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Objective: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression. Methods: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients’ changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed. Results: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (n = 38/65; 58.5%) and without (n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean −8.9 (standard error: 6.8); p < 0.001) and without PCs (−9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab. Conclusions: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.

Gepants are small molecules targeting the calcitonin gene-related peptide (CGRP) that have been recently introduced and are under additional clinical development as preventive and abortive treatment options for migraine.After providing a narrative overview of current preventive and acute treatment options for migraine and summarizing the pathophysiology of migraine attack and the role of CGRP, we performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on trials on gepants in preventive and acute treatment of migraine. Studies and results were reviewed and discussed, and expert opinion was presented. We also collected data on relevant ongoing trials.Whether direct targeting CGRP pathways within the central nervous system or indirectly modulating them from the peripheral nervous system is more effective and safer in migraine remains still unclear. The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache; thus opening new therapeutic horizons.

Objective: To define, in a real-world population of patients with high-frequency episodic (HFEM) or chronic migraine (CM), the predictive role of socio-demographic or phenotypic profiling of responders to fremanezumab. Patients and methods: Two-hundred and four adult fremanezumab-treated patients with either HFEM or CM, who failed to at least three preventive treatments, provided data at baseline on several individual socio-demographic and phenotypic variables. These variables were analyzed for their ability to independently predict the response (50–74% response rates) or super-response (≥ 75% response rates) to fremanezumab. Patients were followed from 3–18 months of fremanezumab exposure. Results: The main finding to emerge from univariate analyses was that three baseline socio-demographic/clinical variables, i.e., age group 41–70 years (p = 0.02); female gender (p = 0.03); patients with HFEM (p = 0.001), and three clinical phenotypic variables, i.e., strict unilateral pain (p = 0.05); pain in the ophthalmic trigeminal branch (p = 0.04); and the “imploding” quality of pain (p = 0.05), were significantly related to fremanezumab response. However, in multivariate analysis, only HFEM (p = 0.02), the presence of strict unilateral (p = 0.03), and pain location in the ophthalmic trigeminal branch (p = 0.036) were independently associated with good fremanezumab response. Allodynia (p = 0.04) was the only clinical predictive variable of super-responsiveness to fremanezumab. Conclusions: A precise phenotypic profiling with identification of pain characteristics consistent with peripheral and/or central sensitization might reliably predict the responsiveness to fremanezumab in migraine prophylaxis.

OnabotulinumtoxinA (BoNTA) demonstrated a positive benefit-risk in chronic migraine (CM) patients in PREEMPT I and II phase III trials and many subsequent real-world studies. We herein aimed at evaluating the adherence to repeated BoNTA over a period of five years, while secondary objectives included the assessment of its long-term safety/efficacy and patients' satisfaction to treatment.We studied 56 CM patients who had successfully received consequent cycles of BoNTA over five years. Adherence was calculated as the percentage of patients actively choosing to follow with repeated BoNTA treatment, as instructed. Safety and efficacy data were collected throughout the study period. The overall patients' belief in and satisfaction by the efficacy of treatment was assessed at last follow-up, using the self-report 7-point measure patient global impression of change (PGIC).A total of 36 (64.3%) out of 56 patients remained adherent to BoNTA over five years. Long-term BoNTA exposure was safe and well-tolerated, without severe side-effects justifying treatment discontinuation. The mean monthly headache days and associated clinical efficacy outcomes remained consistent and quite low at last follow-up with evidence of continuous improvements in headache monthly frequency between year three and over five years of therapy. All patients who were able to maintain treatment over five years (n = 36), remained very satisfied and scored at least 5 in PGIC.Considerably high adherence, considerable satisfaction and sustained safety/efficacy were observed in patients followed up for five years, supporting a favorable benefit/risk profile for consistently delivering long-term BoNTA in CM.

BACKGROUND Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece. METHODS After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece. RESULTS We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations). CONCLUSIONS The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered.

