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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., (© 2022. The Author(s).)

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.

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.

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.

Background: Non-invasive vagus nerve stimulation (nVNS) has been shown to be practical, safe, and well tolerated for treating primary headache disorders. The recent multicenter, randomized, double-blind, sham-controlled PRESTO trial provided Class I evidence that for patients with episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. We report additional pre-defined secondary and other end points from PRESTO that demonstrate the consistency and durability of nVNS efficacy across a broad range of outcomes., Methods: After a 4-week observation period, 248 patients with episodic migraine with/without aura were randomly assigned to acute treatment of migraine attacks with nVNS (n = 122) or a sham device (n = 126) during a double-blind period lasting 4 weeks (or until the patient had treated 5 attacks). All patients received nVNS therapy during the subsequent 4-week/5-attack open-label period., Results: The intent-to-treat population consisted of 243 patients. The nVNS group (n = 120) had a significantly greater percentage of attacks treated during the double-blind period that were pain-free at 60 (P = 0.005) and 120 min (P = 0.026) than the sham group (n = 123) did. Similar results were seen for attacks with pain relief at 60 (P = 0.025) and 120 min (P = 0.018). For the first attack and all attacks, the nVNS group had significantly greater decreases (vs sham) in pain score from baseline to 60 min (P = 0.029); the decrease was also significantly greater for nVNS at 120 min for the first attack (P = 0.011). Results during the open-label period were consistent with those of the nVNS group during the double-blind period. The incidence of adverse events (AEs) and adverse device effects was low across all study periods, and no serious AEs occurred., Conclusions: These results further demonstrate that nVNS is an effective and reliable acute treatment for multiple migraine attacks, which can be used safely while preserving the patient's option to use traditional acute medications as rescue therapy, possibly decreasing the risk of medication overuse. Together with its practicality and optimal tolerability profile, these findings suggest nVNS has value as a front-line option for acute treatment of migraine., Trial Registration: ClinicalTrials.gov identifier: NCT02686034 .

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication., Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation., Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037)., Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events., Trial Registration: ClinicalTrials.gov identifier: NCT02686034 .

Background: Chronic migraine is a complex clinical condition often undertreated. Onabotulinumtoxin A (OBT-A) was approved in Italy in 2013 for symptom relief in patients with chronic migraine who have failed, or do not tolerate, oral prophylactic treatments. However, the impact of OBT-A in clinical practice remains to be defined., Methods: To investigate the current management of chronic migraine with OBT-A in clinical practice, a web-based survey was conducted among clinicians working in third-level headache centers across Italy. A 26-item questionnaire was designed and developed by a group of 10 Italian headache specialists to address the following issues: treatment paradigm and OBT-A injection intervals, frequency of treatment and retreatment, definition of responders/non-responders, satisfaction with treatment potential impact of early treatment with OBT-A. Ninety-six headache centers were selected and contacted via e-mail. The online survey was anonymous and carried out using a secure website., Results: Overall, 64 of the 96 centers (66.7%) completed the questionnaire. Most centers (98.4%) had been using OBT-A for >1 year. OBT-A was administered according to the PREEMPT paradigm in most centers (88.9%). While during the first year of prophylaxis with OBT-A most clinicians (93.6%) repeated OBT-A treatment every 3 months, as recommended, in the following years interval duration was variable. Response to OBT-A was defined as a ≥ 50% reduction in the headache days by 58.7% of the clinicians, and as a ≥ 30% reduction by 25.4% of them. Almost 60% of the clinicians considered OBT-A as a long-lasting therapy, while for one-third of them treatment could be discontinued in patients showing a benefit for ≥6 months. According to 80% of the clinicians, early administration of OBT-A after the onset of chronic migraine was associated with better outcomes, and 47.6% felt that OBT-A should be recommended as a first-line option., Conclusions: This survey indicates that in third-level headache centers in Italy OBT-A is used in good compliance with current recommendations. There is agreement about the definition of response as a reduction in headache days by 30% to 50%. Additional effort is required to define response to OBT-A and to establish optimal treatment duration.

