Effect of anti-CGRP-targeted therapy on migraine aura: Results of an observational case series study.

INTRODUCTION: Limited clinical evidence is available regarding the potential effectiveness of anti-CGRP monoclonal antibodies for the preventive treatment of migraine with aura. AIM OF THE STUDY: This observational study involved a series of migraine patients affected by either migraine with or without aura, who were investigated for any changes in their frequencies and their migraine aura attack characteristics observed during treatment with anti-CGRP Mabs over a 1-year period. PATIENTS AND METHODS: Twelve migraine patients were included, seven of whom were treated with erenumab, 2 with fremanezumab, and 3 with galcanezumab. Clinical data were collected at baseline, which were defined as 3 months prior to the initiation of treatment, and thereafter at each trimester, over the 1-year treatment period. The parameters included the number of headache and migraine days/month, the frequency of aura episodes, the number of days with acute drug intakes/month, and the scores from the migraine disability status scale (MIDAS), and the Headache Impact Test 6 (HIT-6). RESULTS: Anti-CGRP Mbs antibodies induced significant decreases in mean headache and migraine without aura days per month, the number of days with medication intake, as well as MIDAS and HIT-6 scores (p < 0.0001). In contrast, the anti-CGRP Mab treatment did not appear to impact the frequency of migraine with aura attacks but seemed to reduce both the intensity and the duration of headache phases of migraine aura. Furthermore, some migraine patients referred to having aura attacks without headache over the course of the treatment period. CONCLUSIONS: Based on the above findings, we hypothesize that anti-CGRP Mabs did not influence neuronal and vascular events related to cortical spreading depression (CSD) which is considered the pathophysiological substrate of aura. Conversely, these antibodies are able to counteract, via their peripheral mechanisms of action, the sensitization of the trigemino-vascular pathway which is triggered by CSD. This aforementioned might explain why in our patients, migraine aura attacks remained unchanged in their frequencies, but the headache phases were either reduced or absent.

Gender-related stress factors and emotional perception in migraine: a structured online questionnaire in migraine patients and controls.

BACKGROUND: While migraine is markedly prevalent in women, gender-related phenotype differences were rarely assessed. For this reason, we investigated, through a multicenter observational cross-sectional study, based on an online questionnaire, gender-related differences in stress factors, emotions, and pain perception in migraine patients and controls and their impact on migraine severity. METHODS: The study was designed as an online questionnaire. The link was emailed to healthy subjects (C) and migraine patients (MIG) (age 18-75, education ≥ 13 years) recruited during the first visit in 8 Italian Headache Centers adhering to Italian Society for Headache Study (SISC). The questionnaire included personal/social/work information, the Perceived Stress Scale, the Romance Quality Scale, the Emotion Regulation Questionnaire, the Beck Anxiety Inventory, the Body Perception Questionnaire, the pain perception, and a self-assessment of migraine severity in the last 3 months. RESULTS: 202 MIG and 202 C completed the survey. Independently from gender, migraine was characterized by higher pain sensitivity and more severe partner relationships. The female gender, in MIG, exhibited higher anxiety scores, body awareness, and reduced emotional suppression. Body awareness and emotional suppression were discriminating factors between genders in control and migraine groups without relevant influence on disease features. Perceived perception of migraine severity was similar between genders. CONCLUSION: Gender-related emotional and stress factors did not contribute to delineate a distinct phenotype in migraine men and women. The possible impact of emotional and stress factors characterizing genders could be considered for a single case-tailored therapeutic approach.

The putative role of neuroinflammation in the complex pathophysiology of migraine: From bench to bedside.

