11th European Headache Federation Congress jointly with 31st Congress of the Italian Society for the Study of Headaches : Rome, Italy. 01-03 December 2017

Background There is a high unmet need for new preventive migraine treatments, especially for patients who have failed existing migraine therapies. Erenumab is a fully human monoclonal antibody that blocks the calcitonin gene-related peptide receptor. In a large, multicenter, double-blind, placebo controlled, phase 3 study (STRIVE), erenumab 70 mg and 140 mg demonstrated efficacy in subjects with episodic migraine and showed a safety profile similar to placebo. Here we report efficacy results in a subgroup of trial subjects with prior preventive treatment failure(s). Methods Subgroup analyses were conducted in subjects from the STRIVE trial who had failed ≥1 (n=369) or ≥2 (n=161) prior preventive treatments due to lack of efficacy and/or intolerability. Analyses included change from baseline in mean monthly migraine days (MMDs) and achievement of ≥50% reduction from baseline in MMDs, assessed over weeks 13–24 (months 4, 5, and 6). In the full trial, subjects (N=955) were randomized 1:1:1 to subcutaneous monthly placebo or erenumab 70 mg or 140 mg for 24 weeks (6 months). P values for subgroup analyses are descriptive and not adjusted for multiple comparisons. Results Greater reductions from baseline in MMDs were observed for the erenumab 70 mg and 140 mg groups compared with placebo in both treatment failure subgroups (Table 1). More subjects who received erenumab achieved ≥50% reduction in MMD in both subgroups compared with placebo. For the 70 mg group, the odds (95% confidence interval) of achieving ≥50% reduction in MMD were 2.9 times higher than that of placebo for both treatment failure subgroups. For the 140 mg group, the odds were 3.1 and 4.5 times higher than placebo, respectively. Conclusion Robust treatment effects were observed for both 70 mg and 140 mg erenumab in subjects who had previously failed preventive migraine treatments. For 140 mg, effects were numerically greater in this subpopulation than in the overall trial population, and as in the overall population, erenumab 140 mg showed numerically greater efficacy than erenumab 70 mg. These results suggest that erenumab may have particular utility in this subgroup of patients. Background Current therapies for reducing raised intracranial pressure (ICP) in conditions such as idiopathic intracranial hypertension have limited efficacy and tolerability. As such, there is a pressing need to identify novel drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. Here, we investigate whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP. Methods GLP-1R mRNA and protein was assessed by quantitative PCR, immunohistochemistry and fluorescently tagged exendin-4 in human and rat choroid plexus. The effect of exendin-4 on GLP-1R activation and CSF secretion was evaluated in cultured rat choroid plexus epithelial cells using cAMP assays and a Na+ K+ ATPase activity assay. The effect of Exendin-4 on ICP was assessed in adult female rats with normal and raised ICP. Results We demonstrated that the GLP-1R is present in human and rat choroid plexus. Exendin-4 significantly increased cAMP levels (2.14 ± 0.61 fold, P<0.01) part of the GLP-1R signalling pathway, in a concentration-dependant manner and this response could be inhibited by the addition of the GLP-1R antagonist exendin 9-39. Exendin-4 also significantly reduced Na+ K+ ATPase activity, a marker of CSF secretion (39.3±9.4% of control; P<0.05). Finally, in vivo ICP recording in female adult rats demonstrated that subcutaneous administration of 20μg/kg exendin-4 significantly reduced ICP in normal (65.2 ± 6.6% of baseline; P<0.01) and raised ICP rats (56.6 ± 5.7% of baseline; P<0.0001). Conclusion We demonstrate that exendin-4 reduces CSF secretion by the choroid plexus, and ICP in normal rats and rats with raised ICP. Repurposing existing GLP-1 drugs may represent a novel therapeutic strategy for conditions of raised ICP such as idiopathic intracranial hypertension. Additionally, GLP-1R agonist therapy promotes weight loss, which would be advantageous in idiopathic intracranial hypertension. Background Efficacy and safety/tolerability of erenumab, a human anti-CGRP receptor monoclonal antibody, were evaluated in episodic migraine (EM) subjects in a multinational, phase 3 trial ( NCT02456740 ). Methods Adults with EM (n=955) were randomised 1:1:1 to subcutaneous monthly placebo or erenumab 70 mg or 140 mg for 24 weeks. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 13-24. Secondary endpoints were ≥50% reduction in MMDs; change in acute migraine-specific medication days; change in Physical Impairment (PI) and Impact on Everyday Activities (EA) (as measured by the Migraine Physical Function Impact Diary [MPFID]). P-values are for pairwise comparisons of each erenumab dose with placebo, statistical significance determined after multiplicity adjustment. Results Subjects reported 8.3 MMDs at baseline and experienced -3.2, -3.7, and -1.8-day reductions in the 70 mg, 140 mg, and placebo groups, respectively (p<0.001). A ≥50% reduction in MMDs was achieved by 43%, 50%, and 27% in the 70 mg, 140 mg, and placebo groups (p<0.001), and monthly acute migraine- specific medication was reduced by -1.1, -1.6, and -0.2 days (p<0.001). Subjects had improved PI scores (-4.2, -4.8, -2.4 points in the 70 mg, 140 mg, and placebo groups; p<0.001) and EA scores (-5.5, -5.9, and -3.3 points; p<0.001). The safety/tolerability profile of erenumab was similar to placebo; subjects most frequently reported nasopharyngitis, upper-respiratory-tract infection, and sinusitis. Conclusion Erenumab 70 mg and 140 mg significantly reduced migraine frequency and use of migraine-specific medications, reducing migraine’s impact on physical impairment and everyday activities in this EM trial. Numerically greater efficacy was observed for the 140 mg dose consistently across endpoints. Trial registration Clinical trials.gov NCT02456740 . Background Cortical spreading depression (SD) is thought to underlie migraine aura but mechanisms of triggering SD and propagation in the structurally normal cortex of migraine patients is still unknown. Some studies showed that the sensory predominance of migraine aura is likely due to a greater susceptibility of primary sensory cortex to CSD probably for their structural complexity [1]. We used MRI imaging registration in migraine with aura patients to elaborate a CSD propagation logarithm that takes into account the morphology of the various cortical areas involved. Materials and methods We process the data sets with the Freesurfer software to obtain the geometry and labelling for the different brain regions (Desikan-Kiliani Atlas or Brodman areas 1, 2, 3, 4, 44, 45, 17, 18) in five migraine with aura patients. According to the map of the disturbed areas suggested by the aura symptoms, we then initialize the region first affected in the respective hemisphere. Starting the propagation of the CSD in this region we recorded the arrival time in each point of the brain cortex. Results We obtained the different brain geometries and the Brodman areas 1, 2, 3, 4, 44, 45, 17 and 18 of the five subjects. In order to run a simulation of the CSD propagating on the cortex we need to identify an initial region as a starting point for the wave. We take a bearing on the map of the disturbed regions provided along with the MRI data from the patients. For the simulation of the CSD we started the wave in these regions and recorded the propagation. In each point we recorded the arrival time of the wave. We visualize the arrival times of the wave in the Fig. 1. This was in accord with the reported evolution of the clinical symptoms. Conclusions The way CSD propagates can change in relation to brain morphology. The specific algorithm was able to provide for a simulation of the electrical phenomenon, explaining the progressive evolution of clinical symptoms. Further tests in larger series, could give an aid in understanding the pathophysiological peculiarities of migraine-with-aura brain. Fig. 1 (abstract O13). EM and CM respondents self-reporting (SR) an assessed symptom or a physician diagnosis (SR-PD) of a condition EM and CM respondents self-reporting (SR) an assessed symptom or a physician diagnosis (SR-PD) of a condition References 1. Bogdanov VB, Middleton NA, Theriot JJ, Parker PD, Abdullah OM, Ju YS, Hartings JA, Brennan KC. Susceptibility of Primary Sensory Cortex to Spreading Depolarizations . J Neurosci. 2016 ;36(17):4733-43. Interventional treatment is an important but underevaluated issue for neurologist. However peripheral nerve blocks have been used for both acute and preventive treatment of headaches for decades and are safe and effective therapeutic options for many patients with headache disorders. They can cause a long lasting (several weeks to months) pain relief. This long lasting effect is thougt to be due to central pain modulation. Nerve blocks may be an option for the patients who have failed their home medications or who doesn’t want to use drugs. Blocks may also be used to treat patients who need relief between onabotulinum toxin A injections and in medication overuse headache during their acute therapy. Nerve blocks are safe and can be appropriate for children and pregnant patients, and also in patients with kidney-liver diseases. In pregnancy, lidocaine is considered a category B drug. Greater occipital nerve blockade is the most common procedure in peripheral nerve blocks. But lesser occipital nerve blockades, sphenopalatine ganglion blockades, supratrochlear, auriculotemporal, supraorbital, infraorbital and mental nerve blockades, cervical root blockades, their combinations can be used in patients with headache disorders. Local anestetics and steroids are being used for nerve blockades. Botulinum toxin injections are also approved effective methods for migraine all over the World. There is some other indications under search and experineces increases the applications in every day. We want to show the injection techniques and efficacy by sharing our cases. Deepending on the time, after the presentation some audience keep a chance to applicate tehmselves on the model provided by authors. Background A study was conducted to determine if galcanezumab (120 or 240 mg monthly), a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, was superior to placebo in the prevention of chronic migraine. Materials and methods Eligible patients 18-65 years of age with chronic migraine (≥15 headache days per month, of which at least 8 met criteria for migraine) were randomized 2:1:1 to subcutaneous monthly injections of placebo (N=558), galcanezumab 120 (N=278) or 240 mg (N=277). The primary endpoint was the overall mean change-from-baseline in the number of monthly migraine headache days (MHD) during the 3-month double-blind treatment period. Key secondary measures included rates of ≥50%, ≥75%, and 100% reduction in monthly MHD, as well as the changes in monthly MHD with acute migraine treatments, the Role Function-Restrictive domain score of the