Background: Medication overuse headache (MOH) is a very heterogeneous disorder for which a recommended treatment is not yet available. The purpose of this study was to investigate any possible roles of demographic and clinical characteristics of MOH patients that might predict a response to detoxification and advice with or without preventive treatment., Findings: This ancillary study is part of the Sodium vAlproate in the treatment of Medication Overuse HeadAche (SAMOHA) study that randomized 88 MOH patients for 3-month treatment period with sodium valproate (VPA) (800 mg/day) or placebo after a 6-day outpatient detoxification regimen. Demographic and clinical characteristics obtained on patients from both study arms were analyzed to point out an association with the response to the treatment. While for patients from VPA arm no significant results were obtained, comparing responders to non-responders to detoxification and advice to withdraw from MOH, a significant difference in headache duration was observed. Specifically, the efficacy of such treatment resulted ineffective in headache lasting longer than 30 years., Conclusions: Our findings suggest that the benefit from detoxification and advice can be excluded in MOH of long duration. Therefore, a preventive treatment is suggested particularly for these patients.

Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K⁺ and glutamate, as well as rises in intracellular Na⁺ and Ca²⁺. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for "gepants", which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.

Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed.

This study aimed at determining the causes of failure of the different proposed strategies to ensure improvement of medication-overuse headache (MOH) patients, since they have not been investigated so far, especially with regard to aspects related to cognitive and behavioural aspects of symptomatic drugs overused by them. One hundred and twenty in-patients, 82 females (68.3 %), median age 49 (42-56) years, affected by MOH were admitted to the study and treated with abrupt discontinuation of the medication overused, a 6-day in-patient detoxification regimen and an immediate start of personalized prophylactic treatment, then followed for 1 year. Leeds Dependence Questionnaire (LDQ), among all the clinical variables, was administered at baseline and at 1-year follow-up visit to assess substance dependence. Of the 120 patients enrolled, 68 (56.7 %) were successfully detoxified (Responder-group), while 52 (43.3 %) were not (Non-Responder-group). At baseline, the mean LDQ total score was slightly higher in the Non-Responder group than in the Responder group (12.08 ± 2.14 vs. 11.94 ± 1.98). Although this difference was not significant at baseline (p > 0.05), the LDQ total score was significantly different (p < 0.001) at the 1-year follow-up visit between the responder group (7.8 ± 2.3) and the Non-Responder group (12.1 ± 2.1). Moreover, the pattern of the responses of the patients in the responder group differed from that of the Non-Responder-group in the items relating to the compulsion to start, compulsion to continue, primacy of effect, constancy of state and cognitive set. The results showed that patients of the Non-Responder group showed a drug dependence pattern similar to that previously described in addicts. Conversely, in patients who positively responded to the procedure, drug-abuse behaviour seemed to be a consequence of chronic headache, reflecting the need for daily analgesic use to cope with everyday life.

Medication overuse headache (MOH) is a severe burden to sufferers and its treatment has few evidence-based indications. The aim of this study is to evaluate efficacy and safety of nabilone in reducing pain and frequency of headache, the number of analgesic intake and in increasing the quality of life on patients with long-standing intractable MOH. Thirty MOH patients were enrolled at the University of Modena's Interdepartmental Centre for Research on Headache and Drug Abuse (Italy) in a randomized, double-blind, active-controlled, crossover study comparing nabilone 0.5 mg/day and ibuprofen 400 mg. The patients received each treatment orally for 8 weeks (before nabilone and then ibuprofen or vice versa), with 1 week wash-out between them. Randomization and allocation (ratio 1:1) were carried out by an independent pharmacy through a central computer system. Participants, care givers, and those assessing the outcomes were blinded to treatment sequence. Twenty-six subjects completed the study. Improvements from baseline were observed with both treatments. However, nabilone was more effective than ibuprofen in reducing pain intensity and daily analgesic intake (p < 0.05); moreover, nabilone was the only drug able to reduce the level of medication dependence (-41 %, p < 0.01) and to improve the quality of life (p < 0.05). Side effects were uncommon, mild and disappeared when nabilone was discontinued. This is the first randomized controlled trial demonstrating the benefits of nabilone on headache, analgesic consumption and the quality of life in patients with intractable MOH. This drug also appears to be safe and well-tolerated. Larger scale studies are needed to confirm these preliminary findings.

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105-190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.

It is well known that physical activity can aggravate the intensity of the headache, but the pathophysiological relationship between exertion and aura is still unknown. Anecdotal reports describe episodes of migraine preceded by head trauma and visual symptoms, migraine prodrome symptoms after unusually strenuous running with no subsequent head pain or recurrent attacks of hemiplegic migraine induced only by exertion. We describe the cases of three young men with recurrent episodes of migraine with aura occurring in the locker room shortly after a football match. Since the symptoms could mimic important pathologies in approximately 10% of these of headaches, it was mandatory to exclude a secondary form of headache in these patients. Several theories exist regarding the cause of primary exertional headache, but the pathogenesis of migraine triggered by physical activity has still not been identified. The present International Classification of Headache Disorders does not mention sport/exercise-induced migraine with aura episodes as primary headache. Since there are many cases described in the literature of migraine with aura triggered only by exercise, it may be helpful to specify, in the typical aura with migraine headache comments, that in some cases it can be exclusively triggered by sport/exercise.

