Low urinary 6-sulphatoxymelatonin concentrations in acute migraine

Substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms, sleep, and headache disorders. The objective of the study was to assess 6-sulphatoxymelatonin (aMT6s) levels in a large consecutive series of patients with migraine, comparing with controls. A total of 220 subjects were evaluated-146 had migraine and 74 were control subjects. Urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day (12-h period) and aMT6s was measured with quantitative ELISA technique. Among patients with migraine, 53% presented pain on the day of the urine samples collection. Their urinary aMT6s concentration was significantly lower than in the urine of patients without pain [14.0 +/- 7.3 vs. 49.4 +/- 19.0; t(143) = -15.1; 95% CI = -40.0 to -30.8; P<0.001]. There was no significant difference in the aMT6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [49.4 +/- 19.0 vs. 42.5 +/- 27.9; t(140) = 1.7; 95% CI = -1.2 to 14.8; P = 0.094]. To our knowledge, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine.

Functional effects of Na+,K+-ATPase gene mutations linked to familial hemiplegic migraine.

Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha2-subunit of the Na+,K+-ATPase. We have introduced these mutations in the alpha2-subunit of the human Na+,K+-ATPase and the corresponding mutations in the Bufo marinus alpha1-subunit and studied these mutants by expression in Xenopus oocyte. Metabolic labeling studies showed that the mutants were synthesized and associated with the beta-subunit, except for the alpha2HW887R mutant, which was poorly synthesized, and the alpha1BW890R, which was partially retained in the endoplasmic reticulum. [3H]ouabain binding showed the presence of the alpha2HR689Q and alpha2HM731T at the membrane, whereas the alpha2HL764P and alpha2HW887R could not be detected. Functional studies with the mutants of the B. marinus Na+,K+-ATPase showed a reduced or abolished electrogenic activity and a low K+ affinity for the alpha1BW890R mutant. Through different mechanisms, all these mutations result in a strong decrease of the functional expression of the Na+,K+-pump. The decreased activity in alpha2 isoform of the Na+,K+-pump expressed in astrocytes seems an essential component of hemiplegic migraine pathogenesis and may be responsible for the cortical spreading depression, which is one of the first events in migraine attacks.

New insights into pathophysiology of vestibular migraine.

Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory-inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM.

Étude du mécanisme de transport des cations par la Na, K-ATPase et de son implication dans la migraine familiale hémiplégique de type 2