Migraine-Specific Quality of Life Questionnaire (MSQ-RFR), and the Patient Global Impression-Severity of Illness (PGI-S). Results Baseline mean number of monthly MHD was 19.4. Both galcanezumab doses demonstrated a statistically significant difference (p<.001) compared with placebo in overall mean reduction in number of monthly MHD during the treatment period (placebo= -2.74; galcanezumab 120-mg= -4.83; galcanezumab 240-mg= -4.62), with statistical separation from placebo starting at Month 1. The rate of patients with ≥50% reduction from baseline in MHD was significantly greater for both galcanezumab doses compared with placebo (both p<.001). Compared with placebo, the 240-mg dose-group also had significantly higher rates of ≥75% response (p<.001), greater reductions in monthly MHD with acute migraine treatment (p<.001), and greater improvement in the MSQ-RFR (p<.001) and PGI-S (p<.001). There were no clinically meaningful differences between either galcanezumab dose-group and placebo on any safety parameters except for a higher incidence of injection site reaction (p<.05), injection site erythema (p<.01), and sinusitis (p<.05) all in the 240-mg dose-group relative to placebo. Conclusions Both doses of galcanezumab were superior to placebo in the reduction of monthly MHD, with significantly more patients reducing their monthly MHD by ≥50%. The 240-mg dose was also superior to placebo on most other key secondary measures. Both galcanezumab doses appeared to be efficacious, safe, and well-tolerated for the preventive treatment of chronic migraine. Acknowledgements This study is registered as NCT02614261 at ClinicalTrials.gov. Background The differential diagnosis between migraine with aura (MA) and transient ischemic attacks (TIA) is difficult. Misclassification occurs often and has grave consequences for the patients. In the International classification of headache disorders 3 rd edition beta (ICHD-3beta) this was recognized and appendix criteria were given in the hope that they might better discriminate between these diseases. Conversely, misclassifications occur often in TIA clinics because of a lack of explicit diagnostic criteria for TIA. Methods We prospectively included 120 patients with TIA who were diagnosed according to the tissue based TIA definition and 1390 Danish patients and 152 Russian patients with MA. TIA was defined as new neurologic deterioration lasting less than 24 hours with no infarction in the relevant area on neuroimaging [1]. All received extensive semi structured face to face interviews about relevant clinical characteristics. Eligible patients with TIA had focal brain or retinal ischemia with resolution of symptoms without presence of new infarction on magnetic resonance imaging with diffusion weighted imaging (n=112) or computed tomography (n=8). We then tested main body and appendix criteria for MA for specificity against TIA patients and for sensitivity against the migraine materials. We developed explicit diagnostic criteria for TIA and tested them for sensitivity in the TIA patients and for specificity in the MA patients. Results The appendix criteria for MA had specificity versus TIA of 0.91 while the main body criteria were much less specific: 0.73. There was no major difference in sensitivity and we therefore recommend that the appendix criteria should replace the current main body criteria for MA. Our proposed explicit diagnostic criteria for TIA had a sensitivity of 1.0 which means that all 120 TIA patients fulfilled the criteria. The specificity of the TIA criteria tested against the Danish material of MA was 95% and tested against the Russian material it was 96%. Conclusion The field testing has led to preference for the appendix criteria for MA. We were able to design explicit diagnostic criteria for TIA with a very high sensitivity and specificity. We strongly recommend implementation of these criteria in migraine and cerebrovascular clinics. References 1. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack. Stroke. 2009; 40: 2276–2293. Background Primary headache disorders are classified as rare when their prevalence in the general population is below 1%. The criteria for the diagnosis of rare primary headaches are detailed in Chapter 3 and Chapter 4 of part one of the International Classification of Headache Disorders, 3 rd edition (ICHD-3) [1]. For the majority of rare headaches, prevalence and incidence have been estimated by case reports or underpowered observational studies. This paucity of evidence also concerns the Italian population. Our study aims to estimate specific and overall prevalence and incidence of rare headaches, according to ICHD-3, in patients referred to tertiary Headache Centres in a 3-year period. Material and method Data regarding patients referred to tertiary Headache Centres from April 30, 2017 to May 1, 2014 were retrospectively collected, by means of a web-based open source platform (SurveyMonkey.org). Each participating Centre received the approval of the competent Ethics Committee before commencing any study procedures. Patients were asked to give their consent according to Italian law. Patients were identified through Italian Health System unique identifier, in order to avoid duplications of patients referred to more than one Centre. Results Eleven Headache Centres were asked to participate and 10 participated in the study as data can be easily retrieved from electronic sources used for clinical practice. To date, data from 6 centres have been collected. In the study period, a total of 15847 patients referred to the Centres, and 724 (4.5%) of them had a diagnosis (prevalence) of rare headaches. Headache disorders with higher prevalence were cluster headache, either episodic or chronic (n=393, 2.4%), primary stabbing headache (n=49, 0.3%) and new daily persistent headache (n=26,0.2%). Three hundred-ninety four (2.5%) patients received their first diagnosis of a rare headache in the same period. Conclusions Data collected in participating Headache Centres allow to initially depict rare headaches epidemiology. Retrospective data will be integrated by prospective data collected in a registry that has been started by participating Centres. These epidemiologic data will serve for investigations about clinical features, diagnostic and therapeutic management of rare, often neglected, primary headaches in Italy. References 1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013; 33:629-808. 2. Holle D, Obermann M. Rare primary headaches. Curr Opin Neurol. 2014; 27:332-336. Background The safety, tolerability, and preliminary efficacy of non-invasive vagus nerve stimulation (nVNS; gammaCore®) have been demonstrated in clinical practice and pilot studies of acute migraine treatment [1,2]. The ease of use, flexibility, and favourable adverse event profile of nVNS make it an attractive option for patients. The aim of this study was to explore the efficacy, safety, and tolerability of nVNS for the acute treatment of migraine. Methods This multicentre, double-blind, randomised, controlled trial (RCT) included 248 patients with episodic migraine with or without aura from 10 Italian tertiary headache centres. Entry criteria and efficacy end points were consistent with existing guidelines and those of previous nVNS studies. Within 20 minutes from migraine pain onset, patients self-administered bilateral 120-second stimulations to the right and left sides of the neck. Patients were instructed to repeat both stimulations if pain did not improve by 15 minutes. Patients administered an optional additional set of stimulations at 120 minutes if not pain-free. Rescue medication use before 120 minutes was considered treatment failure. Up to 5 migraine attacks were treated in the double-blind period. Results Acute nVNS treatment (n=120) led to significantly higher pain-free rates than sham (n=123) for the first treated migraine attack at 30 minutes (12.7% vs 4.2%; P =0.012) and 60 minutes (21.0% vs 10.0%; P =0.023) but not at 120 minutes (30.4% vs 19.7%; P =0.067; primary end point; sensitivity analysis). To address the inconsistency between the 120-minute finding and the 2 earlier findings, a post hoc repeated-measures test confirmed that nVNS was superior to sham through 120 minutes (odds ratio: 2.3; 95% CI: 1.2, 4.4; P =0.012). Superiority of nVNS over sham was also seen for the rate of mild/no pain at 120 minutes (40.8% vs 27.6%; P =0.030) and ≥50% responder rates for no pain (32.4% vs 18.2%; P =0.020) and mild/no pain (47.6% vs 32.3%; P =0.026). Adverse event incidences were low, and most were mild and transient. Conclusions This RCT demonstrates that nVNS is rapidly effective, extremely well tolerated, and practical for the acute treatment of episodic migraine with or without aura. Significant benefits of nVNS versus sham were observed for pain freedom at 30 and 60 minutes but not at 120 minutes (primary end point). A repeated-measures test validated the primary end point, indicating the superiority of nVNS over sham through 120 minutes. Findings provide a clinical rationale for acute nVNS treatment in episodic migraine. Acknowledgements This study was sponsored by electroCore, LLC. We present this abstract on behalf of the PRESTO Study Group. Trial registration NCT02686034 . References 1. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia . 2014;34(12):986-993. 2. Barbanti P, Grazzi L, Egeo G, Padovan AM, Liebler E, Bussone G. Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study. J Headache Pain . 2015;16:61-65. Background Several studies indicated that migraine patients have tract-specific alterations in several white-matter tracts as compared to controls [1-12]. We investigated differences in white-matter tracts between episodic migraine (EM) patients and chronic migraine (CM) patients. Materials and methods We included consecutive eligible patients with EM or CM and referring to a tertiary headache center. We selected Caucasian women aged from 30 to 60 years. EM and CM patients were matched by age ±1. Imaging was conducted on a single 3-Tesla magnetic resonance imaging (MRI) scanner. Diffusion tensor data (DTI) data were processed using TRActs Constrained by Underlying Anatomy (TRACULA) for automatic reconstruction of a set of major white-matter pathways from diffusion-weighted MRI. Results We included 20 EM patients (mean age±SD 43.2±6.9) and 20 CM patients (mean age±SD 43.8±6.9). Years lived with migraine were similar in EM (mean±SD 14.3±7.0) and CM (mean±SD 18.6±9.0) patients (P=0.118). Mean±SD number of days with headache per month was 3.3±1.8 for EM; 9 (45%) CM patients had drug abuse. We found differences in mean diffusivity (MD) between EM and CM patients in the left superior longitudinal fasciculus temporal (Table 1). We found differences in mean fractional anisotropy (FA) between EM and CM patients bilaterally in the right inferior longitudinal fasciculus and in the left superior longitudinal fasciculus temporal (Table 1). EM patients showed a negative age-adjusted correlation between years lived with migraine and FA in the uncinate fasciculus (r=-.501; P=.048). CM patients showed a positive age-adjusted correlation between years lived with migraine and MD in the corpus callosum forceps major (r=.500; P=.049) and in the right anterior thalamic radiation (r=.492; P=.050). We did not find any correlation between frequency of migraine attacks and MD or FA nor in the EM nor in the CM group. Conclusions We found differences in white matter tracts between EM and CM patients. Our results also indicate that the longer the years lived with migraine the greater is the impairment in selected white-matter tracts. In summary, our data suggest that migraine type and number of years with migraine affects white-matter tract status. References 1. Chong CD, Schwedt TJ. Migraine affects white-matter tract integrity: A diffusion-tensor imaging study. Cephalalgia 2015;35:1162-1171. 