Pathophysiology of migraine and cluster headaches

There have been remarkable advances in the last decade in unraveling the mystery of primary headache disorders such as migraine and cluster. The vascular theory has been superseded by the neurovascular phenomenon, which seems to be the permissive triggering factor in migraine and cluster headache. This has been achieved through new imaging modalities such as positron imaging tomography (PET) and functional magnetic resonance imaging (fMRI). Prior to these imaging techniques, it was not possible to study the primary headache disorders because there was no structural basis. There is now an increasing body of evidence that the brain is primarily involved in cluster and migraine and that vessel dilation is an epiphenomenon.     

Exciting excitable brains: an update on migraine pathophysiology

This last decade has seen remarkable progress made towards unraveling the mystery of primary headache disorders like migraine and cluster. The vascular theory has been superseded by recognition that neurovascular phenomena seem to be the permissive and triggering factors in migraine and cluster headache. This understanding has been achieved through new imaging modalities such as positron emission tomography and functional magnetic resonance imaging. Prior to these imaging techniques it was impossible to study the primary headache disorders because these had no structural basis. There is now an increasing body of evidence that the brain is involved primarily in cluster and migraine and that vessel dilatation is an epiphenomenon. Received: 28 August 2002, Accepted in revised form: 9 October 2002 Correspondence to S.K. Aurora     

Functional neuroimaging of primary headache disorders

Until recently, primary headache disorders such as migraine and cluster headache were considered to be vascular in origin. However, advances in neuroimaging techniques, such as positron emission tomography, single photon emission computerized tomography, and functional magnetic resonance imaging, have augmented the growing clinical evidence that these headaches are primarily driven from the brain. This review covers functional imaging studies in migraine, cluster headache, rarer headache syndromes, and experimental head pain. Together with newer techniques, such as voxel-based morphometry and magnetic resonance spectrometry, functional imaging continues to play a role in elucidating and targeting the neural substrates in each of the primary headache syndromes.     

MIGRAINE BASIC SCIENCE RESEARCH

Until recently, primary headache disorders such as migraine and cluster headache were considered to be vascular in origin. However, advances in neuroimaging techniques, such as positron emission tomography, single photon emission computerized tomography, and functional magnetic resonance imaging, have augmented the growing clinical evidence that these headaches are primarily driven from the brain. This review covers functional imaging studies in migraine, cluster headache, rarer headache syndromes, and experimental head pain. Together with newer techniques, such as voxel-based morphometry and magnetic resonance spectrometry, functional imaging continues to play a role in elucidating and targeting the neural substrates in each of the primary headache syndromes.
Comment: If you are interested in imaging, this is an excellent review with which to begin.—Stewart J. Tepper, MD     

Sex Hormones and Primary Headaches Other than Migraine

The relation between sex hormones and migraine has been examined in a series of studies, leading to the definitions of pure menstrual migraine and menstrually-related migraine. The relation between sex hormones and other types of primary headache has been studied less extensively, but there is at least some evidence that hormones in general, and menstruation, pregnancy, or menopause in particular, also impact these disorders. This article reviews the available literature on changes of tension-type headache, cluster headache, other trigeminal autonomic cephalalgias, and hemicrania continua during women’s reproductive periods.     

Classification and epidemiology of headache

Headache disorders are remarkably common. Like back pain, headache is a symptom that has a broad range of possible causes. Diagnosis of primary headache disorders (migraine, tension-type headache, cluster headache) depends on systematic exclusion of secondary disorders and systematic identification of the specific features of the primary disorders. Thus, migraine should be viewed as an episodic syndrome of pain, involving intracranial structures associated with other neurologic disturbances. Because of the large number of potential etiologies, clinicians must approach headache classification systematically. In this chapter, we provide an overview of headache classification followed by discussions of epidemiology.     

Vessel-wall MRI in primary headaches: The role of neurogenic inflammation

Objective

The purpose of this study was to investigate if vessel-wall magnetic resonance imaging (VW-MRI) could differentiate among primary headaches disorders, such as migraine and cluster headache (CH), and detect the presence of neurogenic inflammation.

Background

The pathophysiology of primary headaches disorders is complex and not completely clarified. The activation of nociceptive trigeminal afferents through the release of vasoactive neuropeptides, termed “neurogenic inflammation,” has been hypothesized. VW-MRI can identify vessel wall changes, reflecting the inflammatory remodeling of the vessel walls despite different etiologies.

Methods

In this case series, we enrolled seven patients with migraine and eight patients with CH. They underwent a VW-MRI study before and after the intravenous administration of contrast medium, during and outside a migraine attack or cluster period. Two expert neuroradiologists analyzed the magnetic resonance imaging (MRI) studies to identify the presence of vessel wall enhancement or other vascular abnormalities.

Results

Fourteen out of 15 patients had no enhancement. One out of 15, with migraine, showed a focal parietal enhancement in the intracranial portion of a vertebral artery, unmodified during and outside the attack, thus attributable to atherosclerosis. No contrast enhancement attributable to neurogenic inflammation was observed in VW-MRI, both during and outside the attack/cluster in all patients. Moreover, MRI angiography registered slight diffuse vasoconstriction in one of seven patients with migraine during the attack and in one of eight patients with cluster headache during the cluster period; both patients had taken triptans as symptomatic therapy for pain.

