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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Headaches: Causes, Treatment, and Prevention : Causes, Treatment and Prevention, Nova Science Publishers, Incorporated,

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HEADACHES: CAUSES, TREATMENT AND PREVENTION

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HEADACHES: CAUSES, TREATMENT AND PREVENTION

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

PIETRO G. GALLO AND GIOVANNA M. GIORDANO

EDITORS

Nova Science Publishers, Inc. New York

Headaches: Causes, Treatment, and Prevention : Causes, Treatment and Prevention, Nova Science Publishers,

Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data Headaches : causes, treatment, and prevention / editors, Pietro G. Gallo and Giovanna M. Giordano. p. ; cm. Includes bibliographical references and index. ISBN 978-1-62257-865-8 (eBook) I. Gallo, Pietro G. II. Giordano, Giovanna M. [DNLM: 1. Headache--etiology. 2. Headache--prevention & control. 3. Headache--therapy. WL 342] 616.8'4913--dc23 2011038978

Published by Nova Science Publishers, Inc. † New York

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Contents

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Preface

vii

Chapter I

Cluster Headache Reinaldo Teixeira Ribeiro, André Leite Gonçalves, and Mario Fernando Prieto Peres

Chapter II

Temperament Patterns and Vulnerability to Anxiety and Depression in Children with Migraine: A Study Model Michela Gatta, Andrea Spoto, Barbara Nigri, Lara Dal Zotto, and Pier Antonio Battistella

Chapter III

Pathophysiology of Migraine: The Neurovascular Theory Daniele Spiri, Luigi Titomanlio, Laura Pogliani, and Gian Vincenzo Zuccotti

1

27

51

Chapter IV

Headache Associated with Intracranial Aneurysms Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença, Daniella A. Oliveira, Joacil Carlos da Silva, and Carolina Martins

65

Chapter V

Blood Pressure and Allodynic Migraine C. Lovati, M. Zardoni, D. D’Amico, L. Giani, L. Scandiani, P. Bertora, M. Cortellaro, G. Bussone, and C. Mariani

95

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vi Chapter VI

Chapter VII

Contents Personality Characteristics in Men Suffering from Chronic Tension-Type and Cervicogenic Headaches Wanzhen Chen, Wenjun Yu, Wei He, and Wei Wang

107

Role of Melatonin in Health and Diseases: Headache Disorders Mario Fernando Prieto Peres

119

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Index

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141

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Preface In this book, the authors present topical research in the study of the causes, treatment and prevention of headaches. Topics discussed in this compilation include the role of melatonin in headache disorders; the mechanisms and treatment options for cluster headaches; temperament patterns and vulnerability to anxiety and depression in children with migraines; the neurovascular theory and pathophysiology of migraines; headaches associated with intracranial aneurysms; blood pressure and allodynic migraine and personality characteristics in men suffering from chronic tension-type and cervicogenic headaches. Chapter I – Cluster headache (CH) is the trigeminal autonomic cephalalgia whose pain is considered to be one of the most severe known to man. Although diagnosed less frequently than migraine and tension-type headaches, CH is nonetheless an important clinical entity, particularly given our evolving understanding of its actual epidemiology, pathophysiology, current diagnostic criteria and treatment approaches. The author carried out a systematic review through the United States National Library of Medicine (PUBMED) by using the search term “cluster headache” and the results were narrowed to manuscripts published in the last five years with subsequent reference searches and verification of source data. This article presents a review of the current understanding of the most important aspects of CH, with emphasis on mechanisms and treatment approaches. Chapter II – The aim of this study was to investigate the relationship between the temperament and anxious-depressive disorders in young patients suffering from migraine. With a view to ascertain whether the models in the literature relating to a temperamental predisposition and whether such disorders are also applicable to such cases. In particular, analytical methods were adopted to undertake a detailed assessment of the role of “attention” as a

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cognitive domain of temperament. Much discussed in literature with regard to its correlation with the other emotional temperament domains and the various psychopathological traits. The results point to a causal relationship between temperament and psychopathological domains. Emphasizing the influence of the attention temperamental variable, which appears to be associated with the variables indicative of introversion, and which correlates inversely with internalizing psychopathological aspects. Chapter III – Migraine is a common and disabling type of primary headache which is divided into migraine with or without aura and some rare genetic disorders. Whereas it is understood that Cortical Spreading Depression (CSD) causes the aura, the headache mechanisms are less clear. Today it is known that migraine is a neurovascular disorder, in which afferent innervation of intracranial blood vessels, forming the Trigemino-Vascular System (TVS), is the essential substrate for migraine attack. The TVS consist of primary neurons whose cell bodies lie within the ipsilateral trigeminal ganglion (TG). Peripherally, these neurons innervate the dura mater, as well as intracerebral and meningeal vessels. A rich sympathetic and parasympathetic innervation is also present at these sites. The central fibers of TG neurons form synapses within the trigeminal nucleus in the caudal brainstem from where peripheral pain perception is carried to the thalamus and cerebral cortex. Histochemical studies have revealed that calcitonin gene-related peptide (CGRP) is a neuropeptide strongly expressed by TG and trigeminal nucleus neurons. It is postulated to be directly involved in dilatation of cerebral and dural blood vessels, in release of inflammatory mediators from mast cells and in the transmission of nociceptive information from intracranial blood vessels to the nervous system. In the belief that brainstem centers probably have an important role in regulating vascular tone and pain sensation, many authors argue a hypothetical pathophysiology of migraine supported by current functional and radiological studies. Migraine-specific triggers cause the activation of sensory fibers of the trigeminal nerve that innervate intracranial blood vessels, causing a pain response. This information is conveyed to the brainstem and evokes release of vasoactive peptides such as CGRP and substance P from trigeminal fibers, inducing vasodilation and neurogenic inflammation. These events increase the activation of the sensory trigeminal fibers and perpetuate the release of vasoactive peptides (supporting the transmission of pain impulses to the brain) over hours to days in correspondence with the duration of a typical migraine episode. Current data provide a complex model in which vascular and neuronal mechanisms cooperate. The generation of migraine pain is probably a consequence of

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Preface

ix

multiple pathophysiological changes in meningeal tissues, TG, trigeminal brainstem nuclei and descending inhibitory systems that are still not fully clarified and worthy of further studies. Chapter IV – Headache may be an alarm signal of intracranial aneurysms. Thunderclap headache is typically related to a rupture of an intracranial aneurysm, particularly when loss of consciousness, vomiting or seizure occurs. Furthermore, a primary form of thunderclap headache has also been described. However, thunderclap headache may also be encountered in cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome, pituitary apoplexy, and may even be caused by an unruptured aneurysm. Other forms of headache may also be triggered by aneurysms, mimicking a primary form of headache such as migraine, cluster headache, stabbing headache, among others. In addition, after microsurgical treatment of patients with aneurysm, headache may be an important cause of suffering. Patients with intracranial aneurysm located at the internal carotid artery-posterior communicating artery (ICAPComA) often present pain on the orbit or fronto-temporal region ipsilateral to the aneurysm, as a warning sign a few days before rupture. Given the close proximity between ICA-PComA aneurysm and the oculomotor nerve, palsy of this cranial nerve may occur during aneurysmal expansion (or rupture), resulting in progressive eyelid ptosis, dilatation of the pupil and double vision. In addition, aneurysm expansion may cause compression not only of the oculomotor nerve, but of other skull base pain-sensitive structures (e.g. duramater and vessels), and pain ipsilateral to the aneurysm formation is predictable. The author reviewed the functional anatomy of circle of Willis, oculomotor nerve and its topographical relationships in order to better understand the pathophysiology linked to pain and third-nerve palsy caused by an expanding ICA-PComA aneurysm. Silicone-injected, formalin fixed cadaveric heads were dissected to present the microsurgical anatomy of the oculomotor nerve and its topographical relationships. In addition, the relationship between the right ICA-PComA aneurysm and the right third-nerve is shown using intraoperative images, obtained during surgical microdissection and clipping of an unruptured aneurysm. This chapter discusses when and how to investigate patients with headache associated with an isolated third-nerve palsy. Chapter V – Background: the transformation from an episodic form of migraine to a chronic and invalidating form is under investigation to put in evidence possible factors able to enhance this progression. A number of studies found an association between hypertension and migraine chronification and this observation induced the hypothesis that hypertension may possibly

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modify the vascular wall and the endothelial function in the cerebral vasculature. Allodynia, the perception of pain by non-painful stimuli, is considered as a marker of migraine transformation. Objective: In this chapter the author study planned to investigate presence of headache in patients that underwent a blood pressure 24 hours monitoring. The aim of the study was to assess the distribution of headache and allodynia in this particular population and to investigate possible relationships between the presence of headache and blood pressure pattern, including its circadian rhythm. Materials and Methods: Population: 195 subjects; among them, 122 did not suffer from headache (mean age 60.4 ± 11.6 years, 78 men and 44 women) and 73 with history of headache, (mean age 54.2 ± 12.5 years, 18 men and 55 women) of which 51 migraineurs (Mig) (mean age 52.6 ± 11.7 years, 11 men and 40 women) and 22 with tension type headache (TTH - mean age 58.0 ± 13.5 years, 7 men and 15 women). Among headache patients, allodynia was found in 23 out of 51 migraineurs and in 7 out of 22 tension-type headache. Headache diagnosis was made according to ICHD-II criteria. Presence of allodynia and sleep behavior were evaluated through semi-structured ad hoc questionnaires. Blood pressure 24hours monitoring was performed by an Ambulatory Blood Pressure (ABP) Monitor (Space Labs) with its ad hoc software. Results: No significant difference was observed between headache patients and subjects without headache in terms of mean systolic and diastolic pressure, neither between migraine and TTH. With regard to the circadian rhythm of the blood pressure it was observed that the physiological reduction of blood pressure during night (dipping) was more conserved among headache patients (34 dippers out of 73 subjects) with respect to subjects without headache (40 dippers out of 122) and that this border-line difference was more strongly significant comparing allodynic subjects (19 dippers out of 30) with both non-headache (40 dippers out of 122 , p 4) 2008 (all ages)

0/100000 100/100000

Spain Greece

1992 1993-1994

96 (students) 588 (students)

1520/100000 0/100000

Norway Sweden Italy Germany

1995 1999-2002 2002-2003 2004

1838 (ages 18-65) 31750 (twins) 7522 (ages > 14) 3336 (ages 18-65)

381/100000 151/100000 279/100000 119/100000

Germany Georgia

2005 2008

1312 (ages 25-75) 1145 (ages > 18)

150/100000 87/100000

* Authors’ mathematical extrapolation from own reference data.

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Cluster Headache

5

Despite the selection bias present in many of the population-based studies available, Fischera et al published a meta-analysis in 2008, which pooled the data from almost all epidemiological study on CH to obtain a lifetime prevalence of 124 per 100000 along with a 1-year prevalence of 53 per 100000 [39]. Noteworthy, most previously mentioned studies have looked at Caucasian populations and there is little data to date on racial differences in CH. In 2001, Rozen et al published a retrospective chart review that has shown that AfricanAmerican women develop CH more commonly than African-American men (25% and 17,4% respectively).[40] Methodological issues have interfered in the other few studies done with non-Caucasian populations: the prevalence of CH in Nigeria[26] and China[27] were measured prior to ICHD era; lay health care workers measured the prevalence of CH in Ethiopia at 32 per 100000;[30] and no CH patient was found in a relatively small sample of the Malaysian population [31]. A decline in male preponderance has been suggested by recent data. In 1997, Manzoni published a review of 482 patients referred to a headache center for CH and the male to female (M:F) ratio was noted to decline with time, from a ratio of 6,2:1 prior to 1960 to 2,1:1 between 1990 and 1995.[41] In 2002, Ekbom et al published similar findings after observing 554 patients between 1963 and 1997.[42] Contradictorily, Bahra et al obtained a patient sample prospectively to find a constant low ratio over the decades of 2,5:1[43] and the meta-analysis of Fischera et al noted an overall ratio of 4,3:1.[39] Studies have reported a mean age of onset of CH between 29,6 years[23] and 35,7 years,[24] some with no statistical difference between men and women,[5] others with significantly lower age of onset for women compared to men (29,2 and 40,5 years respectively).[24] Women seem to have a bimodal peak of onset of CH in the third and fifth decade, whereas men appear to have a single peak of onset in the third decade.[40, 44] ECH is tremendously more common in both men and women, affecting at least 80% of patients with CH, while chronic CH (CCH) is rare, having been reported in only 4% to 20% of patients.[42, 45] The meta-analysis of Fischera et al noted a higher M:F ratio in CCH compared to ECH (15:1 and 3,8:1, respectively), and an overall ECH to CCH ratio of 6:1.[39] Interestingly, the mean age of onset of CCH for women is higher than it is for men (50,8 years and 31,8 years, respectively) with M:F ratio reversal with age of onset after 50 years (0,6:1).[42] CH in children is rare with few cases reported [46-48].

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4. Pathophysiology The exact cause of CH is currently unknown, but its underlying mechanism must account for the trigeminal distribution of the pain, the accompanying autonomic features and the circadian rhythmicity of the attacks [49]. Historically, the first hypotheses on CH were based on the vascular theory that oriented the initial studies toward the trigeminal-vascular system (TVS). The innervation of encephalic blood vessels and meninges is mostly provided by fibers from the trigeminal ganglion,[49] nerves containing calcitonin generelated peptide (CGRP),[50] nitric oxide[51] and others substances that cause vasodilatation. Nociceptive stimulation, such as a vascular dysfunction or inflammation suggested by the first studies,[52] activates neurons in the trigeminal nucleus caudalis (TNC), which project to multiple subcortical sites that in sequence distribute sensory data to multiple cortical regions. The activated trigeminal pain pathways play a major role in the modulation and experience of pain.[49] Although the TVS is actually activated in CH, associated with increased CGRP in jugular veins during typical attacks,[50] it is not specific for CH and whether it is cause or consequence of CH is not clear. Later on, the autonomic features of CH have oriented the studies toward the trigeminal-autonomic reflex (TAR). This brainstem reflex is generated when a stimulation of the TVS via the trigeminal ganglion results in a rebound activation of the parasympathetic outflow via the facial nerve.[53] The activation of the TAR releases acetylcholine and vasoactive intestinal peptide (VIP), important regulators of lacrimation and vasodilatation.[54] TAR is believed to be a normal physiological response to pain because it occurs in migraine[55] and it can be elicited to some extent even in healthy volunteers with experimental trigeminal pain.[56] There is evidence that the severity of pain is correlated with the intensity of the TAR, which is most severe in CH.[49] Despite the activation of TAR in CH, associated with increased VIP in jugular veins during typical attacks,[57] the increased prevalence of autonomic features in CH points to further autonomic dysfunctions that require supplementary research. More recently, the circadian rhythmicity of CH has oriented the studies toward the hypothalamus. The suprachiasmatic nucleus (SCN) is the main control center of the biological clock, which receives retinal information on luminosity and projects it to the pineal gland where melatonin needs to be produced in a circadian rhythm to act satisfactorily.[49] During the symptomatic phase of CH, the melatonin production is reduced until its nocturnal peak