2. Coppola G, Tinelli E, Lepre C, Iacovelli E, Di Lorenzo C, Di Lorenzo G, Serrao M, Pauri F, Fiermonte G, Bianco F, Pierelli F. Dynamic changes in thalamic microstructure of migraine without aura patients: A diffusion tensor magnetic resonance imaging study. Eur J Neurol 2014;21:287-e13. 3. Granziera C, DaSilva AF, Snyder J, Tuch DS, Hadjikhani N. Anatomical alterations of the visual motion processing network in migraine with and without aura. PLoS Med 2006;3:e402. 4. Kara B, Kiyat Atamer A, Onat L, Ulusoy L, Mutlu A, Sirvanci M. DTI findings during spontaneous migraine attacks. Clin Neuroradiol 2013;23:31-36. 5. Liu J, Lan L, Li G, Yan X, Nan J, Xiong S, Yin Q, von Deneen KM, Gong Q, Liang F, Qin W, Tian J. Migraine-related gray matter and white matter changes at a 1-year follow-up evaluation. J Pain 2013;14:1703-1708. 6. Rocca MA, Colombo B, Inglese M, Codella M, Comi G, Filippi M. A diffusion tensor magnetic resonance imaging study of brain tissue from patients with migraine. J Neurol Neurosurg Psychiatry 2003;74:501-503. 7. Rocca MA, Pagani E, Colombo B, Tortorella P, Falini A, Comi G, Filippi M. Selective diffusion changes of the visual pathways in patients with migraine: A 3-T tractography study. Cephalalgia 2008;28:1061-1068. 8. Schmitz N, Admiraal-Behloul F, Arkink EB, Kruit MC, Schoonman GG, Ferrari MD, van Buchem MA. Attack frequency and disease duration as indicators for brain damage in migraine. Headache 2008;48:1044-1055. 9. Yu D, Yuan K, Zhao L, et al. Yuan K, Zhao L, Dong M, Liu P, Yang X, Liu J, Sun J, Zhou G, Xue T, Zhao L, Cheng P, Dong T, von Deneen KM, Qin W, Tian J. White matter integrity affected by depressive symptoms in migraine without aura: a tract-based spatial statistics study. NMR Biomed 2013;26:1103-1112. 10. Yu D, Yuan K, Qin W, Zhao L, Dong M, Liu P, Yang X, Liu J, Sun J, Zhou G, von Deneen KM, Tian J. Axonal loss of white matter in migraine without aura: A tract-based spatial statistics study. Cephalalgia 2013; 33: 34-42. 11. Yuan K, Qin W, Liu P, Zhao L, Yu D, Zhao L, Dong M, Liu J, Yang X, von Deneen KM, Liang F, Tian J. Reduced fractional anisotropy of corpus callosum modulates inter-hemispheric resting state functional connectivity in migraine patients without aura. PloS One 2012;7:e45476. Objective To explore whether subjects exposed to head injury more often developed a new headache or experienced exacerbation of previously reported headache compared to non-exposed. Methods This population-based historical cohort study included headache data from two large epidemiological surveys performed with an 11-year interval. This was linked with data from hospital records on exposure to head injury occurring between the health surveys. Participants in the surveys who had not been hospitalized because of a head injury comprised the control group. The head injuries were classified according to the Head Injury Severity Scale (HISS). Multinomial logistic regression was performed to investigate the association between head injury and new headache or exacerbation of pre-existing headache in a population with known pre-injury headache status, controlling for potential confounders. Results The exposed group consisted of 294 individuals and the control group of 25,662 individuals. In multivariate analyses, adjusting for age, sex, anxiety, depression, education level, smoking and alcohol use, mild head injury increased the risk of new onset headache suffering (OR 1.74, 95% CI 1.05 – 2.87), stable headache suffering (OR 1.70, 95% CI 1.15 – 2.50) and exacerbation of previously reported headache (OR 1.93, 95% CI 1.24 – 3.02). The reference category was participants without headache in both surveys. Conclusion Individuals exposed to a head injury were more likely to have new onset and worsening of pre-existing headache and persistent headache, compared to the surrounding general population. The results support the entity of the ICHD-3 beta diagnosis “persistent headache attributed to traumatic injury to the head”. Background Few neuroimaging studies have explored brain morphometry in patients affected by chronic migraine (CM). Most of these studies were performed in patients with medication overuse. Here, we performed voxel-based morphometry (VBM) analysis to investigate the grey matter (GM) density of the whole brain in patients affected by CM without medication overuse. Our aim was to investigate whether there are fluctuations in the GM densities in relation to the patients’ clinical features. Materials and methods Twenty untreated CM patients without a past medical history of medication overuse underwent 3T MRI scans and were compared to a group of 20 healthy volunteers (HV). SPM12 and CAT12 toolbox were used to process MRI data and to perform VBM analysis of structural T1-weighted MRI scans. The patients’ versus HV relative GM density was assessed with an uncorrected threshold of p < 0.005. To check for possible correlations, patients’ clinical features and GM maps were regressed. Results Compared to HV, CM patients presented 4 clusters of significantly lower GM densities: I) right cerebellar lobules (VIIIa, CrusII), II) the left occipital areas (BA17/BA18), III) the left middle temporal gyrus, and IV) the left temporal pole /amygdala /pallidum /orbitofrontal cortex. The GM density of cerebellar hemispheres correlated negatively with the years of headache disease, and positively with the number of tablets intake per month. Conclusions To summarize, CM is associated with lower GM density in several brain areas known to be involved in antinociception, multisensory integration, and analgesic dependence. The GM density within the cerebellum was significantly related to longer duration of headache disease and to higher consumption of acute headache medications. We hypothesize that this morphological pattern we identified may be considered as a predisposing ground on which to develop medication overuse headache. Background Migraine is comorbid with various conditions, many with a greater relative frequency in chronic migraine (CM) versus episodic migraine (EM). The objective of this study was to replicate and extend work on the comorbidity of pain, psychiatric, and endocrine/neurological symptoms and conditions in a systematically recruited sample of people with EM and CM. Materials and Methods Data from the prospective web-based baseline survey of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study were used to identify people, recruited from an online panel using quota sampling, with EM and CM based on criteria modified from the International Classification of Headache Disorders, third edition, beta version. Participants completed a Comorbidities/Endophenotypes module that assessed 64 symptoms (e.g., neck pain) and conditions (e.g., rheumatoid arthritis). Respondents were asked (1) if they ever had a specific symptom (“Self-Reported [SR]”) and, if present, (2) if the SR symptom or condition had been confirmed/diagnosed by a “doctor” (“SR-physician diagnosis [SR-PD]”). Chi-square analysis was used to compare the relative frequency of symptoms and conditions in respondents with EM versus CM. This report presents data on symptoms and conditions from the Pain, Psychiatric, and Endocrine/Neurological comorbidity categories. Results Available CaMEO respondents with migraine (16,763) were sent the Comorbidities/Endophenotype module and 12,810 (76.4%: EM, 11,699; CM, 1,111) provided valid responses. Compared with the EM group, the CM group had a similar mean age (EM, 41.3 years; CM, 41.9 years), was more likely to be female (EM, 74.2%; CM, 81.5%; P <0.001) and white (EM, 84.0%; CM, 88.7%; P <0.001), and had a mean higher body mass index (EM, 27.7 kg/m 2 ; CM, 28.7 kg/m 2 ; P 10% higher in CM than EM: chronic back pain (EM, 22.5%; CM, 37.6%), chronic pain (EM, 7.4%; CM, 22.2%), neck pain (EM, 38.1%; CM, 55.3%), anxiety (EM, 25.7%; CM, 42.2%), and depression (EM, 28.1%; CM, 45.6%). Conclusions Overall, significantly more respondents with CM versus EM reported having specific symptoms or conditions. Mechanisms explaining this association might include direct causality (e.g., CM causes the comorbidity), reverse causality (e.g., the condition increases CM risk), and shared genetic or environmental risk factors. Confounding, or detection bias (i.e., “Berkson’s Bias”) could also contribute. Fig. 1 (abstract O16). Significant differences between CM and EM groups expressed in log10p and following the application of the False Discovery Rate (FDR) model Significant differences between CM and EM groups expressed in log10p and following the application of the False Discovery Rate (FDR) model Acknowledgments Editorial support for development of this abstract was provided by Lee B. Hohaia, PharmD, and Dana Franznick, PharmD, at Complete Healthcare Communications, LLC (Chadds Ford, PA), a CHC Group company, and funded by Allergan, plc (Dublin, Ireland). Background Human pharmacological imaging has been used with great success to study the cerebrovascular effects of headache-inducing substances, including calcitonin gene-related peptide (CGRP) and sildenafil. The role of the glutamate alterations in the deep brain structures pons and thalamus is of emerging interest but to date, methods to non-invasively study the pharmacologically induced biochemical effects in these areas have not been validated. Materials and methods We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol in a randomized, placebo-controlled, double-blinded, double-dummy, three-way cross-over design, using the headache-inducing substances calcitonin gene-related peptide (CGRP) and sildenafil, with peripheral and central modes of action on the nervous system respectively. Seventeen healthy volunteers were scanned with our optimized 1H-MRS protocol to investigate the CGRP- and sildenafil-induced glutamate+glutamine (Glx) changes in both pons and thalamus. In addition, we systematically investigated the Glx reproducibility and variability in pons and thalamus, based on repeated measurements on the same day and three separate days, in order to validate our method. Results We found that spectral quality was good for measurements in pons and thalamus with relatively low spectral line widths and high signal-noise-ratio. The Glx measurement variation was overall low in both pons and thalamus. The Glx level increased in pons at 40 – 70 min after sildenafil administration, when compared to placebo (5.6%, P=0.037). We