Résumé La Na,K-ATPase est une protéine transmembranaire, présente dans toutes les cellules de mammifères et indispensable à la viabilité cellulaire. Elle permet le maintien des gradients sodiques et potassiques à l'origine du potentiel membranaire en transportant 3 Na+ en dehors de la cellule contre 2 K+, grâce à l'énergie fournie par l'hydrolyse d'une molécule d'ATP. Le potentiel membranaire est indispensable au maintien de l'excitabilité cellulaire et à la transmission de l'influx nerveux. Il semblerait que la Na,K-ATPase soit liée à l'hypertension et à certains troubles neurologiques comme la Migraine Familiale Hémiplégique (1VIFH). La MFH est une forme de migraine avec aura, qui se caractérise par une hémiparésie. Cette forme de migraine est très rare. Elle se transmet génétiquement sur un mode autosomique dominant. Plusieurs mutations localisées dans le gène de la Na,K-ATPase ont été identifiées durant ces 3 dernières années. C'est la première fois qu'une maladie génétique est associée au gène de la Na,K-ATPase. La compréhension du fonctionnement de cette protéine peut donner des informations sur les mécanismes conduisant à ces pathologies. On sait que la fonction d'une protéine est liée à sa structure. L'étude de sa fonction nécessite donc l'étude de sa structure. Alors que la structure de la SERCA a été déterminée à haute résolution, par cristallographie, celle de la Na,K-ATPase ne l'est toujours pas. Mais ces 2 ATPases présentent une telle homologie qu'un modèle de la Na,K-ATPase a pu être élaboré à partir de la structure de la SERCA. Les objectifs de cette étude sont d'une part, de comprendre le contrôle de l'accessibilité du K+ extracellulaire àses sites de liaison. Pour cela, nous avons ciblé cette étude sur la 2ìème et la 31eme boucle extracellulaire, qui relient respectivement les segments transmembranaires (STM) 3-4 et 5-6. Le choix s'est porté sur ces 2 boucles car elles bordent le canal des cations formés des 4ième' Sième et 6'ème hélices. D'autre part, nous avons également essayer de comprendre les effets des mutations, liées à la Migraine Familiale Hémiplégique de type 2 (MFH2), sur la fonctionnalité de la Na,K-ATPase. Alors que les STM et les domaines cytoplasmiques sont relativement proches entre la Na,KATPase et la SERCA, les boucles extracellulaires présentent des différences. Le modèle n'est donc pas une approche fiable pour déterminer la structure et la fonction des régions extracellulaires. Nous avons alors utilisé une approche fonctionnelle faisant appel à la mutation dirigée puis à l'étude de l'activité fonctionnelle de la Na,K ATPase par électrophysiologie sur des ovocytes de Xenopus. En conclusion, nous pouvons dire que la troisième boucle extracellulaire participerait à la structure de la voie d'entrée des cations et que la deuxième boucle extracellulaire semble impliquée dans le contrôle de l'accessibilité des ions K+àses sites de liaison. Concernant les mutations associées à la MFH2, nos résultats ont montré une forte diminution de l'activité fonctionnelle de la pompe Na,K, inférieure aux conditions physiologiques de fonctionnement, et pour une des mutations nous avons observés une diminution de l'affmité apparente au K+ externe. Nous poumons faire l'hypothèse que l'origine pathologique de la migraine est liée à une diminution de l'activité de la pompe à Na+. Summary The Na,K-ATPase is a transmembrane protein, present in all mammalian cells and is necessary for the viability of the cells. It maintains the gradients of Na+ and K+ involved in the membrane potential, by transporting 3Na+ out the cell, and 2K+ into the cell, using the energy providing from one ATP molecule hydrolysis. The membrane potential is necessary for the cell excitability and for the transmission of the nervous signal. Some evidence show that Na,K-ATPase is involved in hypertension and neurological disorders like the Familial Hemiplegic Migraine (FHM). La FHM is a rare form of migraine characterised by aura and hemiparesis and an autosomal dominant transmission. Several mutations linked to the Na,KATPase gene have been identified during these 3 last years. It's the first genetic disorder associated with the Na,K-ATPase gene. Understand the function of this protein is important to elucidate the mechanisms implicated in these pathologies. The function of a protein is linked with its structure. Thus, to know the function of a protein, we need to know its structure. While the Ca-ATPase (SERCA) has been crystallised with a high resolution, the structure of the Na,K-ATPase is not known. Because of the great homology between these 2 ATPases, a model of the Na,K-ATPase was realised by comparing with the structure of the SERCA. The aim of this study is on one side, understand the control of the extracellular K+ accessibility to their binding sites. Because of theirs closed proximity with the cation pathway, located between the 4th, 5th and 6th helices, we have targeted this study on the 2nd and the 3rd extracellular loops linking respectively the transmembrane segment (TMS) 3 and 4, and the TMS 5 and 6. And on the other side, we have tried to understand the functional effects of mutations linked with the Familial Hemiplegic Migraine Type 2 (FHM2). In contrast with the transmembrane segments and the cytoplasmic domains, the extracellular loops show lots of difference between Na,K-ATPase and SERCA, the model is not a good approach to know the structure and the function of the extracellular loops. Thus, we have used a functional approach consisting in directed mutagenesis and the study of the functional activity of the Na,K-ATPase by electrophysiological techniques with Xenopus oocytes. In conclusion, we have demonstrated that the third extracellular loop could participate in the structure of the entry of the cations pathway and that the second extracellular loop could control the K+ accessibility to their binding sites. Concerning the mutations associated with the FHM2, our results showed a strong decrease in the functional activity of the Na,K-pump under physiological conditions and for one of mutations, induce a decrease in the apparent external K+ affinity. We could make the hypothesis that the pathogenesis of migraine is related to the decrease in Na,K-pump activity. Résumé au large publique De la même manière que l'assemblage des mots forme des phrases et que l'assemblage des phrases forme des histoires, l'assemblage des cellules forme des organes et l'ensemble des organes constitue les êtres vivants. La fonction d'une cellule dans le corps humain peut se rapprocher de celle d'une usine hydroélectrique. La matière première apportée est l'eau, l'usine électrique va ensuite convertir l'eau en énergie hydraulique pour fournir de l'électricité. Le fonctionnement de base d'une cellule suit le même processus. La cellule a besoin de matières premières (oxygène, nutriments, eau...) pour produire une énergie sous forme chimique, l'ATP. Cette énergie est utilisée par exemple pour contracter les muscles et permet donc à l'individu de se déplacer. Morphologiquement la cellule est une sorte de petit sac rempli de liquide (milieu intracellulaire) baignant elle-même dans le liquide (milieu extracellulaire) composant le corps humain (un adulte est constitué environ de 65 % d'eau). La composition du milieu intracellulaire est différente de celle du milieu extracellulaire. Cette différence doit être maintenue pour que l'organisme fonctionne correctement. Une des différences majeures est la quantité de sodium. En effet il y a beaucoup plus de sodium à l'extérieur qu'à l'intérieur de la cellule. Bien que l'intérieur de la cellule soit isolé de l'extérieur par une membrane, le sodium arrive à passer à travers cette membrane, ce qui a tendance à augmenter la quantité de sodium dans la cellule et donc à diminuer sa différence de concentration entre le milieu extracellulaire et le milieu intracellulaire. Mais dans les membranes, il existe des pompes qui tournent et dont le rôle est de rejeter le sodium de la cellule. Ces pompes sont des protéines connues sous le nom de pompe à sodium ou Na,K-ATPase. On lui attribue le nom de Na,K-ATPase car en réalité elle rejette du sodium (Na) et en échange elle fait entrer dans la cellule du potassium (K), et pour fonctionner elle a besoin d'énergie (ATP). Lorsque les pompes à sodium ne fonctionnent pas bien, cela peut conduire à des maladies. En effet la Migraine Familiale Hémiplégique de type 2, est une migraine très rare qui se caractérise par l'apparition de la paralysie de la moitié d'un corps avant l'apparition du mal de tête. C'est une maladie génétique (altération qui modifie la fonction d'une protéine) qui touche la pompe à sodium située dans le cerveau. On a découvert que certaines altérations (mutations) empêchent les pompes à sodium de fonctionner correctement. On pense alors que le développement des migraines est en partie dû au fait que ces pompes fonctionnent moins bien. Il est important de bien connaître la fonction de ces pompes car cela permet de comprendre des mécanismes pouvant conduire à certaines maladies, comme les migraines. En biologie, la fonction d'une protéine est étudiée à travers sa structure. C'est pourquoi l'objectif de cette thèse a été d'étudier la structure de la Na,K-ATPase afin de mieux comprendre son mécanisme d'action.