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disappears,[58] thus altering biological rhythms and decreasing its additional analgesic effect related to gabaergic reinforcement,[59-60] calcium modulation[61-62] and prostaglandin synthesis inhibition[63-64]. Some clinical data on CH bouts, such as hypersexuality and hyperphagia, have suggested hypothalamic dysfunction beyond the biological clock found in the SCN.[65] Abnormal blood levels of prolactin, testosterone, thyrotropin and corticotropin during CH attacks have added laboratory evidence of perturbations in the hypothalamic-pituitary axis.[58, 66-67] Functional neuroimaging studies have shown an activation of the ipsilateral posterior hypothalamus during CH attacks[68-70] associated with neuronal loss or dysfunction,[71-72] while structural neuroimaging studies with Voxel-based morphometry demonstrated an increase in the gray matter volume of the same hypothalamic area in CH patients compared to controls [73]. Indeed, the hypothalamus receives connections from the frontal cortex and projects them to the periaqueductal gray, nucleus raphe magnus, nucleus tractus solitarius, and rostroventromedial medulla, a system that have been implicated in the descending modulation of pain and nociceptive processing.[74] Additionally, the posterior hypothalamus contains direct connections to the TNC (trigeminal-hypothalamic tract),[75] to the parasympathetic (superior salivatory nucleus)[76] and sympathetic systems (preganglionary neurons)[77] that modulate the activity of the TVS and TAR. Finally, the posterior hypothalamus produces orexins A and B, two excitatory neuropeptides formerly known as hypocretins 1 and 2 in that order, with orexin-A demonstrating equal affinity for both orexin receptors 1 and 2, while orexin-B has a 10-fold higher affinity for receptor 2 than receptor 1.[49] The activation of the orexin receptors 1 and 2 has been shown to differentially modulate nociceptive inputs to the TNC,[78] where receptor 1 elicits an antinociceptive effect and receptor 2, whose gene (HCRTR2) 1246G>A polymorphism has been associated with increased risk of CH,[79-80] elicits a pronociceptive effect. The orexinergic system in the posterior hypothalamus is modulated by the SCN,[49] which explains how a dysfunctional biological pacemaker can originate periodic attacks of trigeminal pain with prominent autonomic features and endocrine abnormalities. Whether hypothalamic dysfunction is the primary generator of CH or a response to a remote one is not elucidated yet. Apart from being a sensitive marker of disrupted endogenous rhythms, melatonin may play a role in CH pathophysiology via several other mechanisms.[81] It has been shown to possess anti-inflammatory effects, including the ability to directly scavenge toxic free radicals ensuing reduction in macromolecular damage in all body tissues.[82] The free radicals and reactive

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oxygen and nitrogen species known to be scavenged by melatonin include: the highly toxic hydroxyl radical (-OH); peroxynitrite anion (ONO2-); and hypochlorous acid (HOCl) among others. Melatonin also prevents the translocation of nuclear factor-kappa B to the nucleus and its attachment to deoxyribonucleic acid, thereby reducing the upregulation of a variety of proinflammatory cytokines, interleukins and tumor necrosis factor-alpha.[83] In addition, melatonin inhibits the production of adhesion molecules that promote binding of leukocytes to endothelial cells, attenuating transendothelial cell migration and oedema.[84] Moreover, melatonin inhibits the activity of nitric oxide synthase and subsequent prostaglandin production,[63-64] as well as acting in membrane stabilization. [85]. Melatonin rapidly and reversibly potentiates the gamma-aminobutyric acid (GABA)A receptor-mediated response and it is thought that the hypnotic activity of melatonin, along with part of its additional analgesic effect, is mediated by the gabaergic system.[59-60] The antagonistic effects of melatonin on glutamate release and neurotoxicity in the cerebral cortex has also been reported.[86] It has been found that melatonin induces activated T lymphocytes to release opioid peptides with immunological-enhancing and anti-stress properties, thus a melatonin-immunological-opioid network has been proposed.[87] Cytokines named melatonin-induced opioids have been found to act at an opioid-binding site. Since melatonin may behave as a mixed opioid receptor agonist/antagonist, the potentiation of the opioid analgesic efficacy is possible. Melatonin is also involved in cerebrovascular regulation, where it generally decreases vascular reactivity and modulates the serotonergic neurotransmission, both spontaneous efflux and evoked release [88].

5. Clinical Aspects Physicians and researchers have recognized the unique features of CH since its earliest descriptions. Studies on clinical features[43, 89-90] have shown that CH attacks usually lasts between 15 minutes and 3 hours and this short-lasting characteristic is one of the first to help differentiate it from migraine. The pain is recurrent with a frequency from one every other day to eight per day. CH is one of the most painful conditions known to man, usually described as a severe or very severe unilateral orbital pain, but it may be located in other areas within the first trigeminal branch territory. The duration, frequency, severity and localization of attacks were included in the ICHD diagnostic criteria due to their

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marked constancy.[1] However, about 15% of patients had attacks lasting less than 15 minutes or more than 3 hours, [90] the pain sometimes extends to other trigeminal branches territories or even the occipito-cervical region, and at least 15% of patients experience a change of attack side during their clinical course,[43, 89] which is notably common in CCH with 50,8% of side shift [91]. CH pain rises and ends abruptly, often leaving patients asymptomatic between attacks. There may be a continuous discomfort on the affected side in severe CCH or ECH with numerous daily attacks. [92] Although very suggestive of CH, the presence of cluster peaks around solstices [93] and dramatic regularity of timed attacks on day or during sleep (circannual and circadian rhythmicity) are not included in the ICHD diagnostic criteria because they are not seen in all patients. Ipsilateral autonomic signs are another distinctive feature of CH with parasympathetic hyperactivity (conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, and sweating) and sympathetic hypoactivity (miosis and ptosis) [94] included in the ICHD diagnostic criteria. A sense of restlessness or agitation is so typical of a CH attack,[95] only approximately 3% of patients can lie still during a bout, [96] that it was accepted as an alternative criterion when the autonomic signs are subtle or even absent in up to 7% of patients. [90, 94]. Other relevant features of CH include few recognized triggers such as alcohol, smoking, nitrates, increase in body heat, hypoxia and napping, which occur only during cluster periods. Symptoms generally attributed to migraine, including nausea, vomiting, photophobia and phonophobia, can be observed in approximately 50% of patients, whilst up to 14% of patients report aura symptoms, with transient visual, motor or sensory disturbances preceding an attack.[43] Particularly, nausea and vomiting are more common in women with CH than men (46,9% and 17,4%, respectively)[40] and auras have been reported in 20% of patients with CCH.[92] Noteworthy, patients with CH and visual symptoms have been reported since 1972, [97] but the first four cases of hemiplegic cluster were published only thirty years later, in 2002.[98] In these cases, the symptomatology is remarkably similar to familial hemiplegic migraine and one patient also had a family history suggestive of an autosomal dominant disorder. Graham was the first to notice that some patients have a leonine facies with broad head and reddish thick furrowed brows and cheeks.[99] Rare case reports have described patients with “CH sine headache”. [100-101] When it comes to associated conditions, increased prevalence of obstructive sleep apnea (OSA),[102-105] patent foramen ovale [106] and right-to-left shunt [107] has been reported in patients with CH, and whether this reflects a clinical phenotype,

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parallel processes or a causal relationship remains to be determined. Particularly to OSA, its prevalence in CH patients has ranged from 58,5%[105] to 80,64%[104] with some reports of benefit of continuous positive airway pressure (CPAP) to the CH of patients suffering from both conditions.[105, 108109] However, the demonstration that increased activation of temperaturesensitive neurons in the preoptic/anterior hypothalamus, which also controls body metabolic rate, suppress the activity of the airway dilator muscles and diaphragmatic muscle during non-rapid eye movement sleep[110] suggest that OSA and CH are parallel processes generated in different areas of the hypothalamus [111]. Traditionally, CH has been associated with excessive smoking. Early studies on smoking in CH were conducted on a small number of patients with similar high prevalence results until the decade of 1990, when changing habits in the population determined a sustained decrease in the prevalence of smoking.[112] Noteworthy, a large Italian cohort demonstrated that the increased propensity of CH patients to smoking remained almost unaltered through time:[113-114] the prevalence of smoking in Italy in 1975 and in 1993 was 53,2% and 35% for men, and 16,3% and 19,2% for women, respectively; whereas the prevalence of smoking in CH patients before 1990 and after 1990 was 89,4% and 87,8% for men, and 56,5% and 57,1% for women, correspondingly. Two small case series hypothesized that smoking may impact the perpetuation and onset of CH. In the first series, 9 CH patients actually stopped smoking: 6 patients noted abolition or marked improvement of their symptoms, and another patient noted improvement after reducing cigarette consumption.[115] In the second series, from 11 patients with CH, 8 had parents who smoked during childhood creating a potential causal relationship [116]. In 1999, a case-control study of the frequency of mood and anxiety disorders among patients with ECH was published.[117] When compared with a group of patients with tension-type headache (TTH) who were matched for sex, age, educational level and degree of functional impairment, ECH patients showed a higher frequency of anxiety disorders (23,8% with Diagnostic and Statistical Manual of Mental Disorders 4th edition – DSM-IV – criteria for either panic disorder or generalized anxiety disorder) during the year preceding the onset of headaches and significantly greater anxiety scores during the clinical episode than TTH patients (4,8% with DSM-IV criteria for adjustment disorder with mixed anxiety and depressed mood). Alike a later study,[118] this study demonstrated that ECH patients presented impaired neuropsychological evaluations on verbal memory, visuospatial memory and executive performance.[117] Both studies have shown that this cognitive decline was not

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related to a mood disorder (none of the ECH patients with high depression scores) and not statistically different from those presented by patients with migraine[118] or TTH.[117] Further studies restore confidence that all cognitive impairments in CH are transient, mild, and do not relevantly contribute to the morbidity associated with the disease [119-120].

6. Diagnosis

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Diagnosis of CH is based on the clinical history. The diagnostic criteria for CH according to the ICHD is as follows:[1] A. At least five attacks fulfilling B through D. B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 180 minutes if untreated. C. Headache is accompanied by at least one of the following: ipsilateral conjunctival injection and/or lacrimation; ipsilateral nasal congestion and/or rhinorrhea; ipsilateral eyelid edema; ipsilateral forehead and facial sweating; ipsilateral miosis and/or ptosis; a sense of restlessness or agitation. D. Attacks have a frequency from one every other day to eight per day. E. Not attributed to another disorder. CH is divided in ECH and CCH, whose additional ICHD diagnostic criteria are described below:[1] A. All fulfilling criteria A through E of CH. B. At least two cluster periods lasting from 7 to 365 days and separated by pain free remissions of > 1 month (for ECH); Attacks recur for > 1 year without remission periods or with remission periods lasting < 1 month (for CCH). Exclusion of a secondary cause of CH is matter of debate. A recent review of 56 cases of symptomatic trigeminal autonomic cephalalgias (TACs) found a wide range of both intracerebral and extracerebral cranial and cervical lesions and diseases that could be associated with them, and a persistently abnormal neurological examination directed towards additional neuroimaging in almost all reports.[121] A first attack suggestive of CH and all atypical cases must always

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be thoroughly investigated to exclude vascular lesions, tumors, demyelinating disease and other treatable causes. Conversely, when the history is so typical with numerous periods, attacks and without interictal neurological deficits, complimentary investigation is not mandatory. Apart from symptomatic cases of CH, its differential diagnosis includes migraine, other TACs, trigeminal neuralgia (TN or “tic douloureux”) and hypnic headache (HH). In migraine, attacks are longer than 4 hours,[1] sometimes bilateral, with female preponderance, accompanied with prostration and quietness, and triggered by hormonal and dietary triggers other than alcohol.[43] Other TACs differs from CH by the shorter length and higher frequency of their attacks, and absolute response to at least 150mg of indomethacin.[1, 43] TN attacks are briefer and more frequent than CH, rarely affecting the first trigeminal branch territory, with female preponderance, trigger zones and without autonomic signs.[1, 122-123] HH affects elderly patients with exclusively sleep attacks, usually bilateral, diffuse and without autonomic signs.[1, 124] When CH symptoms are associated or overlapped with another headache, such as cluster-migraine[125] and cluster-tic,[126] the patient should receive both diagnoses and be treated with a medication efficient for both conditions preferentially. Overlap between attack duration in TACs is inherent in the ICHD,[1] but some overlap in treatment response among the TACs has emerged[127-129] and some clinical overlap exist in the same patient including coexistence of CH and chronic or episodic paroxysmal hemicrania (EPH),[130133] CH and hemicrania continua,[134-136] and a case of EPH with seasonal variation similar to CH [137].

7. Treatment In clinical practice, CH drug treatment can be divided into three groups.[96] Abortive therapy is aimed at aborting individual attacks and preventive therapy is aimed at preventing recurrent attacks during the cluster period, while transitional therapy provides attack relief until the maintenance preventive medication reaches a therapeutic dosage. The main goal of CH preventive therapy is to suppress attacks and to maintain remission over the expected duration of the cluster period.[96, 138] In ECH, medications are only used while a patient is in a cycle and then tapered off after a sustained remission period of at least 1 month. The first option for the abortive therapy of CH should be pure oxygen inhalation via a non-rebreathing facial mask with a flow rate of at least 7l/min

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over 15 minutes.[138-139] It is the safest abortive method available, supported by a review for the Cochrane Collaboration[140] and a recent double-blind, randomized, placebo-controlled crossover trial,[141] which suggested that normal pressure oxygen therapy was likely to be effective in acute CH attack treatment with a therapeutic response in up to 78% of the cases. Subcutaneous injection of sumatriptan 6mg is the most effective medication for the abortive therapy of CH with a symptomatic relief in up to 75% of all patients,[96, 138139, 142] but it should only be considered for patients without uncontrolled hypertension, previous myocardial infarction or stroke. Other first option alternatives include the nasal sprays of sumatriptan 20mg or zolmitriptan 5mg with slower onset, but being able to treat more attacks in a day than with injected sumatriptan.[138] If all first option medications are ineffective or contraindicated, subcutaneous octreotide 100mcg and oral zolmitriptan 5 to 10mg can be tried for abortive therapy of CH with some efficacy,[138, 142] while intranasal lidocaine 4 to 10%,[142] ergotamine,[139, 142] oral olanzapine 2,5 to 10mg and suppositories of chlorpromazine or indomethacin[96] lack randomized controlled trials (RCT) and they should be reserved to otherwise intractable CH attacks. The best-known transitional therapy is a short course of corticosteroids.[96, 142] Although there are no adequate RCT available for the use of corticosteroids,[138-139, 142] the review of several open studies and case series has confirmed the clinically well known efficacy of corticosteroids given under different short course regimens with a therapeutic response in up to 80% of all CH patients.[143] Dihydroergotamine (DHE) has also been considered for a more laborious transitional therapy at daily intramuscular injections of 1mg for a week or intravenous infusion of 1mg twice or thrice a day for 3 days.[96] Naratriptan 2,5mg or frovatriptan 2,5mg have been proposed as more tolerable transitional therapies with oral administration of one tablet twice a day for a week [96]. The drug of first choice in preventive therapy for CH is verapamil,[96, 138, 142, 144] at a daily dose of at least 240mg.[96, 138, 142] It is probably the safest preventive agent that can be used with other abortive and preventive medications for CH,[96, 139] although serial electrocardiograms are recommended during dose titration[96, 138, 142, 144] and should probably be monitored in the long term due to eventual PR prolongation during maintenance therapy.[145] If verapamil monotherapy is ineffective or contraindicated, daily doses of lithium 300 to 900mg,[96, 138-139, 142] melatonin 10mg,[96, 138, 146] topiramate 50 to 400mg,[96, 138] methysergide 4 to 8mg,[138] pizotifen 3mg,[138] intranasal capsaicin,[138, 142] and intranasal civamide[138, 142] are

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drugs of second choice with decreasing level or recommendation that can be employed either in mono or polytherapy. Other agents that have been reported to be effective in preventive therapy for CH include baclofen,[96, 138, 142] valproate,[96, 138, 142] gabapentin,[96, 142] tizanidine,[142] transdermal clonidine,[96, 142] leuprolide,[96, 142] mycophenolate,[96] clomiphene,[96] and testosterone,[96] all of them should be considered as third choice drugs. The main interventional therapy includes greater occipital nerve (GON) blockade,[96, 138, 142, 147] botulinum toxin (BTX) injections,[138, 142, 147] radiofrequency (RF) thermocoagulation,[96, 138-139] GON stimulation,[96, 138-139] and hypothalamic stimulation.[96, 138] GON injections have recently been shown to be efficacious,[147-148] either using an anesthetic alone or better associated with steroids,[96, 147] and they are a good alternative to both abortive and transitional therapies when conservative therapy alone is inefficient or contraindicated.[96] BTX injections in some muscles ipsilateral to the pain have shown only limited success in CCH patients.[147, 149] RF thermocoagulation of the trigeminal ganglion is the most commonly used surgical technique for CH, providing one of the best options for pain relief with only approximately 30% of procedure failure.[96] GON stimulation has been studied in 8 patients with refractory CCH and it may take up to 5 months to show any effect, suggesting more central than peripheral neuromodulation.[96, 150] Stimulation of the posterior inferior hypothalamus ipsilateral to the pain is now established as a treatment for selected refractory cases of CCH and almost every patient has had a tremendous reduction in CH frequency.[96, 151-152] As of 2009 April, 54 patients have been submitted to hypothalamic stimulation and 50 to 75% of CCH patients eligible to improvement evaluation, as the response may take weeks to months, were pain free or almost pain free.[152] It is important to emphasize that surgical procedures should be considered with great caution, after inadequate relief from abortive, transitional and preventive therapies had been well documented in CCH patients. In our experience, a fourth type of therapy should cover the prevention of the next cluster of attacks and the adequate treatment of all associated conditions. Smoking cessation and avoidance of second-hand tobacco smoke should be encouraged in all patients as it may impact the onset and perpetuation of CH.[115-116] Patients with concomitant OSA should be offered CPAP therapy because some cases of CH may benefit from it.[105, 108-109] Anxiety and mood disorders should be treated adequately since functional disruption of serotonergic and noradrenergic networks, which are involved in the etiology and pathophysiology of these disorders, may influence CH pathophysiology as well [74, 88].