The implications of neurogenic inflammation and neuroinflammation in the pathophysiology of migraine have been clearly demonstrated in preclinical migraine models involving several sites relevant in the trigemino-vascular system, including dural vessels and trigeminal endings, the trigeminal ganglion, the trigeminal nucleus caudalis as well as central trigeminal pain processing structures. In this context, a relevant role has been attributed over the years to some sensory and parasympathetic neuropeptides, in particular calcitonin gene neuropeptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Several preclinical and clinical lines of evidence also support the implication of the potent vasodilator and messenger molecule nitric oxide in migraine pathophysiology. All these molecules are involved in vasodilation of the intracranial vasculature, as well as in the peripheral and central sensitization of the trigeminal system. At meningeal level, the engagement of some immune cells of innate immunity, including mast-cells and dendritic cells, and their mediators, has been observed in preclinical migraine models of neurogenic inflammation in response to sensory neuropeptides release due to trigemino-vascular system activation. In the context of neuroinflammatory events implicated in migraine pathogenesis, also activated glial cells in the peripheral and central structures processing trigeminal nociceptive signals seem to play a relevant role. Finally, cortical spreading depression, the pathophysiological substrate of migraine aura, has been reported to be associated with inflammatory mechanisms such as pro-inflammatory cytokine upregulation and intracellular signalling. Reactive astrocytosis consequent to cortical spreading depression is linked to an upregulation of these inflammatory markers. The present review summarizes current findings on the roles of immune cells and inflammatory responses in the pathophysiology of migraine and their possible exploitation in the view of innovative disease-modifying strategies.

Validation of the Italian version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. METHODS: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. RESULTS: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. CONCLUSION: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research.

Visual stimulation and frequency of focal neurological symptoms engage distinctive neurocognitive resources in migraine with aura patients: a study of resting-state functional networks.

INTRODUCTION: Several functional neuroimaging studies on healthy controls and patients with migraine with aura have shown that the activation of functional networks during visual stimulation is not restricted to the striate system, but also includes several extrastriate networks. METHODS: Before and after 4 min of visual stimulation with a checkerboard pattern, we collected functional MRI in 21 migraine with aura (MwA) patients and 18 healthy subjects (HS). For each recording session, we identified independent resting-state networks in each group and correlated network connection strength changes with clinical disease features. RESULTS: Before visual stimulation, we found reduced connectivity between the default mode network and the left dorsal attention system (DAS) in MwA patients compared to HS. In HS, visual stimulation increases functional connectivity between the independent components of the bilateral DAS and the executive control network (ECN). In MwA, visual stimulation significantly improved functional connectivity between the independent component pairs salience network and DAS, and between DAS and ECN. The ECN Z-scores after visual stimulation were negatively related to the monthly frequency of aura. CONCLUSIONS: In individuals with MwA, 4 min of visual stimulation had stronger cognitive impact than in healthy people. A higher frequency of aura may lead to a diminished ability to obtain cognitive resources to cope with transitory but important events like aura-related focal neurological symptoms.

Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study.

BACKGROUND: A novel formulation of diclofenac, complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. METHODS: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. RESULTS: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. CONCLUSIONS: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.Trial registration: EudraCT Registration No. 2017-004828-29.

Immunological findings in patients with migraine and other primary headaches: a narrative review.

Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion, and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache (CH) patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine. The present review summarizes available findings to date from genetic and biomarker studies that have explored the role of inflammation in primary headaches.

Sustained Efficacy, Safety and High Adherence Rate of Onabotulinum Toxin Type A in Chronic Migraine Patients: A Multicentric Prospective Real-Life Study.

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into "responders" (R), "partially responders" (PR) and "non-responders" (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A.

Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis.

Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI.

Headache and immunological/autoimmune disorders: a comprehensive review of available epidemiological evidence with insights on potential underlying mechanisms.

