteria. METHODS: A sample of outpatients with PD was evaluated for demographic, clinical, behavioral, and cognitive features. Fatigue was diagnosed according to the new diagnostic criteria and was rated by means of the Parkinson Fatigue Scale (PFS) and Fatigue Severity Scale (FSS). Acceptability, concurrent and discriminant validity, and interrater reliability were evaluated with binary logistic regression analyses and Cohen kappa (κ). RESULTS: Of 241 included patients, 17 (7.1%) met the diagnostic criteria for PD-related fatigue. Eight of nine symptoms described in Section A of the diagnostic criteria occurred in >50% of patients with fatigue. Acceptability (missing data = 0.8%) of the criteria was good, as was their concurrent validity with the PFS (odds ratio = 3.65) and FSS (odds ratio = 3.63). The discriminant validity of fatigue criteria with other PD-related behavioral and cognitive features was good (odds ratio < 1.68). The interrater reliability was excellent (κ = 0.92). CONCLUSIONS: This is the first study to test the clinimetric properties of case definition diagnostic criteria for PD-related fatigue. Our results suggest that current diagnostic criteria may be useful in both clinical practice and research. Future longitudinal studies should examine their long-term stability.

Cluster headache pathophysiology: What we have learned from advanced neuroimaging.

BACKGROUND: Although remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations. OBJECTIVE: Although we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model. RESULTS: Advanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH. CONCLUSION: Altogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the "pain matrix," the model of the "neurolimbic pain network" that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus' role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single "generator." Cortical-hypothalamic-brainstem functional interconnections that can switch between out-of-bout and in-bout periods, igniting the trigeminovascular system (probably by means of top-down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the "neuronal background" of CH.

Telemedicine application to headache: a critical review.

BACKGROUND: Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic. OBJECTIVE: This review aims to propose a practical approach for the virtual management of these patients. METHODS: To do this, we conducted a literature search, including 32 articles relevant to the topic treated in this review. RESULTS: The most challenging step in telemedicine applied to practical neurology remains the clinical assessment, but through a careful headache history and a recently proposed entirely virtual neurological assessment, this hitch can be easily overcome. Electronic diary compilations and virtual administration of disability-measuring scales, conversely, are the key features of effective long-term follow-up although we do not have apps that met the criteria of scientific reliability. Furthermore, tele-rehabilitation seems to be effective and has demonstrated to be a solution to alternatively treat chronic patients at home, and can be considered part of the remote management of headache patients. Moreover, virtual management of headaches finds an application in specific communities of patients, as pediatric patients and for rural communities of low- and middle-income countries suffer from health disparities, with inadequate resources and knowledge gaps. CONCLUSION: Telemedicine could be promising for patients with no regular or convenient access to headache specialists and seems to be a priority in managing migraine patients to avoid non-urgent hospitalizations.

Galcanezumab effect on "whole pain burden" and multidimensional outcomes in migraine patients with previous unsuccessful treatments: a real-world experience.

BACKGROUND: Clinical trials have demonstrated galcanezumab as safe and effective in migraine prevention. However, real-life data are still lacking and overlook the impact of galcanezumab on those different migraine facets strongly contributing to migraine burden. Herein we report the clinical experience from an Italian real-world setting using galcanezumab in patients with migraine experiencing previous unsuccessful preventive treatments. METHODS: Forty-three patients with migraine and failure of at least 3 migraine preventive medication classes received monthly galcanezumab 120 mg s.c. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity. Furthermore, validated questionnaires were administered to explore migraine-related disability, impact, and quality of life as well as symptoms of depression or anxiety, pain catastrophizing, sleep quality and the ictal cutaneous allodynia. RESULTS: After the third and the sixth administration of monthly galcanezumab 120 mg s.c., headache attacks frequency reduced from 20.56 to 7.44 and 6.37 headache days per month, respectively. Moreover, a significant improvement in headache pain intensity (from 8.95 to 6.84 and 6.21) and duration (from 9.03 to 3.75 and 2.38) as well as in scores assessing migraine related disability and impact, depressive and anxious symptoms, and pain catastrophizing was observed. Furthermore, we demonstrated a significant reduction in the values of "whole pain burden", a composite score derived from the product of the average of headache frequency, intensity, and duration in the last three months. CONCLUSION: Real-world data support monthly galcanezumab 120 mg s.c. as a safe and effective preventive treatment in reducing headache frequency, intensity, and duration as well as comorbid depressive or anxious symptoms, pain catastrophizing and quality of life in both episodic and chronic migraine patients with previous unsuccessful preventive treatments. Furthermore, we demonstrated that monthly galcanezumab 120 mg s.c. is able to induce a significant improvement in the scores of "whole pain burden". The latter is a reliable and easy-to-handle tool to be employed in clinical setting to evaluate the effectiveness of preventive drugs (in this case, galcanezumab) or when the decision of continuing the treatment with anti-CGRP mAbs is mandatory.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Enlarging the spectrum of cluster headache: Extracranial autonomic involvement revealed by voice analysis.