OBJECTIVE This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Background: We aimed to prospectively assess the role of needle length in improving the tolerability/safety profile of OnabotulinumtoxinA (BoNTA) for chronic migraine (CM) prophylaxis, with a specific focus on neck pain, based on patients’ body habitus and other variables. Methods: BoNTA was administered quarterly for two consecutive cycles, using the standard 0.5-inch 27 G needle at all pre-defined PREEMPT injection sites, except the left-hand side trapezius and paraspinal muscles, which were injected using longer needles of 1-inch 23 G at first and 1-inch 27 G at second infusion. Participants were interviewed at day 14 following each session for evidence of neck pain. The predictive significance of Body Mass Index (BMI) and other variables with neck pain was also examined. Results: A total of 100 consecutive CM patients were evaluated, and each patient served as her/his self-control. The incidence, duration and intensity of neck pain did not significantly differ using either 1-inch needle compared with standard 0.5-inch 27 G needle, although the incidence and characteristics of neck pain with the use of longer needles appeared slightly higher and more intense. The BMI index and other tested variables remained unrelated to neck pain. Conclusions: We were not able to identify significant differences or correlations in the incidence, characteristics and location of neck pain with the use of different needle length to inject BoNTA, although the use of the longer 1-inch needles likely increased the risk of this adverse event.

BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/− mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/− mice. In contrast, Gnb5−/− mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/− mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening.

Objective Migraine is a chronic neurological disease involving the brain and its vasculature, typically characterized by recurrent attacks of moderate or severe throbbing headache, accompanied by sensitivity to light and sound, and associated with nausea, vomiting, and inability to move due to worsening of pain. About 30% of migraineurs have some type of aura, most often visual. Migraine attacks, if untreated or suboptimally treated, usually result in significant disability, requiring bed rest and resulting in poor quality of life. Increased frequency of attacks and overuse of acute care medication are significant risks for chronification, resulting in the transformation of episodic migraine into chronic migraine. We aim to review most acute care treatments for migraine. Methods Current treatment options for migraine attacks were reviewed from the selected literature and combined with our clinical experience. Results Current acute treatment options for migraine attacks include over-the-counter analgesics, at times combined with caffeine, nonsteroidal anti-inflammatory medications, opioids, and migraine-specific medications such as triptans and ergots. In the near future, we will probably have 3 gepants (small-molecule calcitonin gene-related peptide [CGRP] receptor antagonists). The first one was just approved in the United States. A ditan acting as a stimulator of 5-HT1F receptors, was also just approved by the FDA. Stimulation of the trigeminal, vagal, occipital, and even upper arm peripheral nerves through electrical nerve stimulation devices and magnetic stimulation devices are available as alternative, nondrug treatment options. Several devices have already been FDA-allowed for treatment in the United States and/or approved elsewhere, and others will follow soon. Behavioral medicine techniques such as biofeedback training and mindfulness have been available for some time and are often helpful. Conclusion A wide variety of acute care options to treat migraine are available, and others will soon be and will herein be described in further detail. Some medications have been approved by regulatory authorities in countries other than the United States, and some devices have been given a CE Mark in Europe.

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal ofMED subunit 11 may affect its binding efficiency to otherMED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