found no sildenafil-induced Glx changes in thalamus, and no CGRP-induced Glx changes in pons or thalamus. Conclusions Our findings demonstrate that Glx measurements can be reliably obtained from pons and thalamus. The sildenafil-induced changes in pons likely reflect increased excitability of the pontine neurons. CGRP did not induce pontine or thalamic metabolic changes, indicating that it does not modify the neuronal excitability in these central deep brain structures, but rather exerts its effects on the peripheral nervous system and/or the trigeminal ganglion. Background Calcitonin gene-related peptide (CGRP) and sildenafil are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo . Furthermore, sildenafil is the only migraine inducing compound, where cephalic dilation is not reported. Here, we investigate the effect of CGRP and sildenafil on the extracranial and intradural parts of the middle meningeal artery (MMA). Methods In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison of CGRP and sildenafil, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug administration. Circumferences of extracranial and intradural MMA segments were measured using semi-automated analysis software. The area under the curve (AUC) for circumference change was compared using paired t -tests between study days. Results Twelve healthy volunteers completed the study. The AUC Baseline-120min was significantly larger on both the CGRP and sildenafil days in the extracranial MMA (CGRP, p =0.0003; sildenafil, p =0.021) and the intradural MMA (CGRP, p =0.013; sildenafil, p =0.027) compared to placebo. Peak dilation of the extracranial MMA after CGRP was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil. Peak intradural MMA dilation was 12.5% (95% CI [8.1-16.8]) after CGRP and 9.9% (95% CI [2.9-16.9]) after sildenafil. Conclusion An important novel finding of the present study is that both CGRP and sildenafil dilate intradural arteries, supporting the notion that all pharmacological migraine triggers, so far, do indeed dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by CGRP and sildenafil. Background Chronic migraine (CM) may be associated to specific cortical and subcortical volumetric changes [1-4]. However, it is not clear whether there is a causal relationship between these changes and the clinical course of migraine or whether they are rather an epiphenomenon. The objective of this study was to identify the main structural changes associated with CM and the relationship with the disease duration. Materials and methods We included consecutive eligible patients with episodic migraine (EM) or CM referring to a tertiary headache center. We selected Caucasian women aged from 30 to 60 years. EM and CM patients were matched by age ±1. The assessment was performed through a single 3-Tesla magnetic resonance imaging (MRI) acquisition followed by a morfovolumetric analysis through the Freesurfer software [5-7]. Groups analyses were performed through the QDec software for cortical volumes (level of significance fixed at p 0.01) and through the SPSS V22.0 software for subcortical volumes (level of significance fixed at p 0.05). Results We included 17 EM patients (mean age±SD 42.4±6.1) and 17 CM patients (mean age±SD 43.1±6.4). Years lived with migraine were not significantly different in EM (mean±SD 18.2±10.6) as compared to CM (mean±SD 21.4±11.6) patients (p=0.749). CM patients showed a selective cortical volume loss involving the insular cortex (p<0.005), the medial (p<0.005) and lateral (p<0.001) orbitofrontal cortex, the posterior cingulate cortex (p<0.001) and the inferior temporal cortex (p<0.005) in the right hemisphere, and the lateral orbitofrontal cortex (p<0.001), the posterior cingulate cortex (p<0.001) and the caudal anterior cingulate cortex (p<0.001) in the left hemisphere. At subcortical level volume differences involved the left and the right cerebellar cortex (p<0.05) and the medium and posterior portion of the corpus callosum (p<0.05). With respect to disease duration, a negative age-adjusted correlation between years lived with migraine and volumetric reduction was found in right (p<0.001) and left (p<0.005) middle temporal cortex in EM patients and in the right superior frontal cortex (p<0.001), cuneus (p<0.005) and lingual cortex (p<0.005), and left superior frontal cortex (p<0.001) in CM patients. No correlations between disease duration and subcortical changes were found in the two groups. Conclusions Regions showing a volumetric reduction might represent crucial hubs in migraine activity and pathophysiology. A better understanding of their role in the basal disease as well as in the process of chronification can provide a model to improve treatment options in patients with migraine [8]. References 1. Bilgiç B, Kocaman G, Arslan AB, Noyan H, Sherifov R, Alkan A, Asil T, Parman Y, Baykan B. Volumetric differences suggest involvement of cerebellum and brainstem in chronic migraine. Cephalalgia 2016;36:301-8. 2. Yu ZB, Peng J, Lv YB, Zhao M, Xie B, Liang ML, Li HT, Zhou ZH. Different mean thickness implicates involvement of the cortex in migraine. Medicine (Baltimore) 2016;95:e4824. 3. Neeb L, Bastian K, Villringer K, Israel H, Reuter U, Fiebach JB. Structural Gray Matter Alterations in Chronic Migraine: Implications for a Progressive Disease? Headache 2017;57:400-416. 4. May A, Matharu M. New insights into migraine: application of functional and structural imaging. Curr Opin Neurol 2007;20:306-9. 5. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 1999; 9: 179-94. 6. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000; 97:11050-5. 7. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 1999; 9:195-207. 8. Hubbard CS, Becerra L, Smith JH, DeLange JM, Smith RM, Black DF, Welker KM, Burstein R, Cutrer FM, Borsook D. Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal. Front Hum Neurosci 2016;10:497. We aimed to investigate the prevalence of headache in General Population (adults 18-70 years old) in Greece. A quantitative study, using the form of computer-assisted telephone interviews (C.A.T.I.) was designed. A draft questionnaire consisting of 37 questions was delivered in 145 headache sufferers in a pre-study work to evaluate the diagnosis of the primary headache disorder according to ICH-3beta diagnostic criteria. After the analysis of this questionnaire the specific 37-item questionnaire was decided. In total, N=10,008 interviews, representative of the population of Greece in terms of gender, age, and area, based on the most recent census (ELSTAT, 2011) were performed using the structured evaluated questionnaire. Based on the above contacts, n=1,197 respondents (12% of the sample) were found to suffer from headaches that reduce their performance. The one-year prevalence of Migraine that reduces activity was 8.2% (n=0.6m population) of Tension-Type Headache (TTH) 3.8% (n=0.28m of population) and of Cluster Headache 0.01% (n=0.74K of population). Chronic migraine one-year prevalence was 1% (n=0.7K of population). Females tend to suffer more from migraines and TTH as well as ages 35-54. The average patients has been suffering from headaches for 12 years. Headaches typically occur once a month or more frequently, 8 days per month on average. Although patients rarely misss work due to headaches, they do report headache-induced reductions in performance around 3 days per month. Slighly less than half patients have felt bad/ humiliated because of headaches, while social/family obligations are affected 3 days per month on average. About one fifth of patients seek professional treatment for headaches, most of them in the private sector. The most popular specialty for headache treatment is neurologist, followed by internist. Regarding both prophylactic and acute treatment, patients prefer oral medication to injection, even if the former is administered more frequently. They also prefer oral medication/ injection to a stimulation device. The stimulation device seems to be more attractive to males. Painkillers also are by far the most common acute treatment for headaches and the vast majority of patients have never taken prophylaxis for headaches. Only a small fraction have stopped taking a prophylactic treatment due to adverse effects. Interstingly, patients would be willing to spend 20€ on average per month for headache treatment, on average. Objective Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, was investigated in two Phase 3 studies (EVOLVE-1 and EVOLVE-2) to determine superiority to placebo in the prevention of migraine headache. Methods EVOLVE-1 and EVOLVE-2 were double-blind, 6-month studies in patients with episodic migraine (4 to 14 monthly migraine headache days [MHD]) conducted in North America and globally, respectively. Patients were randomized 2:1:1 to monthly subcutaneous injections of placebo, galcanezumab 120 mg or 240 mg. Primary endpoint was overall mean change from baseline in the number of monthly MHD during Months 1-6. Key secondary measures included rates of ≥50%, ≥75%, and 100% reduction in monthly MHD and overall mean change from baseline in monthly MHD with acute migraine treatments, and mean change from baseline over Months 4-6 on the Role Function-Restrictive domain score of the Migraine-Specific Quality of Life Questionnaire (MSQ-RFR) and Patient Global Impression-Severity of Illness (PGI-S). Results Baseline mean number of monthly MHD was 9.1 for both studies. Both galcanezumab doses demonstrated a statistically significant improvement compared with placebo (both studies p<.001) for overall mean change in monthly MHD (EVOLVE-1: placebo=-2.81; GMB 120 mg=-4.73; GMB 240 mg=-4.57; EVOLVE-2: placebo=-2.28; GMB 120 mg=-4.29; GMB 240 mg=-4.18). Percentage of patients with MHD reductions of ≥50%, ≥75%, or 100% were significantly higher for each galcanezumab dose compared with placebo (both studies p<.001). Patients had a significantly greater overall mean reduction of monthly number of MHD with acute migraine treatment for both galcanezumab doses relative to placebo (both studies p<.001). Mean change in MSQ-RFR and PGI-S ratings were statistically significant for each galcanezumab dose versus placebo (MSQ-RFR: p<.001 and PGI-S: p<.05, in both studies). There were no statistically significant differences between galcanezumab and placebo on the most common treatment-emergent adverse events except for a greater incidence of injection-site pruritus (both studies/doses p<.01) and injection-site reaction (both studies/doses p<.05), and injection-site erythema (p<.05, galcanezumab 240 mg) in EVOLVE-2. Conclusions Both doses of galcanezumab met the primary and all key secondary objectives, after adjusting for multiplicity. Treatment effects were similar across galcanezumab doses for efficacy, and safety; however, there was a higher rate of injection-site pruritus and reaction in galcanezumab-treated patients in both studies. EVOLVE-1 and EVOLVE-2 demonstrated that galcanezumab, at either 120 mg or 240 mg monthly, provided clinical benefit and improved function in patients with episodic migraine. Acknowledgements Studies were registered as NCT02614183 and NCT02614196 at