BACKGROUND: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross-sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated. METHODS: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise-to-harmonics ratios as well as quantities related to the spectral tilt (i.e., H1-H2, H1-A1, H1-A2, and H1-A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects. RESULTS: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1-H2) values compared with HCs (-6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so-called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001). CONCLUSION: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in-bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture.

Refractory migraine profile in CGRP-monoclonal antibodies scenario.

OBJECTIVE: Refractory migraine (Ref-M) represents a conundrum that headache experts have to face with. We aim to investigate whether a peculiar profile may characterize patients with Ref-M according to 2020 European Headache Federation criteria. Furthermore, to substantiate a dysfunctional dopaminergic pathway involvement in these patients, we explored the effectiveness of olanzapine. MATERIALS & METHODS: Eighty-four patients (fitting previous Ref-M criteria of the 2014) were treated with erenumab for six months. Differences between clinical and demographic features of responder (Ref-M according to 2014 criteria) and not-responder (Ref-M according to 2020 criteria) patients to CGRP-mAbs were investigated and their predictive values assessed. In fifteen patients with Ref-M not responders to CGRP-mAbs, olanzapine was administered (5 mg/die) for 3 months and frequency and pain intensity of migraine attacks were estimated. RESULTS: Patients with Ref-M not responsive to CGRP-mAbs (29/84) when compared with Ref-M responsive to CGRP-mAbs showed higher baseline frequency of migraine attacks, medication overuse and pain catastrophizing scale (PCS) scores. Logistic regression analyses showed that frequency of attacks, medication overuse and PCS score represent independent negative predictors of CGRP-mAbs response. A ≥50% reduction of headache days/month was observed after olanzapine treatment in 67% of patients with Ref-M not responsive to CGRP-mAbs. CONCLUSIONS: We outline that higher frequency of migraine attacks, medication overuse and pain catastrophizing characterize patients with Ref-M not responsive to CGRP-mAbs. In this frame, olanzapine effectiveness on frequency and pain intensity of migraine attacks supports the hypothesis that migraine refractoriness may be subtended by a prominent involvement of the dopaminergic pathway.

Can Craniometry Play a Role in Cluster Headache Diagnosis? A Pilot Exploratory TC-3D Based Study.

BACKGROUND: Since the pioneering reports of the so-called leonine face in cluster headache (CH) patients, cranial and facial features of these patients have been poorly investigated with conflicting results. We aimed to investigate whether abnormalities in craniometric measurements could characterize male CH patients and represent reliable and reproducible diagnostic biomarkers able to identify CH patients. METHODS: Brain CT images were recorded between 2018 and 2020 in 24 male patients with CH and in 24 matched healthy controls (HC). Then, craniometric measurements were obtained, and logistic regression and receiver operating characteristic curves analyses were used to identify the craniometric abnormalities able to distinguish CH patients from HC. RESULTS: Logistic regression analyses showed that frontal bone height and facial width were able to discriminate, one independently from the other, CH patients from HC with an overall accuracy of 77%. The optimal cutoff score in detecting the probable presence of CH was 11.50 cm for frontal bone height and 13.30 cm for facial width. DISCUSSION: In the present study we found, for the first time by means of brain 3D computed tomography approach, abnormal craniometric measurements in CH patients when compared with HC. The absence of differences in smoke and alcohol intake suggests that the observed craniometric abnormalities may represent a specific feature of CH patients. CONCLUSION: The craniometric evaluation by means of brain 3D computed tomography could represent a widespread, noninvasive, and accurate tool to support CH diagnosis to avoid frequent misdiagnosis or delay in the diagnostic process.

Disconnectome of the migraine brain: a "connectopathy" model.