ΕΙΣΑΓΩΓΗ. Ο συστηματικός ερυθηματώδης λύκος (ΣΕΛ) είναι μια πολυσυστηματικήαυτοάνοση νόσος. Ο ΣΕΛ μπορεί να προσβάλει οποιοδήποτε οργανικό σύστημα.Νευρολογική συμμετοχή έχει αναφερθεί πως εμφανίζεται κατά την πορεία του ΣΕΛσυχνά κατά τη διάρκεια του πρώτου έτους σε ποσοστό έως και 75% των ασθενών.Ο μηχανισμός της συμμετοχής του κεντρικού νευρικού συστήματος (ΚΝΣ) είναιάγνωστος. Ο επιπολασμός υποτροπιάζουσας κεφαλαλγίας έχει αναφερθεί ναανέρχεται στο 71% και ημικρανίας στο 46%. Η ημικρανία είναι ένα συχνόνευρολογικό σύνδρομο, τυπικό χαρακτηριστικό του οποίου είναι η μέτριας έωςσοβαρής έντασης κεφαλαλγία. Υπάρχει αυξανόμενο ενδιαφέρον στη βιβλιογραφίαπου αφορά τη συσχέτιση μεταξύ ΣΕΛ και των κεφαλαλγιών, ειδικότερα δε τηςημικρανίας κεφαλαλγίας. ΜΕΘΟΔΟΣ. Η παρούσα προοπτικού τύπου εργασίασχεδιάστηκε και διενεργήθηκε έτσι ώστε με τη χρήση ειδικών ερωτηματολογίωνκεφαλαλγίας, να διαλευκανθεί το κατά πόσον η κεφαλαλγία και ειδικότερα ηημικρανία ανήκει στο φάσμα των νευρολογικών εκδηλώσεων του ΣΕΛ. Στη μελέτησυμμετείχαν διαδοχικοί ενήλικες ασθενείς με διάγνωση ΣΕΛ, εξωτερικοί ασθενείςστους οποίους δεν υπήρχε ένδειξη ότι έπασχαν από κάποιο αυτοάνοσο νόσημα καιασθενείς με πολλαπλή σκλήρυνση (ΠΣ). Όλοι οι συμμετέχοντες αξιολογήθηκαν ωςπρος την παρουσία άγχους ή κατάθλιψης με τη χρήση της Κλίμακας ΑξιολόγησηςΆγχους του Hamilton και της Κλίμακας Αξιολόγησης Κατάθλιψης του Hamilton των21 ζητημάτων, αντίστοιχα. Η ποιότητα ζωής αξιολογήθηκε με τη χρήση της«Σύντομης Φόρμας Έρευνας Υγείας-36» (SF-36). Οι ασθενείς με ΣΕΛαντιστοιχήθηκαν με τους μάρτυρες με λόγο 1:1, ως προς την ηλικία (±2 έτη), το φύλοκαι το μορφωτικό επίπεδο (±1 έτος). Στους πάσχοντες από ΣΕΛ προσδιορίστηκε το163συνολικό προφίλ αυτοαντισωμάτων. Οι ασθενείς με ΠΣ ταιριάστηκαν με λόγο 1:1ως προς την ηλικία, το φύλο και το μορφωτικό επίπεδο. με μια μη επιλεγμένηυποομάδα ασθενών με ΣΕΛ. Οι ασθενείς με ΠΣ ταξινομήθηκαν σύμφωνα με τηΔιευρυμένη Κλίμακα Κατάστασης Αναπηρίας του Kurztke (ΕDSS) με βάση ταλειτουργικά συστήματα, τον τύπο της ΠΣ, τις πρόσφατες υποτροπές και τηνενεργότητα στη μαγνητική τομογραφία (MRI). Αξιολογήθηκαν οι μεταβολές στηβαθμολογία της EDSS. Όλοι οι συμμετέχοντες επαναξιολογήθηκαν στους 3, στους 6,στους 9 μήνες και στους 12 μήνες μετά από την αρχική αξιολόγηση. Για τιςσυγκρίσεις χρησιμοποιήθηκε κατάλληλη στατιστική ανάλυση. ΑΠΟΤΕΛΕΣΜΑΤΑ.