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Conclusion CH is a rare disease when compared to other primary headaches such as migraine and tension-type headache; as a result, it gets less attention from private initiatives and public healthcare policies. More research is needed for a better understanding of this condition. Improvement in the management of CH should ultimately affect the quality of life of patients suffering from it.

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[113] Manzoni GC. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia. 1998 Apr;18(3):138-42. [114] Manzoni GC. Cluster headache and lifestyle: remarks on a population of 374 male patients. Cephalalgia. 1999 Mar;19(2):88-94. [115] Millac P, Akhtar N. Cigarette smoking and cluster headaches. Headache. 1985 Jun;25(4):223. [116] Rozen TD. Childhood exposure to second-hand tobacco smoke and the development of cluster headache. Headache. 2005 Apr;45(4):393-4. [117] Jorge RE, Leston JE, Arndt S, et al. Cluster headaches: association with anxiety disorders and memory deficits. Neurology. 1999 Aug 11;53(3):543-7. [118] Meyer JS, Thornby J, Crawford K, et al. Reversible cognitive decline accompanies migraine and cluster headaches. Headache. 2000 Sep;40(8):638-46. [119] Meyer JS, Li YS, Thornby J. Validating mini-mental status, cognitive capacity screening and Hamilton depression scales utilizing subjects with vascular headaches. Int. J. Geriatr. Psychiatry. 2001 Apr;16(4):430-5. [120] Evers S. Cognitive processing in cluster headache. Curr. Pain Headache Rep. 2005 Apr;9(2):109-12. [121] Wilbrink LA, Ferrari MD, Kruit MC, et al. Neuroimaging in trigeminal autonomic cephalgias: when, how, and of what? Curr. Opin Neurol. 2009 Jun;22(3):247-53. [122] Manzoni GC, Torelli P. Epidemiology of typical and atypical craniofacial neuralgias. Neurol. Sci. 2005 May;26 Suppl 2:s65-7. [123] Bennetto L, Patel NK, Fuller G. Trigeminal neuralgia and its management. BMJ. 2007 Jan 27;334(7586):201-5. [124] De Simone R, Marano E, Ranieri A, et al. Hypnic headache: an update. Neurol. Sci. 2006 May;27 Suppl 2:S144-8. [125] Applebee AM, Shapiro RE. Cluster-migraine: does it exist? Curr. Pain Headache Rep. 2007 Apr;11(2):154-7. [126] Monzillo PH, Sanvito WL, Peres MF. [Cluster-tic syndrome: two case reports]. Arq. Neuropsiquiatr. 1996 Jun;54(2):284-7. [127] Buzzi MG, Formisano R. A patient with cluster headache responsive to indomethacin: any relationship with chronic paroxysmal hemicrania? Cephalalgia. 2003 Jun;23(5):401-4. [128] Prakash S, Dholakia SY, Shah KA. A patient with chronic cluster headache responsive to high-dose indomethacin: is there an overlap with chronic paroxysmal hemicrania? Cephalalgia. 2008 Jul;28(7):778-81.

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[129] Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009 Aug;8(8):755-64. [130] Centonze V, Bassi A, Causarano V, et al. Simultaneous occurrence of ipsilateral cluster headache and chronic paroxysmal hemicrania: a case report. Headache. 2000 Jan;40(1):54-6. [131] Tehindrazanarivelo AD, Visy JM, Bousser MG. Ipsilateral cluster headache and chronic paroxysmal hemicrania: two case reports. Cephalalgia. 1992 Oct;12(5):318-20. [132] Pearce SH, Cox JG, Pearce JM. Chronic paroxysmal hemicrania, episodic cluster headache and classic migraine in one patient. J. Neurol. Neurosurg. Psychiatry. 1987 Dec;50(12):1699-700. [133] Shah ND, Prakash S. Coexistence of cluster headache and paroxysmal hemicrania: does it exist? A case report and literature review. J. Headache Pain. 2009 Jun;10(3):219-23. [134] Rozen TD. Verapamil-responsive hemicrania continua in a patient with episodic cluster headache. Cephalalgia. 2006 Mar;26(3):351-3. [135] Saito Y, Manaka S, Kimura S. [Coexistance of cluster headache and hemicrania continua: a case report]. Rinsho Shinkeigaku. 2005 Mar;45(3):250-2. [136] Lisotto C, Mainardi F, Maggioni F, et al. Hemicrania continua with contralateral episodic cluster headache: a case report. Cephalalgia. 2003 Nov;23(9):929-30. [137] Veloso GG, Kaup AO, Peres MF, et al. Episodic paroxysmal hemicrania with seasonal variation: case report and the EPH-cluster headache continuum hypothesis. Arq. Neuropsiquiatr. 2001 Dec;59(4):944-7. [138] May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur. J. Neurol. 2006 Oct;13(10):1066-77. [139] van Kleef M, Lataster A, Narouze S, et al. Evidence-based interventional pain medicine according to clinical diagnoses. 2. Cluster headache. Pain Pract. 2009 Nov-Dec;9(6):435-42. [140] Bennett MH, French C, Schnabel A, et al. Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database Syst Rev. 2008(3):CD005219. [141] Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009 Dec 9;302(22):2451-7. [142] Tyagi A, Matharu M. Evidence base for the medical treatments used in cluster headache. Curr. Pain Headache Rep. 2009 Apr;13(2):168-78.

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[143] Ekbom K, Hardebo JE. Cluster headache: aetiology, diagnosis and management. Drugs. 2002;62(1):61-9. [144] Tfelt-Hansen P, Tfelt-Hansen J. Verapamil for cluster headache. Clinical pharmacology and possible mode of action. Headache. 2009 Jan;49(1):117-25. [145] Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007 Aug 14;69(7):668-75. [146] Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia. 2001 Dec;21(10):993-5. [147] Ailani J, Young WB. The role of nerve blocks and botulinum toxin injections in the management of cluster headaches. Curr. Pain Headache Rep. 2009 Apr;13(2):164-7. [148] Peres MF, Stiles MA, Siow HC, et al. Greater occipital nerve blockade for cluster headache. Cephalalgia. 2002 Sep;22(7):520-2. [149] Sostak P, Krause P, Forderreuther S, et al. Botulinum toxin type-A therapy in cluster headache: an open study. J. Headache Pain. 2007 Sep;8(4):23641. [150] Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet. 2007 Mar 31;369(9567):1099-106. [151] Leone M, Proietti Cecchini A, Franzini A, et al. Lessons from 8 years' experience of hypothalamic stimulation in cluster headache. Cephalalgia. 2008 Jul;28(7):787-97; discussion 98. [152] Sillay KA, Sani S, Starr PA. Deep brain stimulation for medically intractable cluster headache. Neurobiol. Dis. 2009 Jun 6.

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In: Headaches Editor: P. Gallo and G. Giordano

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Chapter II

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Temperament Patterns and Vulnerability to Anxiety and Depression in Children with Migraine: A Study Model Michela Gatta1, Andrea Spoto2, Barbara Nigri1, Lara Dal Zott0,1 and Pier Antonio Battistella1 1

Pediatrics Department, University of Padua, Italy General Psychology Department, University of Padua, Italy

2

Abstract The aim of this study was to investigate the relationship between the temperament and anxious-depressive disorders in young patients suffering from migraine. With a view to ascertain whether the models in the literature relating to a temperamental predisposition and whether such disorders are also applicable to such cases. In particular, analytical methods were adopted to undertake a detailed assessment of the role of “attention” as a cognitive domain of temperament. Much discussed in literature with regard to its correlation with the other emotional temperament domains and the various psychopathological traits. Our results point to a causal relationship between temperament and psychopathological domains.

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Michela Gatta, Andrea Spoto, Barbara Nigri et al. Emphasizing the influence of the attention temperamental variable, which appears to be associated with the variables indicative of introversion, and which correlates inversely with internalizing psychopathological aspects.

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1. Introduction The World Health Organization has recognized a role for primary headache among the twenty major causes of disability, and has consequently promoted a Global campaign to reduce the burden of headache worldwide [1]. Epidemiological investigations have confirmed that a “headache” is the pain most frequently reported in the general pediatric setting, and the main reason for consulting a neurologist. The diagnostic tool used to identify the various types of headache is the International Classification of Headache Disorders (ICHD-II) of 2004 [2]. As regards to headache in developmental age, numerous studies [3] have shown that it is rather rare before four years of age. Although some authors suggest that the prevalence of the idiopathic forms can be assumed to range from 4% to 20% [4,5], this prevalence increases gradually, with a marked increment when children start school [6]. The prevalence curve subsequently rises steadily, with no substantial differences between males and females [7]; peaking again between 12 and 14 years of age [4], when the trend begins to change between the two genders, to a greater degree among females [7,8]. The prevalence of headache in children and adolescents has increased, reaching approximately 15% for migraine [9,10] and 17% for non-migraine headache [11,12]. Migraine is one of the most common forms of pediatric headache, with prevalence rates exceeding 10% in U. S.[9]. Other population-based studies reported the prevalence of migraine in childhood and adolescence ranges from 3% to 14% [13]. Since the beginning of the 1900’s, Wolff tried to make a personality characteristics portrait of migrainous pediatric patients[14]. From that on the research began to explore the association of headache, firstly with broad personality traits and then with distinct psychiatric symptoms [14-18]. Maratos and Wilkinson underlined that an emotional upset is the most frequently reported precipitating factor for migraine [19]. The authors did not suggest a different personality of migrainous children, but that there might be some association between the physiological process that underlies the migrainous attack and the emotional disturbance in these children [20]. Guidetti et al. [21] investigated the relationship between migraine and psychiatric factors in an 8-

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Temperament Patterns and Vulnerability to Anxiety and Depression … 29 year follow-up: they found that the longer chronicity of migraine was related to the presence of anxiety at the beginning of the attack in 75% of children. Anttila et al. [22] found that children with migraine had significantly higher levels of total, internalizing and externalizing symptoms in the CBCL questionnaire, as well as social and family problems, than those without migraine. Other Authors found subclinical level of anxiety and depression rather than diagnosed psychopathologies [23, 24]. In infancy, headache can be the physical expression of a psychological discomfort (e.g. anxiety and depression), and stressful events and situations are often responsible for the onset and/or exacerbation and persistence of the headache [20, 25]. The headache itself may also be a cause of stress that can give rise to anxiety and/or depression [24, 26], also when depressive symptoms do not meet the criteria for a depressive disorder according to the DSM IV [27, 28]. Numerous studies have also shown that depressive mood is a risk factor for the onset of recurrent headache [21, 22, 25, 26, 28, 29] and that chronic migraine patients are considerably more depressive than episodic migraine patients [30]; the results of longitudinal studies seem to indicate that the relationship between migraine and depression is bidirectional [31]. The relationship between primary headache (migraine particularly) and anxiety is bidirectional too, in that several reports have suggested that anxiety could be a precipitating factor that increases the risk, prevalence, frequency and severity of the painful symptoms of migraine [32] and that during the premorbid period migraine patients show significantly higher scores on total, internalizing, anxious-depressive scales at CBCL [20]. Other studies found that anxiety and depression levels increase when the migraine is chronic [30,33], and a history of headache in infancy increases the risk of developing an anxiety disorder in adult age [34]. Furthermore, self-reported stress and anxiety levels are higher in primary headache sufferers than in controls [35]. However in the majority of cases the scores recorded using domain tools do not come within the pathological range, and consequently do not indicate the presence of a specific disorder [23,24]. Before going on to discuss the lack of studies on the relationship between temperament and headache overall in developmental age, it is worth mentioning that the term temperament, as used in this paper, draws from Thomas and Chess [36]. Who define temperament as a “behavioral style”, i.e. something that concerns the formal aspects of behavior, the energy level and its temporal characteristics, while they attribute to the clearly-distinct personality construct the characteristics of content (motivations, expectations, desires, goals).

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Although temperament stems from a strong biological-constitutional component, it is modulated and modified by a child’s life experiences. Consequently it provides the foundations for the individual differences in reactivity and self-regulation in the areas of emotionality, motor activity and attention. Various response patterns have been described in this context, both in terms of their valence (e.g. positive and negative affectivity), and in motivational terms (e.g. behavioral activation or inhibition), and we can generally distinguish between two types of reactivity [37]. The first type of reactivity is called “approach” and is defined as the will to win potential bonuses or rewards, or positive reinforcements, and it has to do with the incisiveness of the reinforcement of learning. It correlates with extrovert personality traits, including various subordinate traits such as positive emotionality, social orientation and level of activity [38]. The second type of reactivity is called “withdrawal” and is defined as a predisposition to withdraw from and avoid potentially non-gratifying or scarcely ‘dependable’ situations; this type of behavior is associated with a corresponding affective reactivity of fear, anxiety and sadness, and this domain correlates with a neurotic personality trait [38]. Various studies have demonstrated that extreme temperamental reactivity levels, be they too low or too high, are associated with psychopathology. The high levels of approach have been described in association with substance abuse [39,40], manic episodes [41,42] and eating disorders [40], while low levels of approach seem to characterize depression [41]. High levels of withdrawal have been correlated with anxious states [43], depressive disorders [41], alcohol abuse [44] and eating disorders [39], whilst low levels of withdrawal seem to be characteristic of psychotic disorders [45]. The contribution of temperament to a person’s vulnerability at the onset of psychopathology should not be seen exclusively in terms of reactivity. Recent research on vulnerability in the aetiology of psychopathological conditions [37,46] has emphasized the influence of self-regulatory processes that make people capable or incapable of modulating their reactivity. From this point of view, a central role can be attributed to the notion of effortful control introduced by Rothbart [47] to describe the self-regulating capacity that emerges as children grow up, enabling them to actively control their overwhelming behavioral and emotional reactions. This includes forms of control over their attention processes, e.g. the ability to deliberately shift the focus of their attention as necessary (attentional control). Effortful control is seen as being similar to the personality trait of awareness [37].