BACKGROUND: In the past decades a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine with conflicting results probably due to the variability and susceptibility of signal fluctuations across the course of RS-FC scan. On the other hand, the structural substrates enabling the functional communications among the brain connectome, characterized by higher stability and reproducibility, have not been widely investigated in migraine by means of graph analysis approach. We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients. Moreover, such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain. METHODS: We investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain "connectome", a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls. RESULTS: We observed in migraine patients compared to healthy controls: i) higher local and global network efficiency (p < 0.001) and ii) higher local and global clustering coefficient (p < 0.001). Moreover, we found changes in the hubs topology in migraine patients with: i) posterior cingulate cortex and inferior parietal lobule (encompassing the so-called neurolimbic-pain network) assuming the hub role and ii) fronto-orbital cortex, involved in emotional aspects, and visual areas, involved in migraine pathophysiology, losing the hub role. Finally, we found higher connection (edges) probability between cortical nodes involved in pain perception and modulation as well as in cognitive and affective attribution of pain experiences, in migraine patients when compared to healthy controls (p < 0.001). No correlations were found between imaging and clinical parameters of disease severity. CONCLUSION: The imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients' susceptibility to triggers. Such changes in connectome topography suggest an intriguing pathophysiological model of migraine as brain "connectopathy".

Erenumab Efficacy on Comorbid Cluster Headache in Patients With Migraine: A Real-World Case Series.

BACKGROUND: Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) or its receptor have emerged as effective and well-tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment. CASE SERIES: We describe the cases of 5 patients with both migraines and CH with previous failures of preventive treatments. All patients were treated with monthly erenumab (70 or 140 mg) showing good results not only on migraine but also on CH attacks frequency and intensity. Improvements of both intensity and frequency of CH attacks occurred only after at least 3 months of treatment, with monthly erenumab 140 mg, suggesting that longer treatment and higher doses are needed in CH in comparison to migraine. DISCUSSION AND CONCLUSION: Our findings support the efficacy and tolerability of monthly erenumab 140 mg as a preventive treatment in patients suffering from both migraines without aura and CH. We speculate that erenumab could represent a low-risk alternative for CH patients (with or without comorbid migraine) who did not tolerate common CH preventatives therapies or for whom the therapies were not successful. Certainly, randomized trials are needed to confirm these observations and we hope that our data, showing a delayed therapeutic effect only with the highest dose of erenumab (140 mg/month), can be taken into account in designing future trials.

Migraine as a Cortical Brain Disorder.

PURPOSE: Migraine is an exclusively human chronic disorder with ictal manifestations characterized by a multifaceted clinical complexity pointing to a cerebral cortical involvement. The present review is aimed to cover the clinical, neuroimaging, and neurophysiological literature on the role of the cerebral cortex in migraine pathophysiology. OVERVIEW: Converging clinical scenarios, advanced neuroimaging data, and experimental neurophysiological findings, indicate that fluctuating excitability, plasticity, and metabolism of cortical neurons represent the pathophysiological substrate of the migraine cycle. Abnormal cortical responsivity and sensory processing coupled to a mismatch between the brain's energy reserve and workload may ignite the trigeminovascular system, leading to the migraine attack through the activation of subcortical brain trigeminal and extra-trigeminal structures, and driving its propagation and maintenance. DISCUSSION: The brain cortex emerges as the crucial player in migraine, a disorder lying at the intersection between neuroscience and daily life. Migraine disorder stems from an imbalance in inhibitory/excitatory cortical circuits, responsible for functional changes in the activity of different cortical brain regions encompassing the neurolimbic-pain network, and secondarily allowing a demodulation of subcortical areas, such as hypothalamus, amygdala, and brainstem nuclei, in a continuous mutual crosstalk.

Readability Analysis of Online Headache and Migraine Information.