Εβδομήντα δύο ζεύγη ασθενών με ΣΕΛ και μαρτύρων και 48 ασθενείς με ΠΣσυμπληρώσαν 12 μήνες παρακολούθησης. Ο επιπολασμός της ημικρανίας με ήχωρίς αύρα ήταν παρόμοιος μεταξύ των ασθενών με ΣΕΛ (21%), των ασθενείς μεΠΣ (23%), και των μαρτύρων, όπως και ο επιπολασμός τηςσυχνής κεφαλαλγίας τύπου τάσεως. Η διάρκεια και η σοβαρότητα των επεισοδίωνημικρανίας ήταν πιο ήπιες σε ασθενείς με ΣΕΛ σε σχέση με τους μάρτυρες. Μόνο ηχρόνια κεφαλαλγία τύπου τάσεως ήταν σε στατιστικά σημαντικό βαθμό συχνότερηστους ασθενείς με ΣΕΛ (12,5%) σε σύγκριση με την ομάδα ελέγχου (1,4%). Οιασθενείς με ΠΣ παρουσίασαν επίσης αυξημένη συχνότητα χρόνιας κεφαλαλγίαςτύπου τάσης (8,3%). Δεν παρατηρήθηκε καμία συσχέτιση του κάθε είδουςκεφαλαλγίας με ιδιαίτερες κλινικές εκδηλώσεις, με αυτοαντισώματα ή με τηδραστηριότητα της νόσου, ανάμεσα είτε σε ασθενείς με ΣΕΛ και σε ασθενείς με ΠΣ.Ανεξάρτητα από την παρουσία της κεφαλαλγίας, τα συμπτώματα άγχους και ημειωμένη ποιότητα ζωής ήταν συχνότερα φαινόμενα στους ασθενείς με ΣΕΛ, σεσύγκριση με τους ασθενείς με ΠΣ και με τους μάρτυρες. ΣΥΜΠΕΡΑΣΜΑΤΑ. Δενυπάρχει διαφορά στον επιπολασμό κεφαλαλγίας μεταξύ ασθενών με ΣΕΛ και164μαρτύρων. Επιπρόσθετα, στους ασθενείς με ΣΕΛ δεν έχει καταδειχτεί κάποιοξεχωριστό σύνδρομο κεφαλαλγίας ή παθογενετικός μηχανισμός κεφαλαλγίας.Επομένως, η εμφάνιση κεφαλαλγίας στους ασθενείς με ΣΕΛ δεν απαιτεί από μόνητης περαιτέρω αξιολόγηση. Η ημικρανία δεν θα πρέπει να θεωρείται νευρολογικήεκδήλωση της συστηματικής ή της ειδικής ως προς όργανο αυτοανοσίας. Αν και ηπαρουσία της «κεφαλαλγίας του λύκου» θεωρείται σημαντική στους δείκτεςενεργότητας των ασθενών με ΣΕΛ, δεν διαπιστώσαμε ούτε αρκετές αλλά ούτε καικαλές ενδείξεις για την ύπαρξη αυτού του συγκεκριμένου τύπου κεφαλαλγίας.Επομένως, θα πρέπει να αποφεύγεται η χρήση του όρου, μέχρι την ύπαρξηπεραιτέρω μελετών. Η κεφαλαλγία στους ασθενείς με ΣΕΛ θα πρέπει ναταξινομείται σύμφωνα με τα κριτήρια της IHS και να αντιμετωπίζεται ωςπρωτοπαθής κεφαλαλγία εφόσον απουσιάζουν άλλοι παράγοντες που περιπλέκουντην κατάσταση. Εάν είναι συχνές οι κεφαλαλγίες, μπορεί να απαιτείται προφυλακτικήθεραπεία. Μόνο η χρόνια ΚΤΤ ενδέχεται να παρουσιάζει συνοσηρότητα με το ΣΕΛ.Η παρουσία οποιουδήποτε τύπου κεφαλαλγίας που πληρεί τα διαγνωστικά κριτήριατης ICHD-II για πρωτοπαθή κεφαλαλγία, συμπεριλαμβανομένης και της χρόνιαςΚΤΤ, δεν υποδηλώνει ενεργότητα της νόσου του ΣΕΛ ή προσβολή του κεντρικούνευρικού συστήματος. Ανεξάρτητα από τη σοβαρότητα της νόσου του ΣΕΛ, τηνενεργότητα, τη διάρκεια ή τη βλάβη οργάνων στα πλαίσια της, η ίδια η παρουσία τηςδιάγνωσης συνοδεύεται από αυξημένο φορτίο άγχους, κατάθλιψης και κακήςαντίληψης για την ποιότητα ζωής μεταξύ αυτών των ασθενών. Ο αυξημένοςεπιπολασμός της χρόνιας ΚΤΤ στους ασθενείς με ΣΕΛ μπορεί στην πραγματικότητανα αντανακλά αυτό το φορτίο. Η αξιολόγηση για διαταραχές της διάθεσης μπορεί ναείναι χρήσιμη κατά τη λήψη αποφάσεων σχετικά με την αντιμετώπιση των ασθενώνμε ΣΕΛ και κεφαλαλγία.165Υπάρχει ανάγκη για μια νέα μεγάλης κλίμακας μελέτη τάξης Ι που θα χρησιμοποιείκαι νευροαπεικόνιση, ιδίως στον παιδιατρικό πληθυσμό, ώστε να επικυρώσει ταευρήματα της παρούσας εργασίας.