ClinicalTrials.gov. Background The REPOSE Study, a European, multicenter, prospective, non-interventional study, investigated the effectiveness and safety of real-life use of onabotulinumtoxinA for chronic migraine (CM). Materials and Methods Adults prescribed onabotulinumtoxinA for CM were enrolled. Patients received onabotulinumtoxinA approximately every 12 weeks according to their physician’s usual practice, guided by the Summary of Product Characteristics. OnabotulinumtoxinA injection practices, safety, headache-day frequency, and Migraine Specific Quality of Life Questionnaire (MSQ) were collected at baseline and follow-up visits. Results Among 644 patients enrolled, 633 patients received ≥1 onabotulinumtoxinA dose for a total of 3499 onabotulinumtoxinA treatments. Patients had a mean (SD) age of 45.4 (12) years, were typically women (85.3%) and had a mean of 20.6 headache days/month. The median dose and median number of injection sites of onabotulinumtoxinA per session (baseline up to follow-up session 8) was 155 U and 31 sites, respectively. Through follow-up session 8, patient-reported estimates of headache days/month (≥4 hours) were significantly reduced from baseline ( P <0.001 at each follow-up session, Fig. 1). The MSQ domain scores (Role Restrictive, Preventive, and Emotional) were significantly reduced from baseline at each follow-up session. Adverse drug reactions, typically of mild to moderate severity, were reported by 18.3% of patients; eyelid ptosis (5.4%), neck pain (3.0%), and musculoskeletal stiffness (2.7%) were most frequently reported. Conclusion Preventive treatment of CM with onabotulinumtoxinA in a longer-term (24-month) real-world setting sustains a reduction in the frequency of headache days and significantly improves quality of life relative to baseline. No new safety concerns were identified. Acknowledgments Editorial support for development of this abstract was provided by Lee B. Hohaia, PharmD, and Dana Franznick, PharmD, at Complete Healthcare Communications, LLC (Chadds Ford, PA), a CHC Group company, and funded by Allergan, plc (Dublin, Ireland). Funding Allergan plc. Fig. 1 (abstract O19). Headache-day frequency calculated using the patient-reported estimate of number of days in a month with headache. Wilcoxon signed-rank test for change versus baseline (level of significance: 5%). The number of patients in follow-up (FU) sessions 9-12 were: FU9, n=67; FU10, n=38; FU11, n=21; FU12, n=16. The mean change from baseline for FU sessions 9-12 were each significant (* P <0.001) Headache-day frequency calculated using the patient-reported estimate of number of days in a month with headache. Wilcoxon signed-rank test for change versus baseline (level of significance: 5%). The number of patients in follow-up (FU) sessions 9-12 were: FU9, n=67; FU10, n=38; FU11, n=21; FU12, n=16. The mean change from baseline for FU sessions 9-12 were each significant (* P <0.001) Objectives: sound induced flash illusion (SIFI) is an illusory cross modal(audio-visual) phenomenon critically dependent upon excitability of visual cortex [1]. A recent study with SIFI confirmed hyperexcitability of visual cortex in migraine [2]; patients with migraine show abnormality of chromatic perception with a more relevant dysfunction in the wave-range of blu(S cones) [3]. Aims of the study were explore the relationship between peripheral chromatic and central visual dysfunction evaluating also the presence of functional receptor impairment in patients with migraine, with and without aura examined interictally. Subjects : 15 migraine patients with aura (MWA) and 15 without aura(MWoA) were compared with 12 healthy controls with no familiarity for migraine, and no significant age and sex differences between groups. Materials : all subjects underwent the following examinations: 1. SIFI text consisting of presentation of flashes and beeps in different combinations to generate illusions of ‘fission’ (one flash with 2 beeps perceived as 2 flashes) or ‘fusion’ (2 flashes with one beep perceived as 1 flash); SIFI has been employed to study excitability of visual cortex as such illusory phenomena critically depend upon visual cortical excitability (more active visual cortex--> less illusions). 2. colorimetric test to explore dysfunction in color perception. 3. Multifocal electroretinogram(mfERG) to evaluate the functional contribution of retinal receptor in different retinal areas. Results : according to previous report, MWA and MWoA patients showed significantly reduced SIFI of fission with respect to controls(p<.01). 8 MWA and 9 MWoA patients presented dysfunction of color perception. In these patients SIFI were significantly more reduced with respect to those showing no abnormality in chromatic perception(p<.05). No significant changes emerged in mfERG when comparing patients vs control; MWA vs MWoA, patients with and without chromatic perception dysfunctions. Discussion : results confirmed increased excitability of visual cortex in MWA and MWoA patients [2]. Moreover, greater excitability levels are found in patients with chromatic perception abnormalities suggesting a potential pathophysiological relationship between peripheral and central visual dysfunction in these patients. However, results of nornal mfERG response seem to exclude direct dysfunctional involvement of visual receptors, making likely abnormalities at different retinal levels of the neural pathway (bipolar cells?) Conclusion : peripheral and central abnormalities of visual can be found in migraine. They could be causally linked or follow to a common basic abnormality. Further study are needed to define the precise mechanism of such dysfunction together with their potential interrelationship and their role in the pathophysiology of the disease. References 1. Bolognini N, Rossetti A, Casati C, Mancini F, Vallar G. Neuromodulation of multisensory perception: a tDCS study of the sound- induced flash illusion. Neuropsycologia 2011;49:231–237. 2. Brighina F, Bolognini N, Cosentino G, Maccora S, Paladino P, Baschi R, Vallar G, Fierro B. Visual cortex hyperexcitability in migraine in response to sound-induced flash illusions. Neurology. 2015 May 19;84(20):2057-61. 3. Shepherd AJ. Color vision but not visual attention is altered in migraine. Headache. 2006 Apr;46(4):611-21. Background Perturbation of neuronal excitability contributes to migraine. Neurosteroids, i.e., allopregnanolone (AP), epiallopregnanolone (EP), dehydroepiandrosterone (DHEA) and deydroepiandrosterone sulfate (DHEAS), rapidly modulate neuronal firing rate and might be involved in the pathogenesis of migraine [1]. We sought to determine the relationship between plasma levels of neurosteroids in patients with migraine and cluster headache. Materials and Methods Patients with episodic migraine (EM, n=19), chronic migraine and medication overuse headache (CM, n=51), and cluster headache (CH, n=18) were studied. Sex- and age-matched subjects were also evalueted (i.e., 31F and 16M). Patients were clinically characterized by using validated questionnaires (BDI, MIDAS, HIT-6, SAS, as appropriate). Menopausal status was also recorded. Plasma levels of AP, EAP, DHEA and DHEAS were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) [2]. Whether sampling was concurrent with migraine/cluster attack was registered. Data have been statistically analysed using Student’s t-test and Spearman’s correlation. Data are presented as mean±SD. Results AP levels were consistently and significantly higher in EM (1.3±0.5 ng/mL) and CM (1.1±0.3 ng/mL) than in controls (0.6±0.3 ng/mL). In contrast, AP levels were significantly reduced in CH patients vs controls (0.3±0.1 vs 0.7±0.2 ng/mL, respectively; p<0.01). DHEA levels were significantly reduced in EM (2.9±1.5 ng/mL) and CM (1.6±1.1 ng/mL) compared to controls (5.1±3.8 ng/mL; p<0.05). The profiles of DHEAS and EAP across groups were inconsistent, being significantly reduced in CM, but not different from controls in EM and CH. In CM patients, the ratio AP/EAP was significantly higher than in controls (3.0±1.7 vs 1.8±1.2, respectively; p<0.01). Discussion Changes of circulating levels of neurosteroids are associated to the presence of migraine. The GABA A receptor agonist, AP, and the NMDA receptor agonist, DHEA, were higher and lower than controls, respectively. This suggests an attempt to modulate neuronal hyperexcitability in migraine patients. Changes of neurosteroids concentrations in CH patients were significant only for AP, which may contribute to the more severe clinical features of CH vs CM and EM. For the first time, we provide evidence for a role of neurosteroids in the pathogenesis of migraine. Novel and more effective therapies may now be devised by targeting neurosteroid-related pathways. References 1. Reddy DS, Estes WA. Clinical potential of neurosteroids for CNS disorders. Trends Pharmacol Sci. 2016; 37:543-561. 2. Lionetto L, De Andrés F, Capi M, Curto M, Sabato D, Simmaco M, Bossù P, Sacchinelli E et al. LC-MS/MS simultaneous analysis of allopregnanolone, epiallopregnanolone, pregnanolone, dehydroepiandrosterone and dehydroepiandrosterone 3-sulfate in human plasma. Bioanalayis 2017; 9:527-539. Objective To compare efficacy on headache pain and the patient-centric measure of most bothersome symptom (MBS; nausea, phonophobia, or photophobia) at 2 hours post dose, time course of migraine response, rescue, and safety following treatment with lasmiditan 200 mg or 100 mg or placebo. Materials and methods In this randomized, double-blind, placebo-controlled study, subjects with at least moderate disability (Migraine Disability Assessment Score [MIDAS] ≥11) were randomized 1:1:1 to a first dose of lasmiditan treatment (200 mg or 100 mg) or placebo within 4 hours of onset of a migraine attack (moderate severity or worse and not improving). Subjects took a randomly assigned second dose of either their previously assigned lasmiditan dose or placebo for rescue or recurrence of migraine if needed (2 to 24 hours post initial dose); subjects randomized to placebo received placebo as the second dose. The primary measures were comparison of the proportions of subjects (modified intent-to-treat population [mITT]) in the lasmiditan 200 mg and placebo groups who, at 2 hours post first dose, were headache pain free and MBS free. Comparisons were made via logistic regression with terms for treatment group and background migraine preventative use. Lasmiditan 100 mg and placebo were also compared and safety parameters assessed. Results At baseline, 1545 subjects assigned to lasmiditan 200 mg (n=518), 100 mg (n=503), or placebo (n=524) had a mean MIDAS score of 31.3 and 82% had ≥1 cardiovascular (CV) risk factors (in addition to migraine). At 2 hours, greater proportions were: headache pain free with lasmiditan 200 mg (32.2%) and 100 mg (28.2%) than placebo (15.3%; P <.001); MBS free with lasmiditan 200 mg (40.7%) or 100 mg (40.9%) than placebo (29.5%; both P <.001); and, had headache relief with lasmiditan (59% each group) than placebo (42.2%; P <.001). In the lasmiditan 200 mg, 100 mg, and placebo groups, 29%, 36%, and 58%, respectively, took a second dose for