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Temperament Patterns and Vulnerability to Anxiety and Depression … 31 Low effortful control levels increase an individual’s vulnerability to several types of psychopathology, depending on the temperamental aspects involved [37]. Very recent findings on temperamental influences on the risk of psychopathology have shown that effortful control moderates the relationship between negative emotionality and attentive bias [48]. The literature is very scarce when it comes to the relationship between temperament and psychopathology in primary juvenile headache sufferers. Some studies about pediatric idiopathic headache patients, particularly migraines ones, have revealed specific traits, such as a degree of rigidity and emotional inhibition [15,16]. A recent study on the role of temperament traits in children with episodic tension-type headaches found differences between their temperament traits and those of a control group: the former demonstrated a greater temperamental instability, with a higher emotionality, an intensified level of fear, a lower level of vigor, and a higher level of shyness than controls [49]. Another study of Mazzone et al (2006) [18] aimed to examine indices of behavioral and emotional problems and temperamental traits in clinically referred children and adolescents suffering from tension-type headache or migraine it emerged that both tension-type headache and migraine patients had higher CBCL total, internalizing, and externalizing scores than normal control (P < 0.001), and tension-type headache patients had higher scores than migraine patients. Tension-type headache and migraine had higher CDI (Children’s Depression Inventory) and MASC (Multidimensional Anxiety Scale for Children) scores than normal control (P < 0.05), with no difference between the headache groups. Tension-type headache patients had higher Emotionality and Shyness scores, and lower Sociability scores than migraine patients. Clinically referred children and adolescents with tension-type headache and migraine had higher scores of behavioral and emotional symptoms, both of internalizing and externalizing type, than normal peers. The tension-type headache group had greater psychological and temperamental difficulties than the migraine group [18]. The aim of this study was to investigate the relationship between temperament and anxious-depressive disorders in young migraine sufferers. We focused on establishing whether the models in the literature relating to a temperamental predisposition to psychopathology are applicable to migraine sufferers. In particular, we chose analytical methods with a view to thoroughly assessing the role of the attention cognitive domain of the temperament. Often discussed in the literature with concern to its relationship with the other emotional temperamental domains, and with the various psychopathological traits.

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Subjects and Methods From among the patients attending the Juvenile Headache Centre at the Department of Pediatrics of the University of Padua, we recruited 81 subjects, 34 females (42%) and 47 males (58%) aged between 6 and 11 years (mean age:8.9  1.8 years), affected by migraine without aura diagnosed according to the current International Classification for Headache Disorders, ICHD-II of the International Headache Society [2]. We screened patients using the Wechsler Intelligence Scale for Children Revised (WISC-R) [50] to exclude those with an IQ < 80; we also excluded cases with known concomitant diseases and individuals of non-Italian nationality, because the questionnaire that we use to assess temperament (QUIT) is validated about Italian children only.

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Materials and Methods During a medical examination for the children’s headache symptoms, we explained the purpose of the study and collected the parents’ informed consent. Parents were given a sheet to record their children’s personal and clinical details plus one questionnaire to identify their temperamental characteristics, the "Questionario Italiano del Temperamento" (QUIT) and another to identify any psychopathological characteristics, the Child Behavior Checklist (CBCL). Parents were asked to complete the questionnaires jointly. Ninety-one of the 103 distributed questionnaires were returned (88,3%), and 81 of these had been completed correctly. The QUIT enabled us to assess the temperamental domains of the sample of young headache sufferers, while the CBCL investigated any internalizing problems (anxiety, depression and somatization). The CBCL 6-18 by T. Achenbach, in the 2001 version [51], is one of the most commonly used scales for rating juvenile behavior, adopted internationally in the clinical setting and for research. In the form of a questionnaire completed by the parents, it has been translated and validated for Italian people too [52,53]. It yields two profiles: one for competences (activities, social functioning, school performance) and one for behavioral and emotional problems, which are assessed as “normal”, “borderline” or “clinical” on specific syndrome scales, grouped as: internalizing problems (anxiety, depression and withdrawal, somatization), externalizing problems

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Temperament Patterns and Vulnerability to Anxiety and Depression … 33 (aggressive and role-breaking behavior), and other problems (social problems, thought-related problems, attentive problems). The QUIT has been standardized and validated for the Italian population [54], and it consists of four questionnaires that depart from the same theoretical construct to measure temperament in four different age groups (112 months, 13-36 months, 3-6 years, 7-11 years). The QUIT focuses the respondent’s attention on the child’s typical behavior in three different settings:   

the child with others; the child at play; the child faced with novelties or, for children at least 3 years old, the child completing an activity or task.

The items (from 54 to 60, depending on the age group) briefly describe the child’s behavior using the following parameters:

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   

the frequency of a certain type of behavior; the intensity and/or duration of a certain type of behavior; the speed with which the behavioral reaction is triggered; how much the behavior described is sensitive to external interference.

The behavior patterns are assessed on a frequency scale divided into six levels ranging from almost never to almost always. The questionnaires present behavior patterns in both a positive and a negative light, making the scales fairly objective and reducing the impact of variables foreign to the measurement, such as social desirability, memory problems, and so on. The theoretical model behind the QUIT involves six domains, i.e. three relating to the adaptation of the living environment in general (motor activity, attention, inhibition to novelty), and three relating specifically to the adaptation of the social world (social orientation, positive emotionality, negative emotionality). Each domain is polarized in the high-low sense and the polarity of each domain indicates a positive or negative adaptation to the Italian cultural reality. All the six subscales of QUIT have proved to present a either good or very good internal consistency (see Table 1 for the Cronbach’s alpha values for each subscale).

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Michela Gatta, Andrea Spoto, Barbara Nigri et al. Table 1. Cronbach’s  coefficients for each QUIT subscale Subscale

Cronbach’s 

Motor activity

0.76

Inhibition to novelty

0.84

Attention

0.64

Social orientation

0.64

Positive emotional

0.68

Negative emotional

0.63

To avoid generalizations and standardize the observation window with that of the CBCL, parents were asked to report on their child’s behavior during the last two months.

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Statistical Analysis To gain a better understanding of the relationship among the variables considered in the present study, we used an approach that refers to the construction of a system of structural equations [55]. This statistical approach enabled us to explain how the variables investigated are correlated with one another. Using quantitative fit indexes to test not only the strength of the correlations, but also the plausibility of causal links between the hypothesized factors. In other words, this kind of statistical approach to data analysis enabled us to assess whether and to what degree a theoretical model, hypothesized on the basis of scientific literature on the given topic, is consistent with the empirical findings emerging from the study. In addition to this crucial aspect, the structural equation models enabled us to express, evaluate and quantify which theoretical model among a range of options fit best the observational findings. This model would be then preferable for explaining the causal links and correlations among the considered variables. The model of correlations among the previously-discussed theoretical factors is graphically expressed in Figure 1. The variables included in the model are explained in detail in the next section and listed in Table 2.

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Temperament Patterns and Vulnerability to Anxiety and Depression … 35

Figure 1. Conceptual model of the relations between the variables considered.

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Table 2. Observed and latent variables considered in the study Name PE SO NI

Type Observed Observed Observed

Symbol x1 x2 x3

NE ATTENT ANX DEP SOMAT

Observed Observed Observed Observed Observed

x4 x5 y1 y2 y3

APPROACH WITHDRAW PSYCHO_PR

Latent Latent Latent

1 2 1

Description Positive emotional scale (QUIT) Social orientation scale (QUIT) Inhibition to novelty scale (QUIT) Negative emotional scale (QUIT) Attention scale (QUIT) Anxiety scale (CBCL) Depression scale (CBCL) Somatic complaints scale (CBCL) Extrovert reactivity Introvert reactivity Individual vulnerability

As shown in the figure, two fundamental temperamental constructs, approach and withdrawal, were used to explain the internalizing problems measured in this study through the CBCL syndrome scales for anxiety, depression and somatization.

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Within the model, we focused particularly on the temperamental variable “attention”, which has often been associated, in literature with both the two constructs, approach and withdrawal. For the data analysis proper, we used the LISREL software [56], that comes where two scientific traditions - psychometrics and econometrics converge. The LISREL reveals its dual nature in that it consists of two parts: a measurement model and a structural model. The first model evaluates whether and to what degree latent variables (i.e. theoretical constructs that are not directly observable, but that have implications for the relationships between variables) are measured by observed variables. One of the purposes of this phase is to provide indexes of the validity and reliability of the variables observed. The second model estimates and evaluates causal relationships between latent variables: this is the methodological heart of the present study, providing indications on the causal effects within the model, as well as on the amount of variance of a given finding that is not explained by the model. The algorithm starts from either the correlation or covariance matrix of the observed variables under investigation. Then a set of parameters are chosen by the user to be estimate. Such parameters are mainly referred, on the one hand, to the capacity of the latent variables to explain the scores of the observed ones; on the other hand to estimate causal and correlation theoretical links among latent variables. The user is allowed to select a number of links to estimate and he is provided with a set of goodness of fit indexes showing the plausibility of the specific model tested. A) Exogenous Observed Variables (x) Positive emotional (PE): the capacity to experience positive emotions (QUIT); Social orientation (SO): social orientation and seeking relationships (QUIT); Inhibition to novelty (NI): inhibition when faced with novel situations and unknown people; fearfulness (QUIT); Negative emotional (NE): capacity to experience negative emotions (QUIT); Attention (ATTENT): capacity to stay focused on something despite distracting external stimuli, and capacity to shift the focus of attention (attentional flexibility) from one thing to another if it is considered necessary (QUIT).

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Temperament Patterns and Vulnerability to Anxiety and Depression … 37 B) Endogenous Observed Variables (y) Anxiety (ANX): a dimensional measure of anxious and depressive types of behavior (CBCL syndrome scale); Depression (DEP): a dimensional measure of withdrawn and introverted types of behavior (CBCL syndrome scale); Somatic complaints (SOMAT): dimensional measure of any somatizing behavior (CBCL syndrome scale). C) Exogenous Latent Variables () These are theoretical constructs of temperamental reactivity:  approach: based on descriptions in the literature [37,38], this was seen as being defined by the temperamental variables PE and SO;  withdrawal: based on descriptions in the literature [37,38], this was seen as being defined by the temperamental variables NI and NE ( in their negative sense).

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D) Endogenous Latent Variables () A predisposition to psychopathology (PSYCHO_PR): a theoretical construct of individual vulnerability to internalizing psychiatric disorders.

Results The fit indexes support the assumption that the theoretical model used coincided with the observed data [59] for the sample of individuals considered. The main fit indexes are adequate: Root Mean Square Error of Approximation (RMSEA) = 0.08; Comparative Fit Index (CFI) = 0.96; Non-Normed Fit Index (NNFI) = 0.94. Table 3 gives a summary of the main fit indexes in addition to those already mentioned. Table 3. Main fit indexes for the model hypothesized Index χ2(17) p-value RMSEA CFI NNFI GFI

Value 26.46 0.06 0.08 0.96 0.94 0.92

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Apart from the model’s good global fit, it is also worth commenting on the results observed for the single links comprising the model, which are presented graphically with the corresponding values in Figure 2.

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Figure 2. Standardized parameters estimated for the model hypothesized.

Table 4 shows the values of the links between the exogenous observed variables and the corresponding latent variables (λx), between the endogenous observed variables and the corresponding latent variables (λy), and between the exogenous and endogenous latent variables (γ). Table 4. Standardized values of relations within the model hypothesized Direction of link PE  APPROACH SO APPROACH NI WITHDRAWAL NE  WITHDRAWAL ATTENT  WITHDRAWAL ANX  PSYCHO_PR DEP  PSYCHO_PR SOMATIC PSYCHO_PR APPROACH  PSYCHO_PR WITHDRAWAL  PSYCHO_PR

Symbol λx1 λx2 λx3 λx4 λx5 λy λy λy γ1 γ2

Standardized value 0.87 0.80 0.85 0.70 -0.75 0.84 0.68 0.54 0.31 0.69

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Temperament Patterns and Vulnerability to Anxiety and Depression … 39 Several peculiarities worthy to note emerged from the links established by the iterative estimates generated by the software. First of all, we note that the value of the exogenous observed variables PE and SO are explained by the related latent variable approach. Again for the exogenous observed variables, the withdrawal construct explains the score for the ATTENT observed variable (in the form of an inverse correlation). This displays that the continuum of the latent variable explains the scores for the observed variables considered in the study (i.e. PE, SO, NI, NE, ATTENT). At the same time good results were observed also for the endogenous observed variables (i.e. ANX, DEP, SOMAT). In addition, both the exogenous latent variables proved to be direct predictors of the endogenous constructs analyzed. It may be worth mentioning that, by definition, the causative model moves from the exogenous towards the endogenous latent variables. In other words, the temperamental domains prove to be predictors of internalizing psychopathological conditions. As mentioned in the section on the data analysis, the ATTENT observed variable is particularly interesting. In this study on a sample of young headache sufferers, the model in which this variable was assumed to be explained by the approach presented worse fit indexes; meaning that our proposed model is preferable for the sample analyzed. In other words, it is the withdrawal construct that appears to be able to (inversely) explain the score obtained for the ATTENT observed variable, referred so far to one or other latent variable only on theoretical explanatory, rather than objective quantitative grounds.

Discussion The theoretical model that we hypothesized on the basis of the scientific literature correlated two temperamental constructs, withdrawal and approach, with the predisposition to develop psychopathological conditions. In the construction of the theoretical model these two constructs were defined by temperamental characteristics, based on the scores obtained in the single temperamental emotional domains (QUIT), assuming that withdrawal coincided with the scores for NE and NI, and approach with the scores for PE and SO. It was initially assumed that the role of attention as a cognitive temperamental variable (that is usually considered in the literature as part of the more ample construct of effortful control) is attributed a modulating role in

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any onset of psychopathological conditions [37,47] and could be correlated with both the temperamental constructs. First of all, our data indicate that a relationship exists between certain temperamental profiles and the onset of psychological disorders in individuals suffering from migraine. In particular, high levels of NI and/or NE correlated in our sample with the onset of internalizing psychopathological conditions, such as anxiety, depression, withdrawal and somatization. The presence of such problems in children and adolescents suffering from primary headache has been well documented [21,25,26,29]. As mentioned in the introduction, although reports found in literature state there is a link between primary headache, particularly migraine, and the onset of internalizing psychopathological conditions, they fail to provide any convincing conclusions on how they are connected [21,22,24-26,29,34]. The results of longitudinal studies would seem to indicate that the correlation between headache and anxious-depressive disorder is by no means unequivocal. Judging from our findings on the causal link between temperament and psychopathology in children suffering from migraine, the question begs what part is played by temperament. We can consider two hypothetical situations. One sees migraine, associated with certain temperamental patterns, as a “cumulative” risk factor for the onset of anxious-depressive symptoms. In this sense, migraine can be seen as a primary source of stress that poses problems in every day life, becoming a source of anxiety and even acting as a genuine trigger factor in anxious states, as well as negatively influencing the patient's mood in the long term [26-28]. This is connected to the finding of anxiety disorders increasing with age in headache sufferers [33,35], pointing to a situation in which the individuals’ greater awareness of themselves and their headaches coincides with a greater anxious component. In these individuals, a temperamental profile characterized by high levels of either approach or withdrawal, associated with their headaches, could become a risk factor for the onset of anxious-depressive disorders. About that hypothetical situation, a recent study of Abbate-Daga et al. (2007) [58] about temperament in migraine subjects, found that patients suffering from migraine show more depressive symptoms, difficult anger management with a tendency to hypercontrol, and a distinctive personality profile with high harm avoidance, high persistence and low self-directedness. When a logistic regression was performed, the only significant predictors of migraine were temperament variables: the authors concluded that the personality traits and psychosomatic mechanisms of migraine patients may make them vulnerable to stress and less skilled in

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Temperament Patterns and Vulnerability to Anxiety and Depression … 41 coping with pain. These traits correlate with dysregulated neurotransmitter systems which may also be part of the psychobiological components of personality, depressive disorders and migraine itself [58]. The second situation sees migraine and psychopathology as having “common” underlying etiopathogenetic factors, including a temperamental predisposition. Numerous studies have shown that depressive mood disorders are a risk factor for the onset of headache [17,23], and others have suggested that anxiety could be a factor that precipitating headache [31,59]. Several reports also indicate that some individuals might be less able to cope with the usual stressful events of daily life and this would expose them to a greater prevalence and severity of migraine [32,60]. It is well known, moreover, that headache in infancy can be the physical expression of psychological discomfort [25]. A temperamental profile with high levels of reactivity of the approach and/or withdrawal type in such cases could facilitate the onset of anxious-depressive disorders, that would in turn correlate with the onset of migraine attack [17]. The second finding worth noting in our analysis of young migraine sufferers is that the anxious-depressive psychopathology appears to be caused by high levels of reactivity, be it withdrawal or approach. It is to this that the central values of 1and 2 refer (in medio virtus): the positive values of the links between PSYCHO_PR and both approach and withdrawal mean that extreme levels of both these temperamental constructs correlate with a vulnerability to internalizing psychological disorders (see Table 2). We know from the literature that vulnerability to psychopathology is associated with a temperament characterized by extreme levels of temperamental reactivity (high approach or low withdrawal) in combination with low levels of effortful control (EC) [61,62]: greater vulnerability levels seem to occur in people with a high individual reactivity and a poor capacity for self-regulation, which is needed to modulate the negative consequences of their reactivity. From a behavioral standpoint, EC is directed towards a goal, it demands commitment and a project. From the neuronal standpoint, EC is seen as being connected primarily to the network of attentional functions, located in the prefrontal and frontal cortex (and in the anterior cingulus, in particular) [63]. It is in this light that the attention temperamental domain identified by the QUIT can be seen as resembling the EC construct, though we must bear in mind that it represents only the pure attentional part, not the characteristics of inhibitory and activator control that complete the essence of the EC construct.