Cluster headache (CH) is a primary headache disorder with a complex genetic background. Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The HFE gene encodes for a protein involved in iron metabolism, while genetic variants in HFE have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common HFE H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the HFE rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (p > 0.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the HFE gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that HFE H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in HFE gene may be potentially regarded as a disease modifier genetic factor in CH.

Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.

Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case–control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3′UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.

Introduction: Botulinum neurotoxin type-A (BoNTA) is licensed for the treatment of chronic migraine (CM), but it has been tested off-label as a therapeutic choice in other primary headaches (PHs). We aimed to provide a systematic review and expert opinion on BoNTA use in PHs, beyond CM.Areas covered: After providing an overview on PHs and mechanism of BoNTA action, we report the results of a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of BoNTA therapeutic trials in PHs beyond CM. Studies and results were reviewed and discussed, and levels of evidence were graded. We also collected data on relevant ongoing trials.Expert opinion: Although there are contradictory findings on PHs other than CM, BoNTA may represent a therapeutic option for patients who do not respond to conventional prophylactic treatments. Based on limited available evidence, BoNTA may be considered in refractory tension-type headache, trigeminal autonomic cephalalgias, primary stabbing headache, nummular headache, hypnic headache, and new daily persistent headache, after the primary nature of cephalalgia has been documented and other drugs have failed. Experienced physicians in BoNTA treatment are required to guide the therapeutic protocol for each patient to optimize good and safe outcomes.

Introduction: Although it causes a huge burden to sufferers, cluster headache (CH), remains an undertreated condition, partly due to the absence of established acute and prophylactic treatment opti...

Background: To investigate the efficacy and safety of supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 in episodic migraine (EM) prevention. Methods: A pilot, single-arm, open-label study was conducted. After a one-month baseline period, the above-described supplementation was introduced in 113 EM Greek patients, who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BSL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), Migraine-Specific Quality-of-life questionnaire (MSQ-QOL), Hospital Anxiety and Depression Scale (HADS) were also evaluated. Those with &ge, 50% reduction in monthly migraine days at T3, compared to BSL were considered supplementation-responders. Results: The mean number of migraine days was significantly decreased between BSL and T3 (9.4 &plusmn, 3.7 vs. 6.1 &plusmn, 3.5, p &lt, 0.001). Likewise, days with peak headache intensity of &gt, 4/10 (5.7 &plusmn, 3.4 vs. 4.9 &plusmn, 3.1, 0.001) as well as days using acute headache medications per month (8.9 &plusmn, 3.6 vs. 5.7 &plusmn, 3.4, 0.001) were significantly reduced. At T3, 64 patients (56.6%) were classified as responders. The beneficial effect of supplementation was also associated with significant changes in HIT-6, MIDAS, MTAQ and MSQ-QOL scores. There were no safety concerns. Conclusions: The supplementation we have tested appears to be an effective and well-tolerated preventive approach against EM. A randomized, placebo-controlled study is needed to confirm our results.

Migraine is a chronic neurological disease involving the brain and its vasculature, typically characterized by recurrent attacks of moderate or severe throbbing headache, accompanied by sensitivity to light and sound, and associated with nausea, vomiting, and inability to move due to worsening of pain. About 30% of migraineurs have some type of aura, most often visual. Migraine attacks, if untreated or suboptimally treated, usually result in significant disability, requiring bed rest and resulting in poor quality of life. Increased frequency of attacks and overuse of acute care medication are significant risks for chronification, resulting in the transformation of episodic migraine into chronic migraine. We aim to review most acute care treatments for migraine.Current treatment options for migraine attacks were reviewed from the selected literature and combined with our clinical experience.Current acute treatment options for migraine attacks include over-the-counter analgesics, at times combined with caffeine, nonsteroidal anti-inflammatory medications, opioids, and migraine-specific medications such as triptans and ergots. In the near future, we will probably have 3 gepants (small-molecule calcitonin gene-related peptide [CGRP] receptor antagonists). The first one was just approved in the United States. A ditan acting as a stimulator of 5-HT1F receptors, was also just approved by the FDA. Stimulation of the trigeminal, vagal, occipital, and even upper arm peripheral nerves through electrical nerve stimulation devices and magnetic stimulation devices are available as alternative, nondrug treatment options. Several devices have already been FDA-allowed for treatment in the United States and/or approved elsewhere, and others will follow soon. Behavioral medicine techniques such as biofeedback training and mindfulness have been available for some time and are often helpful.A wide variety of acute care options to treat migraine are available, and others will soon be and will herein be described in further detail. Some medications have been approved by regulatory authorities in countries other than the United States, and some devices have been given a CE Mark in Europe.