rescue. The most frequently reported adverse events (AE) with lasmiditan were dizziness, fatigue, lethargy, nausea, paresthesia, and somnolence. No notable increase in CV AEs occurred in either lasmiditan group even among subjects with ≥1 CV risk factors (eg hypertension). Conclusions Lasmiditan treatment provided more patients freedom from and reduction of headache pain and MBS at 2 hours compared with placebo. This patient population with severe disability associated with migraine, tolerated lasmiditan treatment. Trial registration ClinicalTrials.gov Identifier NCT02439320 . Objective To investigate the mechanism of post-ictal headache. Background Seizures affect 50 million people worldwide and are followed by headache in up to 50% of patients. These headaches are called Post-Ictal Headaches (PIH), they are commonly migraineous in nature, can last many hours, be very painful and since they strikes repetitively, they drive patients to endure a significant hardship. Given that seizures occur in the cortex, we hypothesized that PIH are intracranial at origin and accordingly, aimed in this study to determine whether and how seizures (both generalized and focal) activate peripheral and central neurons of the meningeal sensory pathway. Methods Single-unit electrophysiological techniques were used to study the physiological properties and response profile of C- and Aδ meningeal nociceptors and high-threshold (HT) and wide-dynamic range (WDR) neurons in the spinal trigeminal nucleus – in response to occurrence of seizure underneath their dural receptive fields. Cortical electrodes were used to trace the magnitude, extent and progression of epileptiform seizure. Results The induction of seizure triggered prolonged activation in both meningeal nociceptors and central trigeminovascular neurons. In the ganglion, activity began to increase minutes after the seizure reached their receptive fields and remained elevated for as long the seizure activity continued. In the medullary dorsal horn, neurons exhibited a biphasic response following seizure onset that consisted of an initial inhibition of the spontaneous activity followed by a gradual increase in activity that remained above baseline for at least 2 hours after seizure onset. In separate experiments, we created a focal seizure that was restricted to either the parietal or occipital cortex. Induction of focal seizure in the parietal cortex did not produce any changes in neuronal activity, but induction of focal seizure in the occipital cortex produced the same neuronal changes that we observed with the generalized seizure. Conclusions This study provides evidence for activation of the trigeminovascular pathway by generalized and focal seizures. The importance of this study is that it uses a model of abnormal cortical activity to which there are ample of evidence in human subjects suffering epilepsy (and PIH), and thus, it bypass the bitter debate over the validity of studying the headache phase of migraine using the controversial cortical spreading depression model – to which evidence for actual occurrence in humans are scarce. Background In recent years, an increased attention has been devoted to the potential association between migraine and thyroid function, with conflicting results. A few studies found that migraine may be associated with an increased risk for the development of both overt and subclinical hypothyroidism (SH). On the contrary, the risk of developing migraine in patients with hypothyroidism has been scarcely investigated. Therefore, the main purpose of our study was to investigate the association between subclinical hypothyroidism and migraine in adults, using a case-control strategy. Materials and methods 151 consecutive patients with SH (24 men and 127 women, mean age 48.36± 15.86 years) and 150 controls (37 men and 113 women, mean age 50.86± 9.19 years) were recruited for the study. In all subjects, migraine characteristics were collected through a direct face-to-face interview, using a structured questionnaire. Moreover, clinical characteristics and thyroid parameters (TSH, fT3, fT4, anti-thyroglobulin and anti-peroxidase antibodies) were compared between SH patients with comorbid migraine and SH patients without migraine. Results The prevalence of lifetime migraine was significantly higher in SH patients in comparison with controls (46% vs 13%, p< 0.001; OR 5.80; 95% CI= 3.35-10.34). Both migraine without aura and migraine with aura were significantly higher in SH patients than controls (38% vs. 9%, p< 0.001; and 8% vs. 4%, p= 0.01, respectively). Thyroid hormones and antibodies levels were not different between SH patients with migraine and those SH patients without migraine. Finally, a higher comorbidity for autoimmune diseases was found in SH patients with migraine respect to SH patients without migraine. Conclusions Our data suggest that migraine is significantly more frequent in patients with subclinical hypothyroidism respect to controls. Additional studies are needed in order to corroborate this association and to explore the underlying biological mechanisms.

Background Cystic fibrosis (CF) is autosomal recessive genetic disease caused by mutation in the transmembrane conductance regulator (CFTR) that is involved in Cl - ions transport. Coexistence of cystic fibrosis and sporadic hemiplegic migraine (SHM) has been reported in only two cases in literature so far [1]. Their co-occurrence may be due to more than a simple chance. CFTR is widely expressed in the brain and seems to be important in regulating other channels, suggesting that some shared genetic channel mutation might cause the two diseases at the same time. Case report A 32-y.o. caucasian male was diagnosed with CF at birth. He presented CFTR heterozygosis with a typical CFTR delta F508 mutation in one allele and an unknown mutation on the other allele. He also had patent foramen ovale that was surgically closed when he was 26-y.o. The patient reported occasional cough bouts, triggering hemiplegic migraine attacks In March 2017 a such cough bout, lasting 48 hours, led to a severe hemoptysis and followed by a 15-minutes long loss of consciousness. The patient was transported to emergency rooms (ER) and intubated. An arterial-blood gas test showed severe hypoxia with hypercapnia. The patient recovered in few days. A brain MRI+MRA, performed in ER showed diffuse DWI alterations, affecting left frontal-parietal-occipital areas, which later resolved, except for a persistent small damage in the frontal region. Both large vessel diseases and embolic sources as well were excluded by carotid duplex sonography, transcranial doppler examination and transthoracic echocardiography. In April, he was visited in our Headache Clinic. The neurological examination showed a mild right hemiparesis with asymmetrical increased tendon reflexes and upward plantar reflex on the right. Conclusions The ischemic damage, presented by the patient, suggests a migrainous infarction, since it followed the migraine aura symtpoms and occurred in the brain regions implied in HM. Then, it may be argued that migrainous infarction was caused by the development of CSD in a brain tissue, suffering from hypoxia due to cough bout and hemoptysis. In fact, cerebral infarction, with prompt expansion of the core infarct, following mild hypoxia, is associated to mutation in CACNA1 gene in both mice and humans, possibly related to neural excitability and the following vasoconstrictive vascular coupling in the penumbra [2-3]. In conclusion, in CF patients there is the chance of SHM comorbidity, due to a genetic overlap with a higher risk of developing migrainous infarction. Consent for publication: The authors declare that written informed consent was obtained for publication. References 1) Rao DS, Infeld MD, Stern RC, Chelimsky TC Cough-induced hemiplegic migraine with impaired consciousness in cystic fibrosis. Pediatr Pulmonol. 2006 Feb;41(2):171-6 2) Eikermann-Haerter K, Lee JH, Yuzawa I, et al. Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 2012; 125(2): 335–345. 3) Rainer Malik, Bendik Winsvold, Eva Auffenberg, Martin Dichgans and Tobias Freilinger, The migraine–stroke connection: A genetic perspective, Cephalalgia 2015, Vol 36, Issue 7, pp. 658 – 668. Objectives: Chronic migraine (CM), Chronic tension-type headache (CTTH) and new daily persistent headache (NDPH) are the main forms of CPH reported in the ICHD-III beta version. Medication-overuse headache (MOH) is classified among secondary headache but it generally affects patients with a pre-existing primary headache. CPH have been well described in adults and their diagnostic criteria were designed based on the clinical characteristics in the adult population. However, CPH are not a rare condition in children and adolescence with negative impact on their quality of life. Our aim was to investigate the clinical features of CPH in a cohort of pediatric patients. Methods: We retrospectively reviewed the charts of patients attending the Headache Centre of Bambino Gesú Children and Insubria University Hospital. The ICHD-III criteria were used for diagnosis. Statistical analysis was conducted by SPPS version 22.0 and χ2 test was used to study possible correlations between: - CPH and population features (age and sex); - CPH and headache qualitative features; - CPH and risk of MOH; -CPH and response to prophylactic therapies. Results: We included 377 patients with CPH (66.4% female, 33.6% male, age between 0 and 18 years). The most frequent CPH type was CM (73.5%), followed by CCTH (13.5%) and NDPH (13%). MOH was detected in 10.9% of total patients. CPH are less frequent under 6 years of age (0.8%; p <0.05); significant greater frequency in females than in males was found in the age group between 0-6 years (23/31 F, 8/31 M) and between 15-18 years (41/51 F, 10/51 M) (p<0.05). No correlations between age/sex and different CPH types were detected. We found a more frequent incidence of vegetative symptoms (photo/phonophobia and vertigo) in female sex (p< 0.05). Nausea and vertigo are the two most frequent vegetative symptoms under 10 years of age (p<0.05) while photo/phonophobia are more frequently in patients older than 15 years (p<0.05). Possible development of MOH has been found correlated with CM types (p<0.05) and age above 15 years (p<0.05). Our results show that 272 (72.1%) out of 377 CPH patients received a prophylactic therapy. Among them, 190 patients received amitriptyline, 29 patients topiramate, 15 patients L-5 hydroxytryptophan, and 8 patients flunarizine. Thirty patient performed two or more drugs. Positive response to therapy (reduction of attacks by at least 50% in a month) was detected in 54% of patients, while no outcome data were obtained from 29.4% of cases. Amitriptyline and topiramate had the highest efficacy (p<0.05). We found that 59.2% of patients who received amitriptyline showed significant reduction in the attack frequency, while 48.4% patients receiving topiramate improved their headache attack frequency (p>0.05). However, for both drugs more than 30% of patients did not have follow up data. Conclusion: Our results showed that CPH presented a