Análise crítica dos critérios diagnósticos da Sociedade Internacional de Cefaléia (SIC - 1988 e SIC - 2003), das cefaléias na infância e na adolescência

Pós-graduação em Bases Gerais da Cirurgia - FMB

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

Quantas auras deve ter um status de aura?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

An analysis of clinical characteristics in genetically linked migraine-affected pedigrees

Migraine is a common complex disorder characterized by severe recurrent headache and usually accompanied by nausea and vomiting. Previous studies in our laboratory have utilized three large multigenerational Australian pedigrees affected with migraine to indicate that the disease is genetically heterogeneous, with linkage results implicating genomic susceptibility regions on both chromosomes 19p and Xq. The present study explores the possibility of a correlation between genetic and clinical heterogeneity in these affected pedigrees. Specifically, the clinical characteristics of migraine including subtype, age of onset, frequency, duration, and disease symptoms were compared between the migraine pedigrees, and gender differences were also assessed. Our exploratory analyses revealed no significant differences in any of the clinical characteristics tested between the chromosome 19-linked family and the two X-linked families. Also, we did not detect any differences in male vs. female clinical features for these pedigrees. In conclusion, migraine is considered to be a clinically and genetically heterogeneous disorder; however, our study provided no conclusive evidence that variation in genomic susceptibility region is related to heterogeneity at the clinical level in these migraine-affected pedigrees.

Anxiety, depression and school absenteeism in youth with chronic or episodic headache.