BackgroundTo investigate efficacy and safety of a supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 (Vivinor®) in episodic migraine prevention.MethodsAn observational, prospective, real-world study was conducted. After a one-month baseline period, Vivinor® was introduced in 113 Greek patients with episodic migraine who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), MSQ-QOL (Migraine-Specific Quality of life questionnaire), HADS (Hospital Anxiety and Depression Scale) were also evaluated. Those with ≥ 50% reduction in monthly migraine days at T3, compared to BL were considered Vivinor®-responders.ResultsMean number of migraine days was significantly decreased between BL and T3 (9.9 ± 5.0 vs 6.2 ± 4.0; P 4/10 (8.3 ± 3.8 vs 5.8 ± 4.0; P

Cluster headache (CH) has been associated with circadian disturbances. The present systematic review examined available evidence for the utilization of melatonin (MT) in CH prophylaxis. First, case-control studies assessing nocturnal MT or its urine-expelled metabolite 6-sulfatoxymelatonin (aMT6s) in CH individuals and healthy controls (HC) were reviewed and meta-analyzed. Secondly, the results from randomized controlled trials (RCTs) and non-randomized studies evaluating MT's use in the prevention of CH were discussed. Literature search included MEDLINE, EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey. Bouts and remissions were assessed separately. Ten case-control studies (adult participants) were retrieved. Seven evaluated serum MT; meta-analysis involved only three of them (due to deficient reporting, n: bout = 31, remission = 38, HC = 31). Results were compatible with lower nocturnal serum MT levels during bouts [bout-HC; FE-MD = -29.89 pg/mL, 95% CI = (-46.00, -13.78), remission-HC; FE-MD = -2.40 pg/mL, 95% CI = (-16.57, 21.38), bout-remission; RE-MD = -32.10 pg/mL, 95% CI = (-56.78, -7.42)]. Nocturnal urinary melatonin was appraised in two studies, but reporting issues impeded the capitalization of the results. Nocturnal urine aMT6s was evaluated by two studies (n: bout = 29, remission = 22, HC = 20), and pooled results were indicative of lower aMT6s concentration in CH individuals during both active and inactive periods [bout-HC; FE-MD = -9.63 μg/nocturnal urine collection, 95% CI = (-14.40, -4.85), remission-HC; FE-MD = -9.12 μg/nocturnal urine collection, 95% CI = (-14.63,-3.62), bout-remission; FE-MD = -0.58 μg/nocturnal urine collection, 95% CI = (-4.58, 3.42)]. Regarding CH prophylaxis, one RCT and two non-randomized trials were retrieved, involving a total of 41 adult CH individuals (11-episodic, 31-chronic) and rendering the deduction of any conclusions precarious. Overall, available data for the role use of MT in CH are insufficient and inconclusive. Complementary studies evaluating endogenous MT concentrations and MT administration to patients with CH are warranted.

Background The Migraine Disability Assessment (MIDAS) Questionnaire is a reliable and valid instrument for migraine-related disability. Such a tool is needed to quantify migraine-related disability in the Greek population. Objective This validation study aims to assess the test–retest reliability, internal consistency, item discriminant and convergent validity of the Greek translation of the MIDAS. Methods Adults diagnosed with migraine completed the MIDAS Questionnaire on two occasions 3 weeks apart to assess reliability, and completed the RAND-36 to assess validity. Results Participants (n = 152) had a median MIDAS score of 24 and mostly severe disability (58% were grade IV). The test–retest reliability analysis (N = 59) revealed excellent reliability for the total score. Internal consistency was α = 0.71 for initial and α = 0.82 for retest completion. For item discriminant validity, the correlations between each question and the total score were significant, with high correlations for questions 2–5 (range 0.67 ≤ r ≤ 0.79; p

Background Migraine is included in the top-ten disabling diseases and conditions among the Western populations. Non-invasive neurostimulation, including the Cefaly® device, for the treatment of various types of pain is a relatively new field of interest. The aim of the present study was to explore the clinical experience with Cefaly® in a cohort of migraine patients previously refractory or intolerant to topiramate prophylaxis. Methods A prospective, multi-center clinical study was performed in patients diagnosed with episodic or chronic migraine with a previous failure to topiramate treatment requiring prevention with Cefaly® according to the treating physician’s suggestion. A 1-month period of baseline observation was followed by a 3-month period of observation during the use of transcutaneous supraorbital nerve stimulation (t-SNS) with Cefaly® as the only preventive treatment. Results A small but statistically significant decline was shown over time in the number of days with headache (HA), the number of days with HA with intensity ≥5/10, and the number of days with use of acute medication after 3 months (p