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Another significant element emerging from our study concerns this last variable - attention – in that it appears in our model to explain the withdrawal, but not the approach construct. There is no such separation in the literature: withdrawal and approach are both associated with certain temperamental characteristics of emotional type (withdrawal with NE and NI, approach with PE and SO), while the cognitive temperamental characteristic ‘attention’ is generally considered a sort of modulator of either temperamental domains in the development of a psychopathology. A low level of EC increases people’s vulnerability to different types of psychopathology, depending on their temperamental features [37]. For instance, where approach and introversion are normal, very low levels of EC are associated with attention-deficit hyperactivity disorder (ADHD) , particularly of the inattentive-disorganized type; in cases of high levels of withdrawal, a low EC contributes to the individual’s vulnerability in the onset of anxiety disorders; a low approach, or high levels of introversion (withdrawal) and/or high levels of environmental stress increase the risk of depressive disorders. To be more specific, Lonigan and Phillips [61] assume that EC, and attention control in particular, have an important role in the pathogenesis of childhood anxiety disorders. Whilst Eisengerb et al [64] found that externalizing problems (pure or with concomitant internalizing problems) were associated with low EC, high impulsivity and negative emotionality, (especially anger) and internalizing problems were associated with low impulsivity, sadness and, to some degree, with anger. A low attentional EC correlated with internalizing problems only as regards changes in maladjustment. We might therefore wonder whether the model emerged as such because the sample considered consisted of migraine sufferers. A recent study [65] showed that a sample of children with migraine had more difficulty with selective and alternate attention than a control group. This might lead us to believe that there are common aspects involved in the physiopathology of migraine and the attention mechanism, which might predispose these children to psychological disorders (i.e. the previously-discussed pattern 1). It is as if these patients’ limited attentional capacity coincided with an inability to be distracted from negative emotions, consolidating their inhibition in relation to novelties, and thus tending to delineate the withdrawal temperamental domain that predisposes to internalizing problems. In this sense, our results also support recent theories emphasizing the importance of attentional processes for understanding resilience among children and adolescents who are temperamentally vulnerable to pathological anxiety [61,63,66] and related problems such as social withdrawal and poor interpersonal functioning

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Temperament Patterns and Vulnerability to Anxiety and Depression … 43 [67,68]. Some vulnerable young people may prove resilient due to a marked capacity for attentional control, while others prove especially vulnerable due to a low attentional ability. While our results suggest on the one hand that a low attentional capacity is an unfavorable factor in the onset of psychopathology, on the other they pose the question of whether the capacity to modulate and manage one’s own attentional capacity can protect against the onset of psychopathology. From this point of view, it would be sensible to think of attention as the ‘focus’ of any preventive measures in the psychopathological setting [69].

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Conclusion We tested the existence of a causal relationship between temperament and psychopathology in young migraine sufferers. We ascertained the importance of the attention variable in association with the NE and NI emotional variables in measuring the withdrawal construct. As for the possible clinical implications and future research prospects in this setting, it is worth considering: (i) that psychopathology might be prevented in young patients suffering from primary headache by analyzing their individual temperamental predictors; and (ii) the future prospect of research needs to ascertain whether there are different implications in cases between tension-type headaches and migraine patients; and inevitably whether the application of the model discussed here is applicable to different clinical case series.

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Temperament Patterns and Vulnerability to Anxiety and Depression … 49

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[65] Villa T.R., Correa Moutran A.R., Sobirai Diaz L.A., Pereira Pinto M.M., Carvalho F.A., Gabbai A.A. and de Souza Carvalho D. (2009). Visual attention in children with migraine: a controlled comparative study. Cephalalgia, 29(6), 631-4. [66] Degnan K.A. and Fox N.A. (2007). Behavioral inhibition and anxiety disorders: multiple levels of a resilience process. Dev Psychopathol, 19(3), 729-46. [67] Ayduk O., Mendoza-Denton R., Mischel W., Downey G., Peake P.K. and Rodriguez M. (2000). Regulating the interpersonal self: strategic self-regulation for coping with rejection sensitivity. J Pers Soc Psychol, 79(5), 776-92. [68] Calkins S.D. and Fox N.A. (2002). Self-regulatory processes in early personality development: a multilevel approach to the study of childhood social withdrawal and aggression. Dev Psychopathol, 14(3), 477-98. [69] Rueda M.R., Rothbart M.K., McCandliss B.D., Saccomanno L. and, Posner M.I. (2005). Training, maturation, and genetic influences on the development of executive attention. Proc Nat Acad Sci U.S.A., 102(41), 14931–6.

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In: Headaches Editor: P. Gallo and G. Giordano

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Chapter III

Pathophysiology of Migraine: The Neurovascular Theory Daniele Spiri1, Luigi Titomanlio2, Laura Pogliani,1 and Gian Vincenzo Zuccotti1

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1

Pediatric Department, L. Sacco Hospital, University of Milan, Milan, Italy 2 Pediatric Neurology and Emergency Departments, R. Debré Hospital, Paris 7 University, Paris, France

Abstract Migraine is a common and disabling type of primary headache which is divided into migraine with or without aura and some rare genetic disorders. Whereas it is understood that Cortical Spreading Depression (CSD) causes the aura, the headache mechanisms are less clear. Today it is known that migraine is a neurovascular disorder, in which afferent innervation of intracranial blood vessels, forming the Trigemino-Vascular System (TVS), is the essential substrate for migraine attack. The TVS consist of primary neurons whose cell bodies lie within the ipsilateral trigeminal ganglion (TG). Peripherally, these neurons innervate the dura mater, as well as intracerebral and meningeal vessels. A rich sympathetic and parasympathetic innervation is also present at these sites. The central fibers of TG neurons form synapses within the trigeminal nucleus in the caudal brainstem from where peripheral pain perception is carried to the thalamus and cerebral cortex. Histochemical studies have

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revealed that calcitonin gene-related peptide (CGRP) is a neuropeptide strongly expressed by TG and trigeminal nucleus neurons. It is postulated to be directly involved in dilatation of cerebral and dural blood vessels, in release of inflammatory mediators from mast cells and in the transmission of nociceptive information from intracranial blood vessels to the nervous system. In the belief that brainstem centers probably have an important role in regulating vascular tone and pain sensation, many authors argue a hypothetical pathophysiology of migraine supported by current functional and radiological studies. Migraine-specific triggers cause the activation of sensory fibers of the trigeminal nerve that innervate intracranial blood vessels, causing a pain response. This information is conveyed to the brainstem and evokes release of vasoactive peptides such as CGRP and substance P from trigeminal fibers, inducing vasodilation and neurogenic inflammation. These events increase the activation of the sensory trigeminal fibers and perpetuate the release of vasoactive peptides (supporting the transmission of pain impulses to the brain) over hours to days in correspondence with the duration of a typical migraine episode. Current data provide a complex model in which vascular and neuronal mechanisms cooperate. The generation of migraine pain is probably a consequence of multiple pathophysiological changes in meningeal tissues, TG, trigeminal brainstem nuclei and descending inhibitory systems that are still not fully clarified and worthy of further studies.

Introduction Migraine is a frequent and complex brain disorder and its pathophysiological mechanisms remain incompletely understood. In 1938, Graham and Wolff proposed a plausible explanation of headache pain involving cranial vessels in the initiation and pathogenesis of migraine. It was known that extracranial vessels became distended and pulsatile during a migraine attack and the use of vasoconstrictor drugs improved the headache, whereas vasodilator drugs provoked migraine. Moreover, some studies had shown that the stimulation of intracranial vessels induced headache. On the basis of these observations, a vascular theory was proposed. In the prodromal phase, vasospasm caused a focal cerebral ischemia and the related transient neurological symptoms (aura). In the second phase, brain acidosis and stretching of pain fibers in arterial walls due to a compensatory rebound vasodilatation, caused a pulsating headache.

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Pathophysiology of Migraine

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In 1944, with the discovery of Cortical Spreading Depression (CSD) as the mechanism probably responsible of migraine aura, vascular theory was replaced by neuronal theory. Leao suggested that migraine with aura was related to the paroxysmal depolarization of cortical neurons and that migraine pain was caused by abnormal central interpretation of normal sensory input in the trigeminal sensory system. The role of vascular or neural mechanism as primum movens of migraine pain was debated in the medical literature for the last decades. The exact pathophysiology of primary headache is still not fully understood but current molecular and functional studies, conducted using PET (positron emission tomography), intracarotid SPECT (single-photon emission computed tomography), functional MRI (magnetic resonance imaging) and transcranial magnetic stimulation, allowed the formulation of a new neurovascular theory as the current and most widely accepted model of migraine pain (Edvinsson). According to the neurovascular theory, neural and vascular events cooperate in a complex network in which afferent innervations of intracranial blood vessels, forming the Trigemino-Vascular System (TVS), are the essential substrate for migraine pain (Messlinger). Events in the cranial dura mater vessels activate perivascular trigeminal sensory fibers. Cascade of nociception, after crossing trigeminal ganglion (TG), is conveyed to the brainstem. Activation of the brainstem evokes the release of vasoactive peptides such as CGRP (calcitonin gene-related peptide) and substance P from trigeminal fibers, inducing vasodilatation and causing neurogenic inflammation (Durham). These events increase activation of the sensory trigeminal fibers and perpetuate the release of vasoactive peptides over hours to days in correspondence with the duration of a typical migraine episode. Activation of the brainstem also regulates the nociceptive transition to higher structures of the central nervous system (CNS), as thalamus and cortex (Goadsby). The initial events leading to the activation of the TVS are still not entirely clear. Studies of transcranial magnetic stimulation and functional MRI find that at baseline, migraneurs have a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital region. Genetic factors, causing disturbances in the neuronal ion channel, probably make a migraneur more sensitive to multiple migraine trigger factors (Edvinsson). In 2006, Durham proposed that migraine-specific triggers (as foods containing vasoactive amines as tyramine and phenylethylamine, hormonal changes and fluctuation, psychological and environmental triggers as stress, anxiety, worry, depression, fatigue, sleep deprivation, light, barometric

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pressure changes, odors and rapid temperature changes) cause primary brain dysfunction, which induces the dilatation of cranial blood vessels that are innerved by sensory fibers of the trigeminal nerve. According to Durham, the dilated blood vessels mechanically activated perivascular trigeminal sensory fibers and this event causes the activation of TVS. But, more recently, the most accepted theory suggests that the initial phase of migraine attack (as well as the aura) is a wave of CSD which is associated with the suppression of spontaneous electroencephalographic activity and regional oligemia. The CSD begins in the occipital region and, moving anteriorly, stops at the central sulcus and then spreads ventrally to the meningeal trigeminal fibers. Once the CSD occurs, H+ and K+ diffuse to the pia mater and activate meningeal nociceptors (C-fibers) which released pro-inflammatory agents after TVS activation (Ayata). Regardless of the initial factor, however, the result is the activation of the brainstem which is the principal vascular tone regulation and nociceptive processing center.

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Anatomy of the Trigemino-Vascular System In 1992, through many clinical and experimental works, Moskowitz identified a system of cephalic nociception called the TVS. This framework of afferent innervations of intracranial blood vessels is widely believed to be the essential substrate for migraine pain. Like any system of nociception, TVS consists of a primary and secondary order of neurons. Cell bodies of the primary neurons lie within the ipsilateral TG. Each primary bipolar neuron has an afferent (Primary Afferent Fibers, PAF) and a central fiber: PAF peripherally innervate the dura mater, as well as intracerebral and meningeal vessels; central fibers form synapses with the second-order neurons placed in the trigeminal nucleus in the caudal brainstem. Fibers of secondary neurons project to various structures located above in the CNS as the thalamus and the cerebral cortex (Ollat). The PAF have a small diameter and are poorly myelinated (Aδ) or unmyelinated (C). Through the ophthalmic branch of the trigeminal nerve (V1) and the posterior cervical root C2-C3, they innervate mainly intracranial structures: the dura mater, the pia mater and the proximal part of cerebral arteries. The more distal part of arteries are only very weakly innervated by

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PAF and intraparenchymal vessels are not at all (hence the insensitivity of the brain) (Kandel). The V1 and C2-C3 root fibers also innervate the fronto-orbital and the occipito-nuchal skin areas, respectively. The nociception from these areas converge on the second-order neurons explaining why the pain of migraine is a fronto-orbital or occipital projected pain. This also explains why headache can be present in some fronto-orbital (as glaucoma) or spinal diseases. Moreover, one PAF innervates several branches of the Willis’ circle, more branches of meningeal artery and a large area of dura mater, hence the diffuse and poorly localized pain in migraine. However, in most cases, vessels and meninges are innervated by ipsilateral PAF, but median vessels (as sagittal sinus) are innervated by ipsi- and controlateral PAF, hence bilateral pain localization (Ollat). Cell bodies of primary neurons lie within ipsilateral TG located in the floor of skull in the middle cranial fossa, adjacent to the sella turcica. In addition to V1, maxillary (V2) and mandibular (V3) branches emerge from the TG: V2 provides for sensation of skin over the cheek and of the upper portion of the oral cavity; V3 supplies sensation of the skin over the jaw, of the area above the ear and of the lower part of the oral cavity, including the tongue (Kandel). Trigeminal nerve branches are associated with the cephalic vegetative system and this relationship is probably very important to explain pathophisiology of migraine and its related vegetative manifestations. The sphenopalatine ganglion, with its parasympathetic function, supplies vasodilator innervations of the carotid and nasal cavity arteries system. It also provides for secretory innervation of the lachrymal gland. Branches of V2 reach the sphenopalatine ganglion and lead to its activation. In addition, the lachrymal nerve, which is a branch of V1, also participates in the secretory innervation of the lacrimal gland. This neuronal network explains why tearing and rhinorrea are signs associated with migraine. A branch of the V1 gives fibers to the ciliary ganglion which provides for parasympathetic constrictor innervation of the iris muscle. V1 also raises fibers to the long ciliary nerves that innervate the dilator iris muscle. Activation of the TVS can explain the changes in pupil diameter (miosis) during a migraine attack (Ollat). The central fibers form synapses with a secondary order of neurons located in the trigeminal nucleus in the caudal brainstem. The spinal trigeminal nucleus is a continuation of the superficial laminae of the spinal dorsal horn into the medulla and allows sensory information from the head and neck. It receives sensory axons from all cranial nerves concerned with sensation in the