BACKGROUND: Chronic daily headache (CDH) in children has been documented in general and clinical populations. Comorbid psychological conditions, risk factors and functional outcomes of CDH in children are not well understood. OBJECTIVES: To examine anxiety and depression, associated risk factors and school outcomes in a clinical population of youth with CDH compared with youth with episodic headache (EH). METHODS: Data regarding headache characteristics, anxiety, depression and missed school days were collected from 368 consecutive patients eight to 17 years of age, who presented with primary headache at a specialized pediatric headache centre. RESULTS: A total of 297 patients (81%) were diagnosed with EH and 71 were diagnosed with CDH. Among those with CDH, 78.9% presented with chronic tension-type headache and 21.1% with chronic migraine (CM). Children with CDH had a higher depression score than the standardized reference population. No difference was observed for anxiety or depression scores between children with CDH and those with EH. However, children with CM were more anxious and more depressed than those with chronic tension-type headache. Youth experiencing migraine with aura were three times as likely to have clinically significant anxiety scores. Headache frequency and history were not associated with psychopathological symptoms. Children with CDH missed school more often and for longer periods of time. CONCLUSIONS: These findings document the prevalence of anxiety, depression and school absenteeism in youth with CDH or EH. The present research also extends recent studies examining the impact of aura on psychiatric comorbidity and the debate on CM criteria.

Effects of {beta}-blocker selectivity on blood pressure variability and stroke: A systematic review

β-Blockers increase variability in systolic blood pressure (SBP), which probably explains their lesser effectiveness in preventing stroke vs myocardial infarction compared with other agents. This increase in variability in blood pressure (BP) may be particularly marked on non-cardioselective agents, potentially calling into question the widespread first-line use of propranolol in migraine with aura, elderly patients with essential tremor or anxiety, and other groups at risk of stroke.

Syncope

Syncope is defined as an acute, brief and transient loss of consciousness and postural tone with spontaneous and complete recovery. Neurovascular ultrasound has contributed to elucidate the underlying mechanism of different types of syncope. In routine diagnostic work-up of patients with syncope, however, neurovascular ultrasound is not among the first line tools. In particular, an ultrasound search for occlusive cerebro-vascular disease is of limited value because cerebral artery obstruction is a very rare and questionable cause of syncope. Transcranial Doppler sonography monitoring of the cerebral arteries is useful in the diagnostic work-up of patients with suspicion of postural related, cerebrovascular, cough and psychogenic syncope, and in some cases for differentiating focal epileptic seizures from transient ischemic attacks and migraine with aura.

Clinical tests of musculoskeletal dysfunction in the diagnosis of cervicogenic headache

Persistent intermittent headache is a common disorder and is often accompanied by neck aching or stiffness, which could infer a cervical contribution to headache. However, the incidence of cervicogenic headache is estimated to be 14-18% of all chronic headaches, highlighting the need for clear criterion of cervical musculoskeletal impairment to identify cervicogenic headache sufferers who may benefit from treatments such as manual therapy. This study examined the presence of cervical musculoskeletal impairment in 77 subjects, 27 with cervicogenic headache, 25 with migraine with aura and 25 control subjects. Assessments included a photographic measure of posture, range of movement, cervical manual examination, pressure pain thresholds, muscle length, performance in the cranio-cervical flexion test and cervical kinaesthetic sense. The results indicated that when compared to the migraine with aura and control groups who scored similarly in the tests, the cervicogenic headache group had less range of cervical flexion/extension (P = 0.048) and significantly higher incidences of painful upper cervical joint dysfunction assessed by manual examination (all P < 0.05) and muscle tightness (P < 0.05). Sternocleidomastoid normalized EMG values were higher in the latter three stages of the cranio-cervical flexion test although they failed to reach significance. There were no between group differences for other measures. A discriminant analysis revealed that manual examination could discriminate the cervicogenic headache group from the other subjects (migraine with aura and control subjects combined) with an 80% sensitivity. (C) 2005 Elsevier Ltd. All rights reserved.