Background Evidence on whether the therapeutic effect and good safety profile of onabotulinumtoxinA (Botox®) in chronic migraine (CM) patients is maintained over long term treatment is still limited. We herein aimed at assessing whether there is a sustained benefit and good safety with repeated onabotulinumtoxinA sessions in CM over more than three years of treatment. Methods We prospectively enrolled 65 CM patients, who were classified as responders after three sessions of onabotulinumtoxinA and were eligible to further continue treatment. Data documenting longitudinal changes from the trimester after the third onabotulinumtoxinA administration (T1) to the trimester after completing two years of treatment (T2) and eventually to the trimester after completing three years of treatment (T3) in (i) mean number of monthly headache days (ii) migraine severity as expressed by the mean number of days with peak headache intensity of > 4/10, and (iii) mean number of days with use of any acute headache medication, were prospectively collected from patients’ headache diaries. Results A total of 56 (86.1%) of 65 patients achieved to attain onabotulinumtoxinA over three years. At T3, a significant reduction in mean monthly headache days was evident, compared to T1 (3.4 ± 1.7 vs 7.2 ± 3.8; P

Primary headache disorders, such as migraine and cluster headache, are common and often debilitating. When preventive therapy is needed, several oral medications are used. Patients tend to have poor adherence and persistence on their preventive therapy. The introduction of treatments blocking calcitonin gene-related peptide (CGRP) is anticipated to begin a new era in migraine preventive treatment. In addition, non-triptan serotonin receptor agonists, newer delivery systems for older therapies, and innovative devices represent other exciting advances in acute and preventive migraine and cluster treatment and shall also be discussed in this review.

SUMMARY We will describe the pharmacokinetic profile, clinical efficacy and safety data of the sumatriptan iontophoretic transdermal system (Zecuity®, NuPathe Inc., PA, USA), recently approved for the acute treatment of migraine with or without aura in adults, by the US FDA. This transdermal system utilizes a low-level electrical current to deliver sumatriptan transdermally and circumvents the GI tract. Pharmacokinetic studies have shown that iontophoretic delivery of sumatriptan achieves detectable plasma concentrations 15 min after activation with a maximum mean serum concentration of 22 ng/ml. A randomized, double-blind, controlled clinical trial demonstrated minimal triptan-related side effects and superior efficacy versus placebo. The pain-free rate at 2 h postdose was 18% of patients applying the sumatriptan patch versus 9% using the placebo (p = 0.0092). This sumatriptan transdermal system may be a good choice for migraineurs with severe nausea or vomiting, those with intolerable triptan-related adverse events and/or those not responding optimally to oral medications.

BackgroundCluster headache (CH) is considered the most excruciating primary headache syndrome; although much less prevalent than migraine, it is not rare as it affects more than 1/1000 people. While its clinical presentation is considered stereotypic, atypical features are often encountered. Internationally, cluster headache is often misdiagnosed, undertreated and mistreated.MethodsWe prospectively studied 302 CH patients, all examined by the same headache specialist. The aim of our study was to describe the demographic and clinical characteristics of CH patients in Greece and draw attention to under-management, under-treatment and mis-treatment often encountered in clinical practice; our purpose is to improve recognition and successful treatment of cluster patients by Greek neurologists and other physicians.ResultsIn the present cohort, clinical characteristics of CH are similar to those described in other populations. Beyond the standard clinical characteristics, features like side shifts (12.6%), location of maximal pain intensity outside the first trigeminal branch division (10.2%), lack of autonomic features (7%), presence of associated features of migraine and aggravation by physical activity (10%) were encountered. Four out of five patients had consulted a physician prior to diagnosis. The median number of physicians seen prior to diagnosis was 3 and the median time to diagnosis was 5years, though it improved for patients with recent onset. Chronic cluster headache, side shifts, pain location in the face or the back of the head and aggravation by physical activity were found, among others, to be statistically significantly related to delayed diagnosis or more physicians seen prior to diagnosis. Even properly diagnosed patients were often undertreated or mistreated.ConclusionsCluster headache, in a large cohort of Greek patients, has the same phenotypic characteristics as described internationally. Uncommon clinical features do exist and physicians should be aware of those, since they may eventuate in diagnostic problems. Most CH patients in Greece remain misdiagnosed or undiagnosed for rather lengthy periods of time, but time to diagnosis has improved recently. Even after diagnosis, treatment received was suboptimal.