The main aim of this study was to confirm in an Italian population affected by tension-type headache (TTH) the good profile of safety and tolerability of the combination paracetamol 1,000 mg-caffeine 130 mg (PCF) observed in previous studies, by a comparison with naproxen sodium 550 mg (NAP) and placebo (PLA). A secondary objective was to assess the efficacy of PCF in the acute treatment of TTH. This was a multicentre, randomised, double-blind, double-dummy, crossover, placebo-controlled trial. Tolerability was assessed by recording adverse events by the patient in the 4-h post-dose treatment. To assess the efficacy, the sum of pain intensity differences (SPID) and the total pain relief (TOTPAR) were calculated. Comparing PCF and NAP and PCF and PLA for tolerability, the difference was nonsignificant but the result regarding noninferiority was inconclusive, whilst NAP was noninferior to PLA. As regards SPID and TOTPAR, both PCF and NAP were better than placebo (P < 0.05), but not significantly different from each other. In conclusion, PCF was well-tolerated and effective in the treatment of acute TTH.

A new form of headache, whose attacks seem to be stereotyped, has been recently reported; because of the peculiarity of its onset, strictly related to airplane travel, the name of "Airplane headache" was proposed. A total of 7 cases have been published. Here we present the first Italian one. Furthermore the revision of the clinical characteristics of each patient leads us to propose provisional diagnostic criteria.

The objective of this study was to establish if chronic headaches with medication overuse can modify a topo-kinesthetic memory test. Nineteen patients with medication overuse headache (MOH), 13 patients with chronic tension-type headache (CTTH) without medication use and a group of "normal" subjects underwent a topo-kinesthetic memory test at T0 and after one month (T1); a control group of healthy volunteers was also tested to establish the baseline in our experimental setting. After one month, in the MOH patients there was a reduction of medication overuse from 3.3+/-2.65 to 1.1+/-2.23 (p<0.01), but no significant reduction in headache frequency and severity index, quality of life, anxiety and depression scores. The navigation time at T0 was 14.3+/-4.97, 27.9+/-10.12, 34.3+/-15.38 and 7.5+/-2.33, 10.1+/-2.95, 11.4+/-3.21 for control, MOH and CTTH with closed and open eyes, respectively (p<0.02). At T1, the MOH patients reached performances with open eyes similar to the healthy controls, while with closed eyes the navigation test reached times similar to those of CTTH patients. The topo-kinesthetic memory test seems both able to discriminate MOH and CTTH from healthy volunteers and to be related to pain scores but is not influenced by the use of drugs.

We tested the computerised, structured medical record by entering and analysing the consecutive clinical sheets of primary headaches in the episodic forms (200) and chronic headache (200) and the corresponding output diagnoses of patients attending our Headache Centre. A diagnosis of one of the primary headache forms was obtained in 67.9% of cases. A certain diagnosis of primary headache plus that of a probable form was obtained in 24.4% of cases (12.7% represented by chronic migraine (CM) or chronic tension-type headache (CTTH)+probable medication overuse headache). Only probable forms were diagnosed in the remaining 7.3% (as single probable diagnosis in 5.8% of cases or multiple diagnoses of probable forms in the remaining ones). The percentage of certain diagnoses mainly in the chronic headache group (28.4%), and to a lesser extent tension-type headache (6.5%), were obtained in 34.9% of cases. A certain diagnosis of one chronic form plus that of a probable form was obtained in 50.8% of cases (26.9% represented by probable medication-overuse headache). Only probable forms were diagnosed in 13.46% (as single probable diagnosis in 8.73% of cases or multiple diagnoses of probable forms in the remaining ones). In the other cases, the ICHD-II classification does not allow the diagnoses of CM, CTTH or probable forms and medication overuse headache because the mandatory criteria for the diagnoses are too stringent and do not reflect modifications of the headache pattern in relation to its chronicity. These preliminary results underscore the usefulness of a computerised device based on the ICHD 2nd edition for diagnostic purposes in tertiary centres dedicated to headaches in clinical practice as well as its relevance for research. This computerised device may help to validate the new diagnostic criteria and to answer some emerging questions from the application of the new classification version, the relevance of which should be verified in clinical practice.