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head, including axons from the facial nerve (that convey information from the external auditory meatus), from the glossopharyngeal nerve (that carry input from the posterior part of the palate and tonsillar fossa), and from the vagus nerve (that relay sensory information from the posterior wall of the pharynx). The principal sensory trigeminal nucleus receives the sensory information from the face. Axons from the principal sensory trigeminal nucleus join those of the dorsal column nuclei in the medial lemniscus through which they ascend to the ventroposterior medial thalamus. Mesencephalic trigeminal nucleus receives the proprioceptive information from the muscle of mastication. Fibers of secondary neurons project to various structures located above in the CNS as the thalamus and the cerebral cortex. Before arriving to the higher stations, the fibers ascend through the reticular formation. This region consists of groups of interneurons and it is divided in a lateral and a medial part. Interneurons of the medial part have long ascending and descending axons that modulate activation of neurons involved in pain, autonomic functions and arousal (Kandel). Mainly in the dorsal horn and thalamus, a control system that exercises inhibitor effects on nociceptive impulses transmission is present. A linkage to the suprachiasmatic nucleus of the hypothalamus (that governs circadian rhythm) has been proposed to explain periodicity of migraine (Goadsby). Processing of migraine pain in the thalamus occurs in the ventroposteromedial (VPM) portion, in the medial nucleus of the posterior complex and in the intralaminar thalamus. VPM relays fibers from the trigeminal, medial and spinal lemniscus. The pulvinar (a big nucleus of the posterior complex) receives fibers from trigeminal territories and from the rostral basilar artery, hence the frequent bipolarity (frontal and occipital) of migraine pain (Kandel). Crossing thalamus stations, nociception arrives in the different regions of cortex. The cortex regions involved in migraine pain processing are the primary and secondary somesthesic cortex, the insular and the fronto-orbital region, the premotor cortex and the striatum. These regions play a key role in the localization and intensity coding of pain input, in emotional, behavioral and motor reactions to pain, and in the inhibition of nociceptive transmission. Jones identified two separate cortical networks involved in the development of migraine pain using functional imaging techniques: a medial framework (including thalamus, anterior cingulate cortex and prefrontal cortex) and a lateral framework (consisting of primary and secondary somatosensory cortex). Recently, Derbyshire and Dong showed the

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implication of amygdala, basal ganglia and posterior parietal cortex in migraine pain processing. Bahra demonstrated that the anterior cingulate cortex, frontal cortex and also the visul and auditory association cortex are activated during acute attacks of migraine (Goadsby).

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Neurogenic Inflammation, CGRP and Serotonin Intense research has been carried out to identify signal molecules associated with the activation of the neuronal structures involved in the development of migraine pain. In 1990, Moskowitz had provided a series of experiments to suggest the role of a sterile neurogenic inflammation as an important component of the pain in migraine. Markowitz showed that neurogenic plasma extravasation could be seen during electrical stimulation of TG in the rat. A few years later, Dimitriadou demonstrated structural changes in the dura mater (including mast cell degranulation) and in post-capillary venules (including platelet aggregation) during a migraine attack (Goadsby). More recently, the hypothesis of neurogenic inflammation as the mechanism involved in migraine pathophysiology has been supported by studies of MRI that showed reversible edema next to small brain vessels during an acute migraine episode (Lindner). Many molecules are implicated in neurogenic inflammation. Bradykinin is a powerful algogenic substance responsible of the activation and sensitization of nociceptors. In addition, it induces protein extravasation and stimulates the release of prostaglandins by leukocytes and sympathetic terminations. H+ and K+ ions play an important role in nociceptors activation. K+ ions also induce mast cell degranulation with histamine and serotonin release. Prostaglandins also sensitize nociceptors and induce platelet aggregation. The presence of prostaglandins in neurogenic inflammation explains the effectiveness of antiinflammatory drugs during migraine attacks. In the later phases of the inflammatory process, activated macrophages release cytokines as interleukins-1 and -6 that are powerful stimulants of prostaglandin synthesis (Ollat). Migraine has been linked to inflammation for more than 20 years and today it is known that neurogenic inflammation is promoted by TVS activation through several neurotransmitters. Researches of Goasby in 1987, Tran-Dinh in 1992 and Durham in 2006, conducted using electrical stimulation of TG in

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humans and cats, showed an increase of extracerebral blood flow associated with a local cranial release of CGRP and substance P. Substance P is a potent vasodilator that acts on the arteries and veins. Its action depends on the production of nitric oxide (NO) by endothelial cells and it induces protein extravasation through the stimulation of mast cells degranulation and lymphocyte activation. CGRP is a 37 aminoacid neuropeptide and its predominant form expressed in the CNS is the αCGRP. This is a potent vasodilator neuropeptide and multiple experiments show that it is released from FAP (Eftekhari, Edvinsson), explaining its role in inflammation and plasma protein extravasation. Today it is widely believed that CGRP is an important step in the transmission of nociceptive information and several data suggest that it has not only a peripheral vascular action but also a direct neuronal action that sustains migraine in a central way. This would explain why the block of neurogenic plasma protein extravasation does not have a complete anti-migraine effect as evidenced by the failure, in clinical trials, of substance P and neurokinin-1 antagonists, specific plasma protein extravasation blockers (as CP122,288 and 4991w93), an endothelin antagonist and a neurosteroid ganaxolone (Goadsby). Goadsby and Edvisson showed that during a migraine attack, the plasma concentration of CGRP is elevated in the external jugular vein. Ashina noted a higher basal level of CGRP in the cubital fossa vein in migraineurs also outside the attacks, without differences between migraine with aura and migraine without aura. Goadsby and Stepien observed that relief of migraine pain by triptans (sumatriptan and rizatriptan) coincides with the reduction or normalization of CGRP concentrations in the blood. However, the most interesting observation is that CGRP is released from neurons of TVS in the trigeminal nucleus as a neurotransmitter, suggesting a direct neuronal action in the activation of the migraine pain network. As well as in the trigeminal complex (where it is highly represented), CGRP is also present as a neurotransmitter in the brainstem, hypothalamus, amygdala, striatum and in cerebellum (Hokfelt). In humans, the CGRP receptor is present in the membrane of mast cells, in the middle meningeal artery, in the middle cerebral artery, in the superficial temporal artery and in the pial arteries, and it is localized into the smooth muscle layer of arterial blood vessels. However, the CGRP receptor is also present in the membrane bipolar neurons of TG. A specific CGRP antagonist (as BIBN4096) has been shown to be effective in the treatment of acute migraine. These data are further supported by placebocontrolled trials that demonstrate the efficacy of MK-974 (telcagepan), an orally active CGRP receptor antagonist, as abortive treatment in migraine

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attacks (Eftekhari, Edvinsson). These data show that selective CGRP receptor antagonists give a clinical benefit in migraine attack probably through their peripheral and central action. If the release of CGRP is a crucial step involved in migraine pain development, the serotonin (5-hydroxytryptamine, 5HT) is believed to also have an important role in headache pathways (Ferrari). The exact mode of action of serotonin during a migraine attack is not entirely understood. Ostfeld reported that temporal perivascular administration of 5HT induced migraine attacks, whereas i.v. injection of 5HT relieved spontaneous migraine acute episodes. Kimball and Friedman demonstrated that a 5HT depletion condition (as after reserpine administration) can induce migraine which is relieved by 5HT infusion. In addition, during a migraine attack, 5HT turnover increases significantly and levels of the serotonin metabolite hydroxyindoleacetic acid augments significantly in urine and in cerebrospinal fluid. The findings of low interictal plasmatic levels of serotonin in migraineurs suggest that migraine is a syndrome of chronically low serotonin, with acute attacks triggered by a sudden rise in 5HT release. Many authors assume that 5HT is also implicated in CSD. It was observed that intermittent neuronal discharges from serotoninergic neurons in the pons, cause an initial discharge in the ipsilateral occipital cortex. This discharge could then cause a wave of spreading excitation followed by a depression of neuronal activity (Gupta). As with CGRP, serotonin has both a vascular and a neuronal action and this hypothesis is supported by immunohistochemical studies that detected the expression of a 5HT receptor (5HTr) in vessels and in neurons of TVS. There are at least 14 known 5HTr but the 5HTr1 and, to some extent, the 5HTr2, are the most interesting in migraine pathophysiology. 5HTr1B is present on smooth muscle cells of meningeal vessels and through the action on it 5HTr1 agonists (triptans) induce vasoconstriction of intracranial vessels (Bigal). At neuronal level, 5HTr1B/1D/1F are expressed on neurons of TVS (including FAP, neurons in TG and in the trigeminal nucleus caudalis) and they cooperate in modulation of nociceptive processing (Gupta). 5HTr1D is a pre-synaptic receptor expressed to the end of PAF and through it, triptans block the release of vasoactive peptides by TVS neurons (Loder). Colocalization of 5HTr1B, 5HTr1D and 5HTr1F on glutammate-positive TG neurons, suggests that the triptans may reduce the release of glutamate and this phenomenon could contribute to their therapeutic effect (Ramadan).

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TVS Activation and Cortical Spreading Depression CSD is a neural event, characterized by a massive neuronal and glial depolarization as well as important and sustained changes in vascular function (Ayata). Described by Leao in 1944, CSD is a wave with a speed of 2-6 mm/min that propagates centrifugally in gray matter from a focal region without respect for functional divisions and arterial territories. It is often interrupted by a groove or a fissure and it also propagates into subcortical structures (Ayata). The pandepolarization of CSD can be induced by a sudden loss of membrane input resistance, leading a ionic gradient characterized by a massive K+ efflux. It is widely believed that the increase of extracellular K+ concentration from a resting level of 3-4mM to more than 40mM causes depolarization of adjacent cells, supporting the spread process by way of contiguity. The massive and uncontrolled glutamate release, associated with the Ca+ influx, cooperates to depolarization of adjacent cells and to strengthen the wave propagation. The role of glutamate in the development of CDS is supported by data of studies in which NMDA receptor antagonists block the spread of the wave (Ayata). Since 1944, Leao had understood the link between the CSD and the aura pathophysiology. Milner in 1958 and then Lauritzen in 1985 sustained this hypothesis. The cause-effect relationship between CSD and aura is suggested by the analogy of temporal and spatial characteristics of CSD and aura propagation in the visual cortex. Occipital cortex, the region where CSD begins, especially in the primary visual cortex, has a very high neurons density and these neurons are very rich in NMDA receptors. In this region, astrocytes are poorly represented and it is known that these cells have a neuronal protective role because they capture the K+ ions and glutamate in excess in the extracellular medium (Lauritzen). In 1983, Matsuyama had shown a reduced VIP-ergic innervation of the cerebral vessels in the posterior region of the brain rather than the anterior (Goadsby). This may contribute to this region’s vulnerability to vascular changes that accompany neuronal events during CSD. Therefore, using functional MRI, Hadjikhani observed that an important and very short wave of hyperemia appears during the neuronal depolarization phase. Hyperemia is followed by a wave of hypoperfusion that progress slowly through the visual cortex without reaching the ischemic threshold and in lockstep with the developing symptoms of aura. This phase appears with a slight delay compared to the prolonged phase of neuronal quiescence of CSD

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in which any potential generation or synaptic transmission are precluded (Ayata). Generally, hypoperfusion is ipsilateral to the headache and controlateral to the symptoms of the aura (Edvinsonn). Studies demonstrating changes in blood flow and metabolism by MRI have cemented the hypothesis of a causative connection between CSD and the onset of aura. If the role of CSD in the development of aura is now clear, the function of CSD as a trigger of migraine pain remains debated. Zhang provided the first direct evidence that meningeal nociceptors can be activated by a wave of CSD. According to Zhang, a wave of CSD can induce nociceptive signals in meninges, resulting in sequential activation of peripheral (first-order) and central (second-order) neurons of the TVS. In 2002, Bolay had observed that the CSD causes an increase in the expression of gene c-fos within the neurons of trigeminal nucleus caudalis (Meents). Expression of gene c-fos is an indicator of neuronal activation (Gupta), therefore suggesting trigeminal nerve activation, and subsequent neuropeptides release and plasma protein extravasation. In addition, Julius demonstrated that TVS can be activated by a low extracellular pH and it is known that during CSD, there is an important increase of extracellular concentration of K+ and H+ (Meents). However, many points remain unclear regarding the role of CSD in the development of migraine pain. If CSD is the basis of aura and migraine pain development, it is not explained why aura may occur before or after the onset of pain in some patients. Some data of pharmacological research reveal the lack of a fixed relationship between aura and headache. There are treatments that may abolish aura in some patients but they have not effect on their headache; in others patients, therapy may help with headache but not reduce aura. (Charles). Recently, Hauge found that a CSD inhibitor (tonabersat) only prevents attacks of migraine with aura but not episodes of migraine without aura. According to Charles, there is probably another cellular phenomenon that could explain the changes in cortical function. Ca+ intracellular waves have been observed in astrocytes. Although an astrocytic Ca+ wave does not produce the same profound depression of neural activity of CSD, characteristics of these waves are similar. However, a Ca+ wave has a slower propagation rate (1-2 mm/minute) and runs through less distance than CSD. In vitro and in vivo studies demonstrate that the two types of wave are independent but interrelated phenomena. Therefore, an imaging study in mice found that the inhibition of an astrocytic wave abolishes the arteriolar constriction associated with CSD, suggesting a primary role of astrocytes in intracranial changes of blood flow. It is not entirely known the exact meaning

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of these waves, but it is certain that Ca+ astrocytic waves and CSD are just some manifestations of a more complex brain framework.

Conclusion

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Migraine is a complex neurovascular disorder in which several neuronal and vascular systems, neurotransmitters and pro-inflammatory molecules cooperate in a way not yet fully clear. Neuronal events in the cortex surface induce the activation of TVS with a consequent CGRP release from PAF in the dura mater, in TG and trigeminal nuclei. Peripherally, CGRP leads to dilatation of intracranial vessels and promotes neurogenic inflammation. In trigeminal nuclei, CGRP facilitates nociceptive transmission inducing central sensitisation. Models of TVS and CSD explain almost completely migraine pathophysiology, although there are still some unclear points. Migraine neurobiology is a fascinating and evolving subject and its understanding remains the only way to help pharmacological research to develop more specific drugs that improve the quality of life of migraine subjects.

References [1] [2] [3]

[4] [5] [6]

Edvinsson, L; Uddman, R. Neurobiology in primary headaches. Brain Research Reviews, 2005 48, 438-456. Messlinger, K. Migraine: where and how does the pain originate? Experimental Brain Research, 2009 196, 179-193. Durham, PL. Emerging neural theories of migraine pathogenesis. Calcitonin Gene-Related Peptide (CGRP) and migraine. Headache, 2006 46, S3-S8. Goadsby, PJ; Charbit, AR. Neuroscience forefront review. Neurobiology of migraine. Neuroscience, 2009 161, 327-341. Ayata, C. Cortical spreading depression triggers migraine attack: pro. Headache, 2010 50, 725-730. Moskowitz, MA; MacFarlane, R. Neurovascular and molecular mechanisms in migraine headache. Cerebrovascular and Brain Metabolism Reviews, 1993 5, 159-177.