Recent evidence supports the suggestion that migraine is a chronic disorder with episodic attacks that increase in frequency in a subgroup of patients, transforming migraine into a refractory chronic condition with poor outcome and severe impact. Among the risk factors for migraine chronification depression figures notably. Early diagnosis and management of risk factors in migraineurs prevent migraine chronification and its consequences. The scope of this article is to review depression as a potential cofactor for migraine chronification.Population-based studies revealed that migraineurs often have symptoms of depression, with strongest associations for migraine with aura. Patients with depression also have an increased risk for migraine, migraine with aura in particular. Twin studies showed similar findings. This bidirectional relationship suggests that migraine and depression may share common causative factors, possibly genetically determined, that might control migraine chronification. Migraine patients may develop depression as a result of the demoralizing experience of recurrent and disabling headaches and depressed patients may develop migraine because of increased pain sensitivity, in the basis of a common genetic background.We suggest that clinicians consider depression as part of migraine management in order to optimize treatment and avoid migraine progression.

Objective.— To explore the efficacy and tolerability of levetiracetam in medical treatment of trigeminal neuralgia. Background.— Antiepileptic drugs (AEDs) are considered as first-line treatment for trigeminal neuralgia, although their use is often limited due to incomplete efficacy and tolerability. Newer AEDs with improved safety profile may be useful in this disorder. Methods.— Patients suffering from trigeminal neuralgia (either primary or secondary) refractory to previous treatments were recruited to be treated with levetiracetam (3-4 g/day) for 16 weeks as add-on therapy, after a 2-week baseline period. Rescue medication was allowed in both the baseline and treatment phases. The primary efficacy measure was the number of attacks per day. The patients' efficacy evaluation, the patients' global evaluation for both safety and efficacy, changes in the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Quality of Life Measure Short Form-36 were secondary parameters. Results.— Twenty-three patients were included in the analysis. After treatment and compared to the baseline phase, the number of daily attacks decreased by 62.4%. All secondary parameters changed significantly with the exception of the Quality of Life Measure Short Form-36 score. Seven patients withdrew from the study. Five patients (21.7%) reported side effects and 2 withdrew. Conclusions.— Levetiracetam may be effective and safe in trigeminal neuralgia treatment. Confirmation in a randomized controlled study is needed. (Headache 2010;50:1371-1377)

Tabaki NE, Vikelis M, Besmertis L, Vemmos K, Stathis P, Mitsikostas DD. Apraxia related with subcortical lesions due to cerebrovascular disease. Acta Neurol Scand: 2010: 122: 9–14. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – To examine whether ideomotor apraxia exists in patients with subcortical ischemic lesions. Patients and Methods – A matched-control, prospective and multi-centered research design was used. Ideomotor apraxia, anxiety and depression were assessed by the Movement Imitation Test and the Hamilton scales, respectively. Results – Forty two consecutive patients with subcortical ischemic stroke and an equal number of healthy participants, matched in age and sex were included. Paired-sample t-tests showed that patients had significantly more apractic elements in their movements (t = 5.03, P

Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G-protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment.

An iontophoretic transdermal system (ITS) (skin patch) formulation of sumatriptan for the acute treatment of migraine attacks was approved by the US Food and Drug Administration in January 2013. This transdermal system bypasses the gastrointestinal tract, as it uses low electrical current to move sumatriptan transdermally into the subcutaneous tissue. Randomized, double-blind, controlled clinical trials have demonstrated minimal triptan-related side effects and superior efficacy versus placebo, comparable with other sumatriptan formulations. Sumatriptan ITS can be applied successfully during a mild or severe migraine attack. According to pharmacokinetic properties and clinical data, sumatriptan ITS may be a good choice for people with migraine and severe nausea, vomiting or gastroparesis, those with intolerable triptan-related adverse events and those not responding optimally to oral medications.