Several lines of evidence support a role of the immune system in headache pathogenesis, with particular regard to migraine. Firstly, alterations in cytokine profile and in lymphocyte subsets have been reported in headache patients. Secondly, several genetic and environmental pathogenic factors seem to be frequently shared by headache and immunological/autoimmune diseases. Accordingly, immunological alterations in primary headaches, in particular in migraine, have been suggested to predispose some patients to the development of immunological and autoimmune diseases. On the other hand, pathogenic mechanisms underlying autoimmune disorders, in some cases, seem to favour the onset of headache. Therefore, an association between headache and immunological/autoimmune disorders has been thoroughly investigated in the last years. The knowledge of this possible association may have relevant implications in the clinical practice when deciding diagnostic and therapeutic approaches. The present review summarizes findings to date regarding the plausible relationship between headache and immunological/autoimmune disorders, starting from a description of immunological alteration of primary headaches, and moving onward to the evidence supporting a potential link between headache and each specific autoimmune/immunological disease.

Pathophysiological Bases of Comorbidity in Migraine.

Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors.

Dural arteriovenous fistulas and headache features: an observational study.

BACKGROUND: Dural arteriovenous fistulas are intracranial vascular malformations, fed by dural arteries and draining venous sinuses or meningeal veins. Clinical course varies widely and ranges from benign with spontaneous remission to fatal, due to cerebral hemorrhage. In a 10-year single institution experience, clinical presentation of dural arteriovenous fistulas, and in particular headache and angiographic features, as well as long-term outcome were analyzed. METHODS: Data of 42 intracranial dural arteriovenous fistulas of 40 patients concerning demographic characteristics, medical history and risk factors, clinical presentation and headache features, location and neuroimaging findings, as well as treatment and outcome, were collected. Furthermore, we used the modified-Rankin Scale to assess the long-term outcome, by telephone contact with patients and/or their relatives. RESULTS: Patients aged between 25 and 89 years (mean age 55.8 ± 15.5). According to different clinical presentation and evolution, related to their unique drainage pattern into the cavernous sinus, we examined the carotid-cavernous fistulas separately from other dural arteriovenous fistulas. Interestingly, we found that the migraine-like headache was the major onset symptom of dural arteriovenous fistulas different from carotid-cavernous fistulas (p = 0.036). On the other hand, non-migraine-like headache was a typical characteristic of carotid-cavernous fistulas (p = 0.003). Moreover, ocular symptoms were more frequently observed in carotid-cavernous fistulas (92.9% p < 0.001). Seventy percent of patients did not report any impact on quality of life (mRS 0 or 1) at follow-up. CONCLUSIONS: These findings suggest a link between the site of lesion and clinical features of the headache, a symptom that usually leads to hospitalization. In particular, ocular symptoms accompanying non-migraine-like headache should be promptly recognized and raise the suspicion of a carotid-cavernous fistula, while migraine-like headache may suggests other dural arteriovenous fistulas. This study provides new significant insights on headache and its characteristics as a presentation symptom in dural arteriovenous fistulas.

Cerebrospinal fluid free light chains compared to oligoclonal bands as biomarkers in multiple sclerosis.

Cerebrospinal fluid (CSF) free light chains (FLC) may be an alternative biomarker to oligoclonal bands (OCB) in multiple sclerosis (MS). Herein, we compared the diagnostic accuracy of CSF OCB and FLC and we tested the prognostic value of FLC in a cohort of 64 MS patients and 106 controls. A κ-index >7.83 was more sensitive but less specific than OCB in discriminating MS patients from controls. Additionally, a κ-index >10.61 performed better than OCB in the discrimination between MS and controls with inflammatory neurological diseases (p < .001). In clinically isolated syndrome (CIS) patients, a κ-index >10.61 significantly predicted time to conversion to MS (p = .020). κ-index might be a valid alternative to OCB as a diagnostic biomarker for MS and might also be a prognostic marker in CIS.

Current and emerging evidence-based treatment options in chronic migraine: a narrative review.