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Pathophysiology of Migraine [7] [8] [9] [10] [11]

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Ollat, H. Cèphalèes et système trigémino-vasculaire. Neuropsychiatrie : Tendances et Débats, 2000 11, 29-42. Ollat, H. Physiopathologie de la migraine. Neuropsychiatrie : Tendances et Débats, 2004 24, 31-39. Kandel, ER. Principles of neural science. Fourth Edition. USA: McGraw-Hill; 2000. Moskowitz, MA. Basic mechanisms in vascular headache. Neurologic Clinics, 1990 8, 801-815. Lindner, A; Reiners, K. Meningeal hyperperfusion visualized by MRI in a patient with visual hallucinations and migraine. Headache, 1996 36, 53-57. Eftekhari, S and Edvinsson, L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Therapeutic Advances in Neurological Disorders, 2010 3, 369-378. Goadsby, PJ; Edvinsson, L. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of Neurology, 1990 28, 183-187. Goadsby, PJ; Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Annals of Neurology, 1993 33, 48-56. Ashina, M; Bendtsen, L. Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain, 2000 86, 133-138. Stepien, A; Jagustyn, P. Effect of rizatriptan on CGRP level in migraine. Cephalalgia, 2003 23, 738. Hokfetl, T; Arvidsson, U. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Annals of the New York Academy of Sciences, 1992 657, 119-134. Ferrari, MD; Odink, J. Serotonin metabolism in migraine. Neurology, 1989 39, 1239-1242. Gupta, S; Nahas, SJ. Chemical mediators of migraine: preclinical and clinical observations. Headache, 2011 51, 1029-1045. Bigal, ME; Krymchantowski, AV. Migraine in the triptan era. Progresses achieved, lessons learned and future developments. Arquivos de Neuro-Psiquiatria, 2009 67, 559-569. Loder, E. Triptan therapy in migraine. The New England Journal of Medicine, 2010 363, 63-70. Ramadan, NM. The link between glutamate and migraine. CNS Spectrums, 2003 8, 446-449.

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[23] Leao, AP. Spreading depression of activity in the cerebral cortex. Journal of Neurophysiology, 1944 7, 359-390. [24] Lauritzen, M. Pathophysiology of the migraine aura. The spreading depression theory. Brain, 1994 117, 199-210. [25] Hadjikhani, N; Sanchez Del Rio, M. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proceedings of the National Academy of Sciences of the United States of America, 2001 98, 4687-4692. [26] Zhang, X; Levy, D. Activation of central trigeminovascular neurons by cortical spreading depression. Annals of Neurology, 2011 69, 855-865. [27] Meents, JE; Neeb, L and Reuter, U. TRV1 in migraine pathophysiology. Trends in Molecular Medicine, 2010 16, 153-159. [28] Charles, A. Does cortical spreading depression initiate a migraine attack? Maybe not… Headache, 2010 50, 731-733. [29] Hauge, AW; Asghar, MS. Effects of tonabersat on migraine with aura: a randomized, double-blind, placebo-controlled crossover study. Lancet Neurology, 2009 8, 718-723.

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In: Headaches Editor: P. Gallo and G. Giordano

ISBN 978-1-62100-863-7 © 2012 Nova Science Publishers, Inc.

Chapter IV

Headache Associated with Intracranial Aneurysms

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Marcelo Moraes Valença*1, Luciana Patrizia A. Andrade-Valença2, Daniella A. Oliveira1, Joacil Carlos da Silva,1 and Carolina Martins3 1

Neurology and Neurosurgery Unit, Federal University of Pernambuco, Recife, Brazil and Hospital Esperança, Recife, Brazil 2 Neurology Unit, Medical School of the University of Pernambuco, Recife, Brazil 3 Medical School of Pernambuco Imip, Recife, Brazil

Abstract Headache may be an alarm signal of intracranial aneurysms. Thunderclap headache is typically related to a rupture of an intracranial aneurysm, particularly when loss of consciousness, vomiting or seizure occurs. Furthermore, a primary form of thunderclap headache has also *

Correspondence: Marcelo M. Valença, Neurology and Neurosurgery Unit, Department of Neuropsychiatry, Federal University of Pernambuco, 50670-420 Recife, Pernambuco, Brazil.

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66 Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença et al. been described. However, thunderclap headache may also be encountered in cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome, pituitary apoplexy, and may even be caused by an unruptured aneurysm. Other forms of headache may also be triggered by aneurysms, mimicking a primary form of headache such as migraine, cluster headache, stabbing headache, among others. In addition, after microsurgical treatment of patients with aneurysm, headache may be an important cause of suffering. Patients with intracranial aneurysm located at the internal carotid artery-posterior communicating artery (ICAPComA) often present pain on the orbit or fronto-temporal region ipsilateral to the aneurysm, as a warning sign a few days before rupture. Given the close proximity between ICA-PComA aneurysm and the oculomotor nerve, palsy of this cranial nerve may occur during aneurysmal expansion (or rupture), resulting in progressive eyelid ptosis, dilatation of the pupil and double vision. In addition, aneurysm expansion may cause compression not only of the oculomotor nerve, but of other skull base pain-sensitive structures (e.g. dura-mater and vessels), and pain ipsilateral to the aneurysm formation is predictable. We reviewed the functional anatomy of circle of Willis, oculomotor nerve and its topographical relationships in order to better understand the pathophysiology linked to pain and third-nerve palsy caused by an expanding ICA-PComA aneurysm. Silicone-injected, formalin fixed cadaveric heads were dissected to present the microsurgical anatomy of the oculomotor nerve and its topographical relationships. In addition, the relationship between the right ICA-PComA aneurysm and the right third-nerve is shown using intraoperative images, obtained during surgical microdissection and clipping of unruptured aneurysm. We discuss when and how to investigate patients headache associated with isolated third-nerve palsy.

Keywords: Aneurysm, Headache, Oculomotor nerve, Pain, Posterior communicating artery, Internal carotid artery, Anatomy

Introduction Headache may be an alarm signal of intracranial aneurysms.[1,4] Nevertheless, it is believed that unruptured intracranial aneurysms usually cause no symptoms unless they rupture and cause intracranial bleeding. Often, an unruptured intracranial aneurysm is found when a CT scan or MRI is performed for some minor neurologic unrelated symptoms.[5] When the aneurysm gets big enough to compress nearby structures (i.e., cranial nerves, meninges, cerebral tissue and intracranial vessels) diplopia, loss of vision, eye and neck pain and/or headache can happen.[2]

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Sudden and severe headache is the classical indication of intracranial bleeding as a result of an aneurysm rupture. Such particular type of headache, being explosive and spontaneous, and often described as the worse headache of the patient’s life, is called “thunderclap headache”. Thunderclap headache is typically related to rupture of an intracranial aneurysm, particularly when associated with loss of consciousness, vomiting or seizures. Thus, a patient presenting with thunderclap headache must be treated as a neurological emergency. Therefore, subarachnoid hemorrhage (SAH) as result of intracranial aneurysm rupture is clinically expressed as sudden, severe headache, lateralized or not, associated with vomiting (intracranial hypertension syndrome). After the thunderclap headache attack, a continuous form of headache may be present for the next 5-7 days, associated with fotofobia and neck rigidity and is due to aseptic blood-related meningitis (meningeal syndrome).[1-3] Other forms of headache may also be triggered by unruptured intracranial aneurysms, mimicking a primary form of headache such as migraine, cluster headache, stabbing headache, among others.[6-8] A primary form of thunderclap headache has been described, when the cause of it was not determined after neuroimaging and cerebrospinal fluid (CSF) investigation.[9] In addition, after microsurgical treatment of patients with aneurysm, headache may be an important cause of suffering.[10] This chapter reviews the different forms of headache associated with intracranial aneurysms, exemplifying with a series of patients, the different forms of headache encountered, its characteristics, physiopathology and possible treatments. Emphasis is given to a group of headaches - with or without accompanying symptoms - whose correct interpretation can lead to the diagnosis of the aneurysm before rupture, therefore preserving patients of the high morbidity and mortality associated with SAH.

Headache Attributed to Subarachnoid Haemorrhage The diagnostic criteria for headache attributed to subarachnoid haemorrhage established by the Headache Classification Subcommittee of the International Headache Society [IHS, ICHD-2 (2004)][9] can be seen on Table 1.

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68 Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença et al. Intracranial aneurysm rupture accounts for 0.4% to 0.6% of all deaths.[11] Headache associated with intracranial aneurysm may occur before rupture or associated with its investigation, acutely during rupture, subacutely on the days following the intracranial bleeding and even after surgical treatment of an intracranial aneurysm. Table 1. Headache Attributed to Subarachnoid Haemorrhage - Headache Classification Subcommittee of the International Headache Society [IHS, ICHD-2 (2004)][9].

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6. 2. 2 Headache attributed to subarachnoid haemorrhage (SAH) Diagnostic criteria: A. Severe headache of sudden onset fulfilling criteria C and D B. Neuroimaging (CT or MRI T2 or flair) or CSF evidence of non-traumatic subarachnoid haemorrhage with or without other clinical signs C. Headache develops simultaneously with haemorrhage D. Headache resolves within 1 month

“Comments: Subarachnoid haemorrhage is by far the most common cause of intense and incapacitating headache of abrupt onset (thunderclap headache) and remains a serious condition (50% of patients die following SAH, often before arriving at hospital, and 50% of survivors are left disabled). Excluding trauma, 80% of cases result from ruptured saccular aneurysms. The headache of SAH is often unilateral at onset and accompanied by nausea, vomiting, disorders of consciousness and nuchal rigidity and less frequently by fever and cardiac dysrythmia. However, it may be less severe and without associated signs. The abrupt onset is the key feature. Any patient with headache of abrupt onset or thunderclap headache should be evaluated for SAH. Diagnosis is confirmed by CT scan without contrast or MRI (flair sequences) which have a sensitivity of over 90% in the first 24 hours. If neuroimaging is negative, equivocal or technically inadequate, a lumbar puncture should be performed. Subarachnoid haemorrhage is a neurosurgical emergency.”

Acute aneurysmal rupture is usually accompanied by sudden severe headache (thunderclap headache), nausea, vomiting, loss of consciousness and seizure (intracranial hypertension syndrome). On the days following acute rupture, a continuous headache may be present, associated with nuchal rigidity, back pain and photophobia (meningeal syndrome).[2] Furthermore, part of patients with aneurysm may also present headaches before rupture occurs, the sentinel headache.[4]

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Thunderclap Headache Thunderclap headache is defined as a headache attack that in a few seconds to a minute reachs its maximal intensity. As reported by Slivka and Philbrook [12], thunderclap headache may be classified into three subgroups: (I) thunderclap headache without neurological symptoms, (II) thunderclap headache with neurological symptoms, and (III) thunderclap headache associated with intracranial affections (i.e. subarachnoid hemorrhage, aneurysm). The vast majority of the cases of thunderclap headache are associated with an aneurysmal SAH. It is estimated that SAH was the cause of thunderclap headache in around 25% of the patients.[13] It is a known fact that thunderclap headache may also be encountered in cases when SAH was not present, such as in cerebral venous thrombosis, stroke, intracerebral hemorrhage, spontaneous intracranial hypotension, intracranial infection, reversible cerebral vasoconstriction syndrome, pituitary apoplexy, cerebral artery dissection, colloid cyst of the third ventricle, CSF hypotension after dural puncture and acute sinusitis (particularly with barotrauma) and may even be caused by an unruptured intracranial aneurysm.[14] Frequently SAH occurs when the individual is awake, rarely taking place during sleep.[2] Usually the aneurysmal thunderclap headache is triggered by physical exertion. Sexual intercourse, defecation, lifting heavy objects or other types of efforts may precipitate an aneurysm rupture. It seems that sudden increase in the arterial blood pressure[15] and abrupt oscillation of the CSF and venous pressures increase the risk of an intracranial vascular rupture.[16] Table 2. Clinical presentation of 115 patients with subarachnoid hemorrhage. Headache + Loss of Consciousness + Vomiting Headache + Vomiting Headache only Headache + Loss of Consciousness Loss of consciousness Headache + Loss of Consciousness + Vomiting + Convulsion Loss of Consciousness + Convulsion Loss of Consciousness + Vomiting Headache + Loss of Consciousness + Convulsion Headache + Convulsion

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28.7% 27.0% 15.7% 13.0% 5.2% 3.5% 3.5% 1.7% 0.9% 0.9%

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70 Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença et al. Sexual intercourse was previously associated with intracranial vascular rupture, as described in 3.8%,[17] 4.5%,[18] and 12%[19] of the SAH patients. Mean peak coital levels of blood pressure may reach 185/115 mm Hg in normal subjects[20] or 237/138 mm Hg in hypertensive patients.[21] In addition, Valença and Valença[2] reported that in 14.5% of the SAH patients the hemorrhage was precipitated by sexual activity, with the higher rate being observed in men (33.3%), versus 6.8% in women. Only 4.8% of our patients were sleeping at the moment of the SAH. Other activities occurring at the ictus time were also reported by the patients, such as taking a bath (12.9%), sitting (11.1%), talking (6.5%), and washing dishes (6.5%). About half of the patients with SAH present a thunderclap headache without any other symptoms.[13] In a series of 115 cases with SAH the initial presentation included: headache (89.6%), vomiting (60.9%), loss of consciousness (56.5%) and convulsion (8.7%) (Table 2). At the moment of aneurysmal rupture, loss of consciousness (transient or permanent) is explained by a sudden increase of intracranial pressure, which reaches the levels of mean arterial pressure, reducing cerebral perfusion pressure. In 10% of the patients, SAH is severe enough to cause several days of unconsciousness. Curiously, even in case of aneurysm rupture, headache might be absent. In this respect, we had the opportunity to assist a rare case of a woman with a ruptured cerebral aneurysm with subarachnoid hemorrhage, in which the clinical presentation included vomiting and neck stiffness, but without headache and loss of consciousness as expected. In view of the fact that the initial diagnostic hypothesis was purulent meningitis, the lumbar puncture disclosed subarachnoid hemorrhage and following investigation both computer tomography and cerebral angiography revealed the intracranial aneurysm and radiological signs of rupture were present.

Primary Thunderclap Headache Since thunderclap headache is commonly linked with serious vascular intracranial disorders primary thunderclap headache should be the diagnosis only when all organic causes have been exhaustively excluded.[9] The diagnostic criteria for primary thunderclap headache was established by the Headache Classification Subcommittee of the International Headache Society [IHS, ICHD-2 (2004)][9] (Table 3).

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Thunderclap Headache Triggered by Sexual Activity Thunderclap headache may be triggered by sexual activity.[19,22,23] This modality of headache may be classified in a benign form (absence of a known intracranial abnormality)[9] or a malignant one when it is associated to an intracranial hemorrhagic event or other vascular abnormalities (e.g. arterial vasoconstriction). Fatal aneurysm rupture may occurs during sexual intercourse.[24,25]

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Table 3. Diagnostic Criteria for Primary Thunderclap Headache Headache Classification Subcommittee of the International Headache Society [IHS, ICHD-2 (2004)][9] “Previously used terms: Benign thunderclap headache. Coded elsewhere: 4.2 Primary cough headache, 4.3 Primary exertional headache and 4.4 Primary headache associated with sexual activity can all present as thunderclap headache but should be coded as those headache types, not as 4.6 Primary thunderclap headache. Description: High-intensity headache of abrupt onset mimicking that of ruptured cerebral aneurysm. Diagnostic criteria: A. Severe head pain fulfilling criteria B and C B. Both of the following characteristics: 1. sudden onset, reaching maximum intensity in 3 months after craniotomy “Note: 1.When the craniotomy was for head trauma, code as 5.2.1 Chronic posttraumatic headache attributed to moderate or severe head injury. Comments: Immediate post-operative headache may occur in up to 80% of patients after craniotomy but resolves in most patients within 7 days. Fewer than onequarter develop persistent (>3 months) headache related to the surgical procedure. Posterior fossa procedures, especially suboccipital craniotomies performed for acoustic neuromas, are more likely to be associated with post-craniotomy headache. The pathogenesis of chronic headache after craniotomy is unclear but may involve meningeal inflammation, nerve entrapment, adhesion of muscle to dura or other mechanisms. Modifications in the operative procedure, including the use of osteoplastic cranioplasty, may lead to a reduction in the incidence of postcraniotomy headache by preventing adhesion of muscle and fascia to the underlying dura.”