Development and application of magnetoencephalographic methods in the investigation of the human visual system

This thesis is an exploration of the organisation and functioning of the human visual system using the non-invasive functional imaging modality magnetoencephalography (MEG). Chapters one and two provide an introduction to the ‘human visual system and magnetoencephalographic methodologies. These chapters subsequently describe the methods by which MEG can be used to measure neuronal activity from the visual cortex. Chapter three describes the development and implementation of novel analytical tools; including beamforming based analyses, spectrographic movies and an optimisation of group imaging methods. Chapter four focuses on the use of established and contemporary analytical tools in the investigation of visual function. This is initiated with an investigation of visually evoked and induced responses; covering visual evoked potentials (VEPs) and event related synchronisation/desynchronisation (ERS/ERD). Chapter five describes the employment of novel methods in the investigation of cortical contrast response and demonstrates distinct contrast response functions in striate and extra-striate regions of visual cortex. Chapter six use synthetic aperture magnetometry (SAM) to investigate the phenomena of visual cortical gamma oscillations in response to various visual stimuli; concluding that pattern is central to its generation and that it increases in amplitude linearly as a function of stimulus contrast, consistent with results from invasive electrode studies in the macaque monkey. Chapter seven describes the use of driven visual stimuli and tuned SAM methods in a pilot study of retinotopic mapping using MEG; finding that activity in the primary visual cortex can be distinguished in four quadrants and two eccentricities of the visual field. Chapter eight is a novel implementation of the SAM beamforming method in the investigation of a subject with migraine visual aura; the method reveals desynchronisation of the alpha and gamma frequency bands in occipital and temporal regions contralateral to observed visual abnormalities. The final chapter is a summary of main conclusions and suggested further work.

Temporomandibular disorders and cutaneous allodynia are associated in individuals with migraine

The objective of this study was to estimate and contrast the occurrence of ictal and interictal cutaneous allodynia (CA) in individuals with migraine with and without temporomandibular disorders (TMD). Both TMD and CA are common in migraine and may be associated with migraine transformation from episodic into a chronic form. Herein we hypothesize that TMD contributes to the development of CA and to more severe headaches. In a clinic-based sample of individuals with episodic migraine, the presence of TMD was assessed using the research diagnostic criteria for myofascial or mixed (myofascial and arthralgic) TMD. Ictal CA was quantified using the validated Allodynia Symptom Checklist (ASC-12). The ASC-12 measures CA over the preceding month by asking 12 questions about the frequency of allodynia symptoms during headaches. Interictal CA was assessed in the domains of heat, cold and mechanical static allodynia using quantitative sensory testing. Our sample consists of 55 individuals; 40 (73%) had TMD (23 with myofascial TMD and 17 with the mixed type). CA of any severity (as assessed by ASC-12) occurred in 40% of those without TMD (reference group), 86.9% of those with myofascial TMD (P = 0.041, RR = 3.2, 95% CI = 1.5-7.0) and in 82.3% of those with mixed TMD (P = 0.02, RR = 2.5, 95% CI = 1.2-5.3). Individuals with TMD were more likely to have moderate or severe CA associated with their headaches. Interictally (quantitative sensory testing), thresholds for heat and mechanical nociception were significantly lower in individuals with TMD. Cold nociceptive thresholds were not significantly different in migraine patients with and without TMD. TMDs were also associated with change in extra-cephalic pain thresholds. In logistical regression, TMD remained associated with CA after adjusting for aura, gender and age. TMD and CA are associated in individuals with migraine.

Lateral Pterygoid Muscle Volume And Migraine In Patients With Temporomandibular Disorders.

Lateral pterygoid muscle (LPM) plays an important role in jaw movement and has been implicated in Temporomandibular disorders (TMDs). Migraine has been described as a common symptom in patients with TMDs and may be related to muscle hyperactivity. This study aimed to compare LPM volume in individuals with and without migraine, using segmentation of the LPM in magnetic resonance (MR) imaging of the TMJ. Twenty patients with migraine and 20 volunteers without migraine underwent a clinical examination of the TMJ, according to the Research Diagnostic Criteria for TMDs. MR imaging was performed and the LPM was segmented using the ITK-SNAP 1.4.1 software, which calculates the volume of each segmented structure in voxels per cubic millimeter. The chi-squared test and the Fisher's exact test were used to relate the TMD variables obtained from the MR images and clinical examinations to the presence of migraine. Logistic binary regression was used to determine the importance of each factor for predicting the presence of a migraine headache. Patients with TMDs and migraine tended to have hypertrophy of the LPM (58.7%). In addition, abnormal mandibular movements (61.2%) and disc displacement (70.0%) were found to be the most common signs in patients with TMDs and migraine. In patients with TMDs and simultaneous migraine, the LPM tends to be hypertrophic. LPM segmentation on MR imaging may be an alternative method to study this muscle in such patients because the hypertrophic LPM is not always palpable.