Cluster headache in Greece: an observational clinical and demographic study of 302 patients.

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 5 years, 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

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Background: Pathogenic 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. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We 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. Conclusions: Our 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

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Micraine and other headaches in systemic lupus erythematosus: a prospective comparative study

OBJECTIVE: To clarify whether headache, and particularly migraine, belongs to thespectrum of neurologic manifestations of systemic lupus erythematosus (SLE), thearchetypal autoimmune disease. METHODS: Consecutive SLE patients werematched 1:1 for age, gender, and level of education with healthy control subjects. Arepresentative subgroup of SLE patients were also matched with patients sufferingfrom multiple sclerosis (MS), a nervous system-specific autoimmune disease. Allstudy participants were assessed for headache present in the previous year. Anxiety,depression, and quality of life were also estimated at baseline. During the followingyear, all participants were assessed every 3 months using specific headache diaries.RESULTS: Seventy-two SLE/control pairs and 48 MS patients completed 12 monthsof follow-up. Prevalence of migraine, with or without aura, was similar between SLEpatients (21%), MS patients (23%), and controls (22%), as was the prevalence offrequent tension-type headache (TTH). Duration and severity of migraine attackswere milder in SLE patients than controls. Only chronic tension-type headache wassignificantly more prevalent in SLE patients (12.5%) compared to controls (1.4%).MS patients also presented increased frequency of chronic tension-type headache(8.3%). No associations of any headache type with particular clinical manifestations,autoantibody, or disease activity, either in SLE or MS patient groups, were found.Irrespective of the presence of headache, anxiety symptoms and impaired quality oflife were more frequent among SLE than MS patients or controls. CONCLUSIONS:There is no difference in the prevalence of headache among patients with SLE and167controls. Additionally, a distinct syndrome of headache or a pathogeneticmechanism of headache have not been demonstrated in patients with SLE.Therefore, occurrence of headache in patients with SLE does not itself requirefurther evaluation. Migraine should not be considered a manifestation of systemic ororgan-specific autoimmunity. 'Lupus headache' is a term that should better beavoided, until confirmation by further studies. Headache in patients with SLE shouldbe classified according to IHS criteria and treated as a primary headache. Thepresence of any type of headache that meets the diagnostic criteria of ICHD-II forprimary headache, including chronic TTH, does not imply exaggerated diseaseactivity of SLE or impairment of the central nervous system. Regardless of diseaseseverity of SLE, patients show an increased burden of anxiety, depression and poorperception of quality of life. There is also a need for a new large-scale class I studyusing neuroimaging, particularly in the pediatric population.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 in Greece: an observational clinical and demographic study of 302 patients.

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 5 years, 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

The iontophoretic transdermal system formulation of sumatriptan as a new option in the acute treatment of migraine: a perspective

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

A prospective non-interventional study for evaluation of quality of life in patients with Alzheimer’s disease treated with rivastigmine transdermal patch

Objectives: The primary objective of this multicentre, prospective, observational study was to assess whether there is improvement in the patients’ quality of life under treatment with rivastigmine transdermal patch, as it is evaluated both by patients and their caregivers. Compliance to treatment and safety were secondary endpoints. Methods: In total, 1509 patients with mild to moderate Alzheimer’s disease, already treated with rivastigmine transdermal patch 4.6 or 9.5 mg/24 h, were enrolled within a 2.4-month period and prospectively followed up for 2 months on an outpatient basis. The ‘Quality of Life in Alzheimer’s disease (QOL-AD): Patient and Caregiver Report’ questionnaire was used to evaluate quality of life as an effectiveness measure. Results and conclusion: A significant improvement in quality of life, as indicated by a change of 2.7 and 2.5 points in the mean patients’ and caregiver’s QOL-AD: Patient and Caregiver Report score respectively (both p < 0.001) from baseline to end of study was recorded. No serious adverse events were reported. Compliance was high, with 100% compliance reported for almost 9 out of 10 patients at study end