BACKGROUND: Chronic migraine is a disabling condition that is currently underdiagnosed and undertreated. In this narrative review, we discuss the future of chronic migraine management in relation to recent progress in evidence-based pharmacological treatment. FINDINGS: Patients with chronic migraine require prophylactic therapy to reduce the frequency of migraine attacks, but the only currently available evidence-based prophylactic treatment options for chronic migraine are topiramate and onabotulinumtoxinA. Improved prophylactic therapy is needed to reduce the high burden of chronic migraine in Italy. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) pathway of migraine pathogenesis have been specifically developed for the prophylactic treatment of chronic migraine. These anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials, and offer new hope to patients who are currently not taking any prophylactic therapy or not benefitting from their current treatment. CONCLUSIONS: Treatment of chronic migraine is a dynamic and rapidly advancing area of research. New developments in this field have the potential to improve the diagnosis and provide more individualised treatments for this condition. Establishing a culture of prevention is essential for reducing the personal, social and economic burden of chronic migraine.

Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis.

BACKGROUND: The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up. METHODS: We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ±â€¯2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA). RESULTS: At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205-2359 pg/mL vs 329.5 pg/mL, range 156-3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity. CONCLUSION: Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.

Long-Term Risk of Stroke After Transient Global Amnesia in Two Prospective Cohorts.

Background and Purpose- Transient global amnesia (TGA) is known as a benign syndrome, but recent data from neuroradiological studies support an ischemic cause in some cases, which might suggest an increased susceptibility to cerebrovascular events. We determined the long-term risk of stroke after a first TGA in 2 independent prospective cohorts. Methods- In 2 independent prospective cohorts of patients with TGA (OXVASC [Oxford Vascular Study], population-based; NU (Northern Umbria) cohort, TGA registry), cardiovascular risk factors and long-term outcomes, including stroke and major cardiovascular events, were identified on follow-up. Cardiovascular risk factors were treated according to primary prevention guidelines. In OXVASC, the age-/sex-adjusted risk of stroke during follow-up was compared with that expected from the rate in the underlying study population. Results- Among 525 patients with TGA (425 NU and 100 OXVASC), mean (SD) age was 65.1 (9.5) years and 42.5% male. Hypertension (58.1%), dyslipidemia (40.4%), and smoking (36.4%) were the most frequent cardiovascular risk factors. The risk of stroke was similar in the 2 cohorts, with a pooled annual risk of 0.6% (95% CI, 0.4-0.9) and a 5-year cumulative risk of 2.7% (1.1-4.3). Moreover, the stroke risk in OXVASC cases was no greater than that expected in the underlying study population (adjusted relative risk=0.73; 0.12-4.54; P=0.74). Conclusions- TGA does not carry an increased risk of stroke, at least when cardiovascular risk factors are treated according to primary prevention guidelines.

Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is a disabling symptom of multiple sclerosis (MS). Axonal damage disrupts neural circuits and may play a role in determining CI, but its detection and monitoring are not routinely performed. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a promising marker of axonal damage in MS. OBJECTIVE: To retrospectively examine the relationship between CSF NfL and CI in MS patients. METHODS: CSF NfL concentration was measured in 28 consecutive newly diagnosed MS patients who underwent a neuropsychological evaluation with the Brief Repeatable Battery of Neuropsychological tests (BRBN). RESULTS: CSF NfL was higher in patients with overall CI (947.8 ± 400.7 vs 518.4 ± 424.7 pg/mL, p < 0.01), and with impairment in information processing speed (IPS) (820.8 ± 413.6 vs 513.6 ± 461.4 pg/mL, p < 0.05) and verbal fluency (1292 ± 511 vs 582.8 ± 395.4 pg/mL, p < 0.05), and it positively correlated with the number of impaired BRBN tests (r = 0.48, p = 0.01) and cognitive domains (r = 0.47, p = 0.01). Multivariate analyses taking into account potential confounders confirmed these findings. CONCLUSION: CSF NfL is higher in MS patients with CI and impaired IPS and verbal fluency. Large myelinated axons injury, causing neural disconnection, may be an important determinant of CI in MS and can be reliably measured through CSF NfL.

Correction to: Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial.

Following publication of the original article [1], the authors notified us that a part of the Figure 3 legend was omitted during proofing stage.

Correction to: Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial.

Following publication of the original article [1], the authors notified us o that the Table 1 citation within the legend was not presented as initially requested.