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88 Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença et al. Table 10. Modified Diagnostic Criteria for Post-Craniotomy Headache A. Headache of variable intensity ipsilateral to the craniotomy (commonly maximal in the area of craniotomy) B. Presence of craniotomy and absence of head trauma. According to the latent period between the craniotomy and the onset of the headache a post-craniotomy headache may be classified as: 1. Early onset – the headache appears within the 7 days after craniotomy 2. Intermediated onset – between 8 and 30 days after craniotomy 3. Later onset – the headache starts 30 days after the craniotomy

We observed that patients with post-craniotomy headache that were reoperated the temporal muscle presented a strongly adhesion with the painsensitive dura-mater at the inferior temporal craniectomy portion (pterionalsphenoid wing) of the craniotomy. This may be the cause of the headache, mainly during the mastigatory act and temporal muscle contraction and duramater retraction.

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Conclusion Headache is an important feature that can occur in several instances before, after and during the diagnosis of an intracranial aneurysm. In patients without diagnosis of intracranial aneurysm, headache as described above should be considered a valuable alarm signal that may allow for early diagnosis, before rupture occurs. Patients with intracranial aneurysm located at the internal carotid artery (ICA-PComA and ICA-ophthalmic artery) often present pain on the orbit or fronto-temporal region ipsilateral to the aneurysm as a warning sign a few days or months before rupture. Unruptured intracranial aneurysm and particular subtypes of headaches have been reported and these associations, for its prognostic importance, deserve further observations. Thunderclap headache is typically related to the rupture of an intracranial aneurysm, particularly when a loss of consciousness, vomiting or seizure occurs, but other forms of thunderclap headache had also been described and in a broader context, thunderclap headache may be caused by cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome, pituitary apoplexy, and may even be caused by an unruptured aneurysm. Patients with classical sentinel headache (one third of the patients with ruptured aneurysms) frequently are misdiagnosed in the emergency room. Other forms of headache

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may also be triggered by aneurysms, mimicking a primary form of headache such as migraine, cluster headache, stabbing headache, among others. Angiography itself, usually performed to investigate for the presence of an intracranial aneurysm, can cause headaches in patients with or without intracranial aneurysms. In addition, after microsurgical treatment of patients with aneurysm, headache may be an important cause of suffering.

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Valença MM, Andrade-Valença LPA, Martins C. Functional anatomy of headache: circle of Willis aneurysms, third cranial nerve and pain. Headache Medicine 2011; 2:82-88. Valença MM, Valença LPAA. Subarachnoid hemorrhage: causes, clinical manifestation, and treatment. Neurobiol. 2000;63:97-104. [Portuguese] Martins C, Lay J. Estudo das hemorragias subaracnoideas aneurismáticas. Monografia de conclusão de Residência em Neurocirurgia. Ed. Bargaço, Recife, 2000. Asano AGC, Farias da Silva W, Valença MM. Sentinel headache: warning sign of the subarachnoid hemorrhage from intracranial aneurysm rupture. Migraneas Cefaleias 2008; 11:78-83 [Portuguese] Choxi AA, Durrani AK, Mericle RA. Both surgical clipping and endovascular embolization of unruptured intracranial aneurysms are associated with long-term improvement in self-reported quantitative headache scores. Neurosurgery. 2011 Jul;69(1):128-34. Valenca MM, Andrade-Valenca LPA, Oliveira DA, Silva LC, Martins HAL and Medeiros FL. ‘Alarm bell headache’: a secondary stabbing headache. Cephalalgia, 2009; 29 (Suppl. 1): 157. Valença MM, Andrade-Valença LP, Martins C, Aragão MFV, Batista LL, Peres MF, da Silva WF. Cluster headache and intracranial aneurysm. J Headache Pain, 2007;8(5):277-282. Valença MM, Guterman L. Both surgical clipping endovascular embolization of unruptured intracranial aneurysm are associated with long-term improvement in self-reported quantitative headache scores COMMENTS. Neurosurgery. 2011; 29:133-134.

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Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Second Edition. Cephalalgia 2004; Suppl 1:1160. Rocha-Filho P, Gherpelli J, de Siqueira J, Rabello G. Post-craniotomy headache: a proposed revision of IHS diagnostic criteria. Cephalalgia. 2010 Feb 22. [Epub ahead of print] Chmayssani M, Rebeiz JG, Rebeiz TJ, Batjer HH, Bendok BR. Relationship of growth to aneurysm rupture in asymptomatic aneurysms ≤ 7 mm: a systematic analysis of the literature. Neurosurgery. 2011 May;68(5):1164-71; discussion 1171. Slivka A, Philbrook B. Clinical and angiographic features of thunderclap headache. Headache 1995;35(1):1-6. Linn FHH, Wijdicks EFM, Van Der Graaf Y, Van Gijn J. Prospective study of sentinel headache in aneurismal subarachnoid haemorrhage. The Lancet 1994; 344:590-593. Ju YE, Schwedt TJ. Abrupt-onset severe headaches. Semin Neurol. 2010 Apr;30(2):192-200. Epub 2010 Mar 29. King JT. Epidemiology of aneurysmal subarachnoid hemorrhage. In: Hurst, Dudlick, Morrison eds. Neuroimaging Clinics of North America – Cerebral Aneurysms, Vol:7(4) Philadelphia, 1997. Langer DJ, Zager EL, Flamm ES. Parasurgical management of aneurismal subarachnoid hemorrhage. In: Cruz J. Neurologic and Neurosurgical Emergencies. Philadelphia: Saunder, 1998, p. 205-41 Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations: based on 6368 cases in the cooperative study. J Neurosurg. 1966;25:219-239. Fisher CM. Headache in cerebrovascular disease. In: Vinken PJ, Bruyn GW, eds. Headache. Handbook of Clinical Neurology, Amsterdam: North Holland Publishing Co.;1968:124-156. Lundberg PO, Osterman PO. The benign and malignant forms of orgasmic cephalalgia. Headache. 1974;13: 164-165. Littler WA, Honour AJ, Sleight P. Direct arterial pressure, heart rate and electrocardiogram during human coitus. J Reprod Fertil. 1974;40:321331. Mann S, Graig MWM, Gould BA, Melville DI, Raftery EB. Coital blood pressure in hypertensives cephalgia, syncope, and the effects of betablockade. Br Heart J. 1982;47:84-89.

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[22] Valença MM, Andrade-Valença LP, Bordini CA, Speciali JG. Thunderclap headache attributed to reversible cerebral vasoconstriction: view and review. J Headache Pain. 2008 Oct;9(5):277-88. Epub 2008 Jul 31. [23] Valença MM, Valença LP, Bordini CA, da Silva WF, Leite JP, AntunesRodrigues J, Speciali JG.Cerebral vasospasm and headache during sexual intercourse and masturbatory orgasms. Headache. 2004 Mar;44(3):244-8. [24] Portunato F, Landolfa MC, Botto M, Bonsignore A, De Stefano F, Ventura F. Fatal subarachnoid hemorrhage during sexual activity: a case report. Am J Forensic Med Pathol. 2011 Jul 20. [Epub ahead of print] [25] Reynolds MR, Willie JT, Zipfel GJ, Dacey RG. Sexual intercourse and cerebral aneurysmal rupture: potential mechanisms and precipitants. J Neurosurg. 2011 Apr;114(4):969-77. Epub 2010 Jun 11. [26] Valença MM, Bordini CA, Valença LPAA, Leite JP, Antunes-Rodrigues J, Speciali JG. Abrupt severe headache associated with cerebral artery narrowing (ASHCAN): a new headache syndrome? In Migrâneas Cefaléias 2002; 5:91 [27] Gil-Gouveia RS, Sousa RF, Lopes L, Campos J, Martins IP. Postangiography headaches. J Headache Pain. 2008 Oct;9(5):327-30. Epub 2008 Jul 31. [28] Ramadan NM, Gilkey SJ, Mitchell M, Sawaya KL, Mitsias P. Postangiography headache. Headache. 1995 Jan;35(1):21-4. [29] Gil-Gouveia R, Fernandes Sousa R, Lopes L, Campos J, Pavão Martins I. Headaches during angiography and endovascular procedures. J Neurol. 2007 May;254(5):591-6. Epub 2007 Apr 6. [30] Schievink WI. Medical progress: Intracranial aneurysms. NEJM 1997; 336:28-40. [31] Kasner SE, Liu GT, Galetta SL. Neuro-ophthalmologic aspects of aneurysms. Neuroimaging Clin N Am. 1997 Nov;7(4):679-92. [32] Dimopoulos VG, Fountas KN, Feltes CH, Robinson JS, Grigorian AA. Literature review regarding the methodology of assessing third nerve paresis associated with non-ruptured posterior communicating artery aneurysms. Neurosurg Rev. 2005 Oct;28(4):256-60. Epub 2005 Jun 10. [33] Laskowitz DT, Galetta SL, Raps EC Neuro-ophthalmologic emergencies. In: Neurologic and neurosurgical emergencies. Ed. Cruz J, 1st edition, W. B. Saunders Company, Philadelphia, p. 155-185

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92 Marcelo Moraes Valença, Luciana Patrizia A. Andrade-Valença et al. [34] Kissel JT, Burde RM, Klingele TG, Zeiger HE. Pupil-sparing oculomotor palsies with internal carotid-posterior communicating artery aneurysms. Ann Neurol. 1983 Feb;13(2):149-54. [35] Saito R, Sugawara T, Mikawa S, Fukuda T, Kohama M, Seki H. Pupilsparing oculomotor nerve paresis as an early symptom of unruptured internal carotid-posterior communicating artery aneurysms: three case reports. Neurol Med Chir (Tokyo). 2008 Jul;48(7):304-6. [36] Keane JR, Ahmadi J. Third-nerve palsies and angiography. Arch Neurol. 1991 May;48(5):470. [37] Mathew MR, Teasdale E, McFadzean RM. Multidetector computed tomographic angiography in isolated third nerve palsy. Ophthalmology. 2008 Aug;115(8):1411-5. Epub 2008 Feb 15. [38] Wong GK, Boet R, Poon WS, Yu S, Lam JM. A review of isolated third nerve palsy without subarachnoid hemorrhage using computed tomographic angiography as the first line of investigation. Clin Neurol Neurosurg. 2004 Dec;107(1):27-31. [39] Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous malformation: a meta-analysis.Stroke1999; 30:317-320. [40] Horikoshi T, Akiyama I, Yamagata Z, Sugita M, Nukui H. Magnetic resonance angiographic evidence of sex-linked variations in the circle of Willis and the occurrence of cerebral aneurysms. J Neurosurg. 2002 Apr;96(4):697-703. [41] Silva Neto AR. Influence of carotid siphon geometry and circle of Willis variants on the origen of carotid-posterior communicanting aneurysms. MSc Dissertation, Federal University of Pernambuco, Recife, Brazil, 2009, 41p. [Portuguese] [42] Martins C, Yasuda A, Campero A, Rhoton AL Jr. Microsurgical Anatomy of Oculomotor Cistern. Operative Neurosurgery, 58(4): 220-8, 2006. [43] Lanzino G, Andreoli A, Tognetti F, Limoni P, Calbucci F, Bortolami R, Lucchi ML, Callegari E, Testa C. Orbital pain and unruptured carotidposterior communicating artery aneurysms: the role of sensory fibers of the third cranial nerve. Acta Neurochir (Wien). 1993;120(1-2):7-11. [44] Bozzetto-Ambrosi P. Ophthalmic segment of internal carotid artey: clinical and angiographics characteristics and results of endovascular treatment. MSc Dissertation, Federal University of Pernambuco, Recife, Brazil, 2009, 41p. [Portuguese]

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[45] Favier I, van Vliet JA, Roon KI, Witteveen RJ, Verschuuren JJ, Ferrari MD, Haan J. Trigeminal autonomic cephalgias due to structural lesions: a review of 31 cases. Arch Neurol. 2007 Jan;64(1):25-31. [46] Gee JR, Ishaq Y, Vijayan N. Postcraniotomy headache. Headache 2003,43:276. [47] Valença MM, Valença LPA, Carlotti Jr CG, Assirati JÁ, Leite JP, Bordini CA, Speciali JG. Cefaléia pós-lobectomia temporal em pacientes com epilepsia do lobo temporal mesial. Migrânea Cefaléias. 2002; 5:90.

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In: Headaches Editor: P. Gallo and G. Giordano

ISBN 978-1-62100-863-7 © 2012 Nova Science Publishers, Inc.

Chapter V

Blood Pressure and Allodynic Migraine C. Lovati1, M. Zardoni1, D. D’Amico3, L. Giani1, L. Scandiani2, P. Bertora1, M. Cortellaro2, G. Bussone,3 and C. Mariani1 Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

1

Department of Neurology and Headache Unit, L.Sacco Hospital, Milan, Italy 2 Department of Internal Medicine, L.Sacco Hospital, Milan, Italy 3 Headache Centre, Department of Clinical Neurosciences and Headache Unit, “C. Besta” Neurological Institute Foundation, Milan, Italy

Abstract Background: the transformation from an episodic form of migraine to a chronic and invalidating form is under investigation to put in evidence possible factors able to enhance this progression. A number of studies found an association between hypertension and migraine chronification and this observation induced the hypothesis that hypertension may possibly modify the vascular wall and the endothelial function in the cerebral vasculature. Allodynia, the perception of pain by non-painful stimuli, is considered as a marker of migraine transformation. Objective: In our study, we planned to investigate presence of headache in patients that underwent a blood pressure 24 hours

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C. Lovati, M. Zardoni, D. D’Amico et al. monitoring. The aim of the study was to assess the distribution of headache and allodynia in this particular population and to investigate possible relationships between the presence of headache and blood pressure pattern, including its circadian rhythm. Materials and Methods: Population: 195 subjects; among them, 122 did not suffer from headache (mean age 60.4 ± 11.6 years, 78 men and 44 women) and 73 with history of headache, (mean age 54.2 ± 12.5 years, 18 men and 55 women) of which 51 migraineurs (Mig) (mean age 52.6 ± 11.7 years, 11 men and 40 women) and 22 with tension type headache (TTH - mean age 58.0 ± 13.5 years, 7 men and 15 women). Among headache patients, allodynia was found in 23 out of 51 migraineurs and in 7 out of 22 tension-type headache. Headache diagnosis was made according to ICHD-II criteria. Presence of allodynia and sleep behavior were evaluated through semistructured ad hoc questionnaires. Blood pressure 24hours monitoring was performed by an Ambulatory Blood Pressure (ABP) Monitor (Space Labs) with its ad hoc software. Results: No significant difference was observed between headache patients and subjects without headache in terms of mean systolic and diastolic pressure, neither between migraine and TTH. With regard to the circadian rhythm of the blood pressure we observed that the physiological reduction of blood pressure during night (dipping) was more conserved among headache patients (34 dippers out of 73 subjects) with respect to subjects without headache (40 dippers out of 122) and that this borderline difference was more strongly significant comparing allodynic subjects (19 dippers out of 30) with both non-headache (40 dippers out of 122 , p