BACKGROUND: Although migraine is recognized as one of the most common and disabling diseases in the world, it is nonetheless still underestimated, underdiagnosed, and undertreated. The fact that migraine patients often tend to access the Web to search for headache-related information hinders patient-doctor relationships and one should also bear in mind that, unfortunately, text readability and medical literacy in the overall population may be the reason why patients' understanding of health information is compromised. AIM: We aimed to assess the readability of the home page of the top 10 patient - oriented migraine-related websites and the educational level required to be in a position to broach them. METHODS: On April 15, 2018, we conducted a descriptive study on the international version of Google by entering the words "headache" and "migraine." We then analyzed the overall level of readability of texts of the home pages of the top 10 patient-oriented websites, by means of the Simple Measure of Gobbledygook Readability Calculator. RESULTS: Entering "headache" on the home pages of the top 10 patient-oriented websites on Google we found that to understand these particular websites with ease, an average grade level of 12.4 (±1.5 standard deviation, SD) and an average 13.3 years of formal education (±1.7 SD) were required. Similarly, typing "migraine" on Google we found an average grade level of 10.8 (±1.2 SD) and an average of 12.5 years of formal education (±1.9 SD) were required. The most frequently viewed websites all failed to meet the USA National Institutes of Health guidelines, which recommend a range between 6th and 7th grade level readability. DISCUSSION: The present study shows the low readability level resulting from the top 10 patient-oriented headache/migraine websites and the consequent barrier this creates in the dissemination of headache/migraine-related medical information. Although the actual physicians, both primary care physicians and headache specialists are the principal source of understandable headache-related information, only a minority of people consult these professionals. Given the foregoing, the majority of migraine patients is, therefore, unable to obtain adequate comprehensible health information on the Web. Furthermore, the existing gap between migraine-related website content readability and the unmet need for migraine patients to obtain pertinent and correct information might well contribute to the worldwide neglect of migraine as a major public health problem. CONCLUSION: Physician experts in headache and migraine should actively cooperate in planning informative material to establish what information patients need to know, how they should use it, and how readable that material actually is. Readability ought to be established before the final website publication. Plain language ought to be used and written messages should be supplemented with visual content such as simple drawings. We recommend the setting up of a new dynamic, modern, plain-talking, and efficient approach in communication aimed at catching the public's attention with its readability and thus satisfying a migraine and headache web scenario.

Cognitive Networks Disarrangement in Patients With Migraine Predicts Cutaneous Allodynia.

BACKGROUND: Two-thirds of patients with migraine without aura (MwoA) complain ictal cutaneous allodynia (CA), clinical sign of central nociceptive pathway sensitization, and independent predictor for migraine chronification. AIM: We aimed to investigate whether functional abnormalities, structural, or microstructural changes of the main cognitive networks (default mode network [DMN], salience network [SN], and central executive network [CEN]) could predict the development of CA in patients with MwoA. METHODS: Baseline 3-Tesla MRI images of 50 patients with MwoA were analyzed between 2009 and 2015. Over a three-year period, patients were then stratified into 2 groups based on CA development and compared with matched healthy controls (HC). Group-level independent components analysis was used to investigate intrinsic functional connectivity (FC) differences within the cognitive resting-state networks. Voxel-based morphometry (VBM) was used to assess whether group differences in cognitive network FC were related to structural differences. Tract-based spatial statistical analyses (TBSS) were conducted to assess the microstructural properties of white matter tracts. We also compared internetwork connectivity between patients. Finally, a logistic regression analysis was used to investigate baseline imaging predictors of CA development. RESULTS AND DISCUSSION: We observed a significantly reduced FC of both DMN and CEN in patients with MwoA developing CA (MwoA d CA) when compared with both patients with MwoA not developing CA (MwoA nd CA) and HC. Within the DMN, the PCC/precuneus is a key hub aimed to anti-nociception and multisensory integration. The reduced intrinsic PCC/precuneus FC observed in patients with MwoA d CA could subtend abnormal inputs integration, from different sensory modalities, allowing the development of CA. On the other hand, within the CEN, a central role in pain modulation as well as in executive functions is played by ACC and MFG. Our finding of reduced ACC and MFG FC in MwoA d CA may represent the neuronal substrate of both subclinical impairment of complex executive functions and dysfunctional anti-nociceptive pathway, making these patients more prone to migraine chronification. TBSS analyses showed a statistically significant reduced corpus callosum (CC) FA in patients with MwoA d CA as previously demonstrated in migraine patients with other chronification factors such as medication overuse or affective disorders. No VBM differences in both global and local volumes were revealed between groups. No significant correlations have been found between the observed functional and microstructural changes and clinical parameters of disease severity. Logistic regression analysis indicated that the full model containing all predictors was statistically significant while the decreased ACC-FC was significantly associated with CA development. CONCLUSION: We suggest that DMN and CEN FC abnormalities as well as CC microstructural changes could represent a prognostic imaging biomarker able to identify migraine patients more prone to experiencing CA and therefore, more inclined to chronic migraine. In the new pharmacological scenario, it would be useful to address therapeutic resources to specific migraine populations with a high risk of more severe clinical phenotype.