correlation with patients’ age and sex. No significant differences were found between CPH types and population/pain features. Development of MOH was related with CM onset and adolescent age. Amitriptyline and topiramate had the best effectiveness. However, it is to be underlined that follow up data could not be issued from a moderate percentage of patients. It will be useful in the future to reduce the number of missing patients by improving patients’compliance and promoting the concept of migraine as a disease that can cause relevant disability. Disclosure of interest None Declared Background Chronic migraine (CM) is a disabling neurologic condition that affects 2-3% of the general population, and is the first reason of consultation in many tertiary headache centres. Nevertheless, comprehensive descriptions of CM clinical features, risk factors and comorbidity in large case series are very scarce. Aim of this study is to depict the characteristics of CM in a large cohort of patients referred to several tertiary headache centres throughout Italy. Patients and methods Patients with the diagnosis of CM according to ICHD-3 beta, consecutively referred to 16 major Italian headache centres during the period 1 st October 2016 – 31 th March 2017 entered the study, having expressed an informed consent. An especially prepared web-based electronic medical record was filled in with anonymized patients data. Results Eight hundred and thirty-eight patients (female 86.3%; mean age 48.5±13.08 years) were included. CM mean duration was 10.7 years; mean frequency of headache days was 22.7±6.11/month. Mean headache duration was 10.5±6.81 hours; mean headache severity on a 1-10 scale was 7.7±1.56. ICHD-3 beta CM diagnostic criterion C was satisfied by having ≥8 days per month with migraine without aura by the overwhelming majority of patients (95.5%), while a not negligible percentage had migraine with aura (9.1%) or headache relieved by a triptan (9.7%). Criteria for medication-overuse headache were fulfilled in 71.4% of the cases. Most overused drugs were simple analgesics (40.6%), followed by triptans (35.1%), and combination analgesics (15.8%). Beyond medication overuse, the most frequent risk factors for CM were: high baseline headache frequency (39.1%), anxiety (30.3%), sleep disorders (26.0%), depression (22.2%), cutaneous allodynia (14.1%), life events (11.5%), excessive caffeine intake (10.4%), sleep bruxism (9.1%), panic disorder (7.2%), and obesity (6.2%). Most represented comorbid disorders were: anxiety (32.3%), sleep disorders (32.2%), depression (25.4%), hypertension (20.5%), irritable bowel (8.4%), and fibromyalgia (6.6%). CM was highly disabling in our population: mean MIDAS score was 66.6 and mean HIT-6 score 63.7. Mean monthly number of symptomatic drugs was 28.8 (range 0-270). Refractory chronic migraine (no MOH, unsuccessful use of at least 3 preventive drugs) was present in 11.3% of the patients. Conclusions The study of a large case series of patients with CM allows a precise picture of this debilitating condition, of its main clinical features, transformation to CM risk factors and comorbid disorders. Acnowledgements This study was carried out on behalf of the Independent Research section of Società Italiana per lo Studio delle Cefalee (SISC). Background: There are no prospective studies on prolonged auras (PAs). i.e. an aura that includes at least one symptom lasting for >1hr. Objectives: We aimed to evaluate the prevalence of PAs and compare their phenotype with NON-PAs in a prospective diary-aided study. Methods: We recruited 224 consecutive patients affected by migraine aura attending the Headache Centers of Pavia and Trondheim. Patients were asked to report on an ad hoc diary, during three consecutive migraine with aura attacks, quality of each aura symptom (AS), headache features and to insert the time of onset/end of each AS and of the painful phase and describe the features of headache. Results: 72 patients completed the diaries during three consecutive auras for a cumulative number of 216 auras recorded. Out of 216 auras, 38 (17%) were PAs. Out of 72 patients, 19 (26%) have at least one PA. When comparing PAs with non-PAs (n=178) with respect to 20 features collected, PAs were characterized by a higher total number of symptoms (p<0.001), a higher frequency of sensory symptoms (p<0.001) and a higher frequency of dysphasic symptoms (p2 hrs (PA>2, n=23) with the remaining ones (n=193) and auras including at least one symptom lasting for >4 hrs (PA>4, n=14) with the remaining ones (n=202). In the first comparison, the only differences were a higher frequency of sensory symptoms and a higher number of AS in PA>2 (p=0.001 and p=0.005, respectively) and in the second comparison the only difference was a higher number of AS in PA>4 (p=0.043). Conclusion: PA is quite common (17% of all auras, occurring at least once in 26% of patients) and phenotypically differs from the other auras only for a higher number of non-visual symptoms (non-VSs). This latter finding is not surprising if we consider that an AS with a longer duration is likely related to a cortical spreading depression (CSD) that proceeds along a longer path on the respective brain area. Such CSD therefore is more likely to involve other adjacent brain areas, thus conferring a higher number of non-VSs to PA. The substantial phenotypical similarities between PAs and the other auras is maintained also when we increase the limit of duration to 2 and/or 4 hrs. This finding should lead to a discussion about the term “prolonged aura” and how long its duration should be. Background : Many studies support the presence of endothelial dysfunction in migraineurs. In a recent work, the authors have found a coronary microvascular endothelial dysfunction (CMED) in migraine patients compared with control group suggesting that there would be a common pathophysiological pathway of impaired coronary and cerebral endothelial function in migraine. CMED may lead to a coronary microvascular vasospasm. Aim: The aim was to verify the presence of a microvascular vasospasm of cerebral cortex in “prolonged” aura migraine. Methods: We studied the microcirculation of cerebral cortex by Near Infrared Spectroscopy (NIRS) and cerebral macrocirculation by transcranial Doppler (TCD) in 8 subjects (3 M and 5 F, age range 21-41 years) during spontaneous “prolonged” migraine aura in according to ICHD criteria and compared the results with the headache-free periods. Duration of aura symptoms: between 2 and 8 hours. Results: During aura NIRS showed a significant decrease of the Arterial Pulse Wave of Cerebral Microcirculation amplitude (-33 % ± 5.7), p<0.001 contralateral to the symptoms of aura compared with the headache-free periods; TCD showed a significant increase of Pulsatility Index (+36.5 % ± 6.5), p<0.001 and a significant decrease of the diastolic velocity in the posterior and middle cerebral artery contralateral to the symptoms of aura compared with the headache-free periods. Conclusions: In conclusion during “prolonged” migraine aura we find cortical areas of microvascular vasospasm corresponding to the topography of aura symptoms and suggesting the presence of a microvascular endothelial dysfunction. Consent for publication: Written informed consent to publication was obtained from the patient(s). Background : A wide range of medications is now available for migraine prophylaxis but some patients don’t show a significant improvement also with the best tailored drug and some other patients discontinue therapy because of side effects. The interest of clinicians and patients toward nutraceutical medicine is expanding worldwide but limited evidence is to date available in favour of and against their use in migraine prophylaxis [1,2]. Objectives : To compare efficacy and tolerability of a nutraceutical formulation containing Magnesium 185 mg + Tanacetum parthenium 150 mg + Griffonia 100 mg/die (MTG) vs Amitriptyline 25 mg/die (AMI) for 3 months, as prophylactic migraine therapy in a sample of adult outpatients. Patients and Methods : This is a retrospective study conducted by reviewing the medical records of all patients consecutively referred to the Headache Centre from January 2017 to June 2017. 62 patients (52 females and 10 males), who received the diagnosis of migraine with or without aura and were submitted to a 3 months prophylactic therapy with AMI (33 cases) or with MTG (29 cases) were recruited. Primary efficacy parameters were: attack frequency and aura frequency reduction. Secondary efficacy parameters were pain intensity, pain duration and aura duration reduction. Tolerability was evaluated by means of reported side effects. Results: A significant reduction of headache frequency, pain intensity, pain duration, aura frequency and aura duration was found in the whole sample after a 3 months prophylactic therapy. No difference was found between MTG group and AMI group in attack frequency reduction (4,90+6,37 vs 8,30±8,09, p=0,21) and in aura frequency reduction (3,00+4,84 vs 2,34+2,89, p=0,72). Six patients in AMI group reported side effects (weight gain 3 cases, somnolence 1 case, weight gain and somnolence in 2 cases). One patient in MTG group reported both hands paresthesias. Conclusions : The results of this study suggest that the nutraceutical formulation containing Magnesium 185 mg+ Tanacetum parthenium 150 mg+ Griffonia 100 mg, could be a valid therapeutic option with lower occurrence of side effects than Amitriptyline. The strength of evidence of this study is low because of both the retrospective design and the little sample. Double-blind randomized larger studies are needed to correctly estimate the impact of the placebo effect in this promising therapy. References 1. Sarchielli P, Granella F, Prudenzano MP, Pini LA, Guidetti V, Bono G, Pinessi L, Alessandri M, Antonaci F, Fanciullacci M, Ferrari A, Guazzelli M, Nappi G, Sances G, Sandrini G, Savi L, Tassorelli C, Zanchin G. Italian guidelines for primary headaches: 2012 revised version. J Headache Pain. 2012 May; 13 Suppl 2:S31-70. 2. D'Onofrio F, Raimo S, Spitaleri D, Casucci G, Bussone G. Usefulness of nutraceuticals in migraine prophylaxis. Neurol Sci. 2017 May;38(Suppl 1):117-120. Background Some epidemiological studies report many comorbidities in migraine, mostly identified through questionnaires and based on self-reported diagnosis. However, the prevalence of comorbidities should be better performed by a clinical evaluation. Materials and methods We have evaluated prospectively the prevalence of some comorbidities in the first 1000 migraine patients (aged 15-65 years), afferent to Headache Center in the 2011-2013 years and resident in the district of Empoli Health Authority, classified with a diagnosis of migraine without aura (MO), migraine with aura (MA), and chronic migraine (CM) that also includes patients with medication overuse headache who had episodic MO before, according to the revised ICHD-2R classification. The specialist visits were performed by a single physician (A.P.). In addition to a detailed semistructured face to face interview, health information was researched in the database of specialist visits, hospital recovery or emergency department. Results Our clinical survey consisted of 1000 patients aged 15-64 years (mean age 39.5), 780 females (mean age 39.9) and 220 males (mean age 38.2). This population included 866 patients with episodic migraine (EM) (666 ♀ and 200 ♂, mean age 38.2) and 134 with CM (114 ♀ and 20 ♂, mean age 48.0). Out of 866 patients with EM, 767 had MO (mean age 38.4) and 99 had MA (mean age 36.7). The prevalence of treated chronic conditions (CC) was: depression 5.6 %, hypertension, 9.3 %, diabetes 1.2 %, asthma 3.3 %, hypothyroidism 6.4 %, hypercholesterolemia 0.5 %. Out of 56 patients assuming antidepressants only 4 assumed amitriptyline. Out of 93 patients treated for hypertension, 42 used beta-blockers (18 atenolol, 13 nebivolol, 6 propranolol, 3 bisoprolol, 1 metoprolol, 1 carvedilol). Patients who assumed thyroid hormones were 64: they referred thyroiditis (28), thyroidectomy (13), other (primitive, post-hyperthyroidism, etc) hypothyroidisms (16), goitre in euthyroidism (7). Patients with asthma were 65: 33 in current treatment and 32 in the past. Migraine patients suffering of allergies were 198: 132 rhinitis, 42 drugs allergy and 19 food allergy. Other somatic CC were: gallstones (5.4%), kidney stones (5.7%), inflammatory bowel disease (0.5%) including Crohn disease (3 patients) and ulcerative colitis (2 patients), celiac disease (0.5%, all females), endometriosis (1.0%), psoriasis (0.7%), cardiac diseases (1.0%), rheumatic/autoimmune diseases (0.7%) including lupus (0.2%), Behcet disease, mixed connective disease, rheumatoid arthritis, scleroderma, and Sjogren syndrome (0.1%).Vitiligo (0.2%), endometrial/breast cancer (0.5%), meningioma (0.2%), hyperthyroidism (0.3%), restless legs syndrome (0.3%), fibromyalgia (0.2%), were also detected. Other CC whit a prevalence of 0.1% are not reported. Hypothyroidism was more frequent in females (OR 0.163, p < 0.001), and hypertension in CM compared to EM (OR 0.307, p < 0.001) but EM patients were 10 years younger than CM patients (Table 1). Conclusions The percentages of treated CC in migraine patients in our survey, in particular those involved in cardiovascular risk, were not higher than those estimated through the analysis of prescription rate of marker drugs in the general population in the same district [1,2]. In this comparison, the higher prevalence of hypothyroidism was not statistically significant when migraine patients were considered by gender (♀ p = 0.067, ♂ p = 0.38), while epilepsy, diabetes, hypercholesterolemia and asthma, on the contrary, were less frequently reported (p<0.001). Our data are in substantial agreement to a large general practitioner’s database [see 2]. Table 1 (abstract O31). Percentage of treated diseases and lifetime allergies in migraine patients All subjects ♂ ♀ EM CM Depression 5.6 3.1 6.2 5.4 6.7 Hypertension 9.3 8.1 9.6 7.5 20.8 * Diabetes 1.2 1.3 1.1 1.0 2.2 Asthma 3.3 3.2 3.3 3.0 5.7 Hypothyroidism 6.4 1.3 7.8 * 6.3 6.7 Allergy 19.8 21.8 19.2 19.8 19.4 * p < 0.001 Percentage of treated diseases and lifetime allergies in migraine patients * p < 0.001 References 1) Panconesi A, Pavone E, Pagliai C, Coletta D, Mennuti N, Bartolozzi ML, Benemei S, Guidi L. Evaluation of migraine comorbidities through clinical and pharmaceutical data. J Headache Pain 2013; 14(Suppl):13-14. 2) Panconesi A, Bartolozzi ML, Guidi L. Migraineurs: seriously ill or basically healthy? J Headache Pain 2015; 16(Suppl 1):28. Background There is an increasing use of Alternative and Complementary Medicine (CAM) for prophylaxis of pediatric primary headaches [1,2,3,4]. Materials and methods We carried out a search for clinical trials in PubMed of patients aged 0-18 years with primary headaches treated with nutraceuticals or phytotherapeutic compounds. Results A) Nutraceuticals Nutraceuticals The following evidences are available in the literature: Magnesium: significant reduction in attacks, consumption of analgesics and disability in cases with Migraine (M) [5] and Tension-Type Headache (TTH) [6] Riboflavin (vitamin b2): higher efficacy than placebo in the treatment of TTH [7]. In M: effective compared to baseline [8] but not superior to placebo [7, 9] Coenzyme Q10: in CoQ10-deficient patients, CoQ10 supplementation obtained a reduction of attacks’ frequency and disability degree [10]. A trial showed no efficacy versus placebo [11] Alpha lipoic acid: no study available Melatonin: significant reduction in frequency and duration of M or chronic TTH attacks [12]. In another study: reduction of frequency, intensity, duration of M attacks and PedMIDAS score [13] 5-hydroxytryptophan: no significant differences vs placebo in M (Santucci M,1986). B) Phytotherapeutic products Magnesium: significant reduction in attacks, consumption of analgesics and disability in cases with Migraine (M) [5] and Tension-Type Headache (TTH) [6] Riboflavin (vitamin b2): higher efficacy than placebo in the treatment of TTH [7]. In M: effective compared to baseline [8] but not superior to placebo [7, 9] Coenzyme Q10: in CoQ10-deficient patients, CoQ10 supplementation obtained a reduction of attacks’ frequency and disability degree [10]. A trial showed no efficacy versus placebo [11] Alpha lipoic acid: no study available Melatonin: significant reduction in frequency and duration of M or chronic TTH attacks [12]. In another study: reduction of frequency, intensity, duration of M attacks and PedMIDAS score [13] 5-hydroxytryptophan: no significant differences vs placebo in M (Santucci M,1986). Phytotherapeutic products The following evidences are available in the literature: Petasites hibridus: 50% reduction of attacks in 77% of cases with M in an open-label multicentre study [14]. Long term effects better than placebo in another study [15] Tanacetum parthenium: no study available Ginkgo biloba combined to Coenzyme Q10/Vitamin B2/Magnesium: reduction of the M frequency and the use of symptomatic medication in a open-label study [16]; reduction of the M frequency in another open-label study[17]; reductions of M frequency, duration, intensity, PedMIDAS score, behavioural reactions to M were significantly greater in the Ginkgolide group than in the group received L-tryptophan/5-hydroxytryptophan (from Griffonia simplicifolia)/vitamin PP and B6[18]. C) Italian experience in specialized juvenile headache Centers Petasites hibridus: 50% reduction of attacks in 77% of cases with M in an open-label multicentre study [14]. Long term effects better than placebo in another study [15] Tanacetum parthenium: no study available Ginkgo biloba combined to Coenzyme Q10/Vitamin B2/Magnesium: reduction of the M frequency and the use of symptomatic medication in a open-label study [16]; reduction of the M frequency in another open-label study[17]; reductions of M frequency, duration, intensity, PedMIDAS score, behavioural reactions to M were significantly greater in the Ginkgolide group than in the group received L-tryptophan/5-hydroxytryptophan (from Griffonia simplicifolia)/vitamin PP and B6[18]. Italian experience in specialized juvenile headache Centers In a multicentre study of 637 young M and TTH patients, supplements and melatonin were used respectively by 205 (32%) and 61 (10%) patients with a good/excellent efficacy in 68% and 75% of cases respectively, without differences between the two headache types[19]. Conclusions Nutraceuticals and phytotherapeutics showed some positive effects on M and TTH in pediatric patients in open label studies and in some controlled studies with placebo. Further studies are needed to better address therapeutic choices in primary pediatric headaches. References 1. Ledda M G, Porcu L, Cianchetti C. Complementary and alternative therapies in primary headaches. Giornale di Neuropsichiatria dell’Età Evolutiva. 2012; Volume 32. Numero 1:65-72 2. Bethell C, Kemper KJ, Gombojav N, Koch Thomas K. Complementary and Conventional Medicine Use Among Youth With Recurrent Headaches. Pediatrics. 2013;132(5):1173–83. 3. Dalla Libera D, Colombo B, Pavan G, Comi G. Complementary and alternative medicine (CAM) use in an Italian cohort of pediatric headache patients: the tip of the iceberg. Neurol Sci. 2014;35(Suppl 1):S145–8. 4. Orr SL, Venkateswaran S. Nutraceuticals in the prophylaxis of pediatric migraine: Evidence- based review and recommendations. Cephalalgia. 2014;34(8):568–83. 5. Wang F, Van DenEeden SK, Ackerson LM, Salk SE, Reince RH, Elin RJ. Oral Magnesium Oxide Prophylaxis of Frequent Migrainous Headache in Children: A Randomized, Double-Blind, Placebo-Controlled Trial. Headache. 2003;43:601–10. 6. Grazzi L, Andrasik F, Usai S, Bussone G. Magnesium as a preventive treatment for paediatric episodic tension-type headache: results at 1-year follow-up. Neurol Sci. 2007;28:148–50. 7. Bruijn J, Duivenvoorden H, Passchier J, Locher H, Dijkstra N, Arts W-F. Medium-dose riboflavin as a prophylactic agent in children with migraine: A preliminary placebo-controlled, randomised, double-blind, cross-over trial. Cephalalgia. 2010;30(12):1426–34. 8. Condò M, Posar A, Arbizzani A, Parmeggiani A. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009;10:361–5. 9. MacLennan SC, Wade FM, Forrest KML, Ratanayake PD, Fagan E, Antony J. High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child Neurol. 2008;23(11):1300–4. 10. Hershey AD, Powers SW, Vockell A-LB, Lecates SL, Ellinor PL, Segers A, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73–80. 11. Slater SK, Nelson TD, Kabbouche MA, LeCates SL, Horn P, Segers A, et al. A randomized, double-blinded, placebo-controlled, crossover, add-on study of CoEnzyme Q10 in the prevention of pediatric and adolescent migraine. Cephalalgia. 2011;31(8):897–905. 12. Miano S, Parisi P, Pelliccia A, Luchetti A, Paolino MC, Villa MP. Melatonin to prevent migraine or tension-type headache in children. Neurol Sci. 2008;29:285–7. 13. Fallah R, Shoroki FF, Ferdosian F. Safety and Efficacy of Melatonin in Pediatric Migraine Prophylaxis. Curr Drug Saf. 2015; 10(2): 132-5 14. Pothmann R, Danesch U. Migraine Prevention in Children and Adolescents: Results of an Open Study With a Special Butterbur Root Extract. Headache. 2005;45:196–203. 15. Oelkers-Ax R, Leins A, Parzer P, Hillecke T, Bolay H V, Fischer J, et al. Butterbur root extract and music therapy in the prevention of childhood migraine: An explorative study. Eur J Pain. 2008;12:301–13. 16. Usai S, Grazzi L, Bussone G. Gingkolide B as migraine preventive treatment in young age: results at 1-year follow-up. Neurol Sci. 2011;32(suppl 1):S197–9. 17. Esposito M, Carotenuto M. Ginkgolide B complex efficacy for brief prophylaxis of migraine in school-aged children: An open-label study. Neurol Sci. 2011;32:79–81. 18. Esposito M, Ruberto M, Pascotto A, Carotenuto M. Nutraceutical preparations in childhood migraine prophylaxis: Effects on headache outcomes including disability and behaviour. Neurol Sci. 2012;33:1365–8. 19. Toldo I, Rattin M, Perissinotto E, De Carlo D, Bolzonella B, Nosadini M, et al. Survey on treatments for primary headaches in 13 specialized juvenile Headache Centers: The first multicenter Italian study. Eur J Paediatr Neurol. 2017;1–15.