Conclusions

These preliminary results suggest that VW-MRI studies are negative in patients with primary headache disorders even during migraine attacks or cluster periods. The VW-MRI studies did not detect signs of neurogenic inflammation in the intracranial intradural vessels of patients with migraine or CH.     

Coexistence of Migraine and Cluster Headache: Report of 10 Cases and Possible Pathogenetic Implications

We report on 10 patients suffering from two types of primary headache, migraine and cluster, diagnosed according to IHS criteria, and selected from headache patients attending two Italian headache centers. We briefly review the literature on coexisting migraine and cluster headache, considering the time relationships between these two headaches. The present series seems not to confirm the hypothesis that migraine transforms into cluster headache since both headaches persist together in the patients. The series is of clinical interest particularly with regard to diagnosis and to treatment strategies. Furthermore, while migraine and cluster headache comorbidity must be confirmed by population-based epidemiological studies, the possibility arises that the two conditions may be linked pathophysiologically: common genetic factors or functional alterations in the same central neurological circuits may play a role in the pathogenesis of both disorders.     

Clinical features of unilateral headaches beyond migraine and cluster headache and their response to indomethacin

The majority of previous studies on unilateral headaches beyond migraine and cluster headache have focussed on certain disorders such as paroxysmal hemicrania, SUNCT and primary stabbing headache. We assessed headache characteristics, importance of neuroimaging and response to indomethacin in an unselected series of uncommon unilateral headaches. We investigated all consecutive patients presented with unilateral headaches not fulfilling ICHD-II criteria of migraine and cluster headache. Patients underwent cranial magnetic resonance imaging or computed tomography as well as an indo-test, i.e. oral indomethacin 75 mg b.i.d. for 3 days. Among 63 patients we diagnosed primary stabbing headache in 12 patients, (probable) paroxysmal hemicrania in 6 and tension-type headache in 3 patients. One patient each had probable SUNCT, new daily persistent headache and nasociliary neuralgia. Eight patients had a secondary headache and 31 could not be classified according to ICDH-II. Imaging revealed lesions causally related to the headache in 8 patients. Indo-test achieved full remission of headache in 13 of 51 patients. At follow-up 11 ± 3 months after the first visit 29% of the patients were headache-free for ≥3 months. In conclusion, almost half of the patients presented with unilateral headaches beyond migraine and cluster headache cannot be classified according to ICHD-II. Among classifiable headaches primary stabbing headache was the most common. Imaging should be considered to rule out secondary headaches. The course is favourable in one third of the patients.     

Migraine and cluster headache – the common link

Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.     

The primary headaches: genetics,epigenetics and a behavioural genetic model

The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research.     

Familial occurrence in primary headaches

This paper reviews the literature of genetic epidemiology in primary headaches. Migraine without aura and migraine with aura are distinct disorders. Both are caused by a combination of genetic and environmental factors. Tension–type headache. The episodic form is most likely non–genetic, while the chronic form is caused by a combination of genetic and environmental factors. Cluster headache has previously not been thought to be genetic. However, first degree relatives of cluster headache sufferers have a 14–46 fold significantly increased risk of cluster headache, compared to the general population.     

Functional imaging in primary headache disorders

Over the past two decades, the development of new functional neuroimaging techniques has improved our understanding of the brain events underlying several primary headache disorders. In migraine and cluster headache, the advent of these techniques has shifted the emphasis in pathophysiological research away from the vessel and back to the brain.     

Clinical,anatomical, and physiologic relationship between sleep and headache

The intimate relationship between sleep and headache has been recognized for centuries, yet the relationship remains clinically and nosologically complex. Headaches associated with nocturnal sleep have often been perceived as either the cause or result of disrupted sleep. An understanding of the anatomy and physiology of both conditions allows for a clearer understanding of this complex relationship and a more rational clinical and therapeutic approach. Recent biochemical and functional imaging studies in patients with primary headache disorders has lead to the identification of potential central generators which are also important for the regulation of normal sleep architecture. Medical conditions (e.g. obstructive sleep apnea, depression) that may disrupt sleep and lead to nocturnal or morning headache can often be identified on clinical evaluation or by polysomnography. In contrast, primary headache disorders which often occur during nocturnal sleep or upon awakening, such as migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache, can readily be diagnosed through clinical evaluation and managed with appropriate medication. These disorders, when not associated with co-morbid mood disorders or medications/analgesics overuse, seldom lead to significant sleep disruption. Identifying and classifying the specific headache disorder in patients with both headache and sleep disturbances can facilitate an appropriate diagnostic evaluation. Patients with poorly defined nocturnal or awakening headaches should undergo polysomnography to exclude a treatable sleep disturbance, especially in the absence of an underlying psychological disorder or analgesic overuse syndrome. In patients with a well defined primary headache disorder, unless there are compelling historical or examination findings suggestive of a primary sleep disturbance, a formal sleep evaluation is seldom necessary.     

A review of diagnostic and functional imaging in headache

The neuroimaging of headache patients has revolutionised our understanding of the pathophysiology of primary headaches and provided unique insights into these syndromes. Modern imaging studies point, together with the clinical picture, towards a central triggering cause. The early functional imaging work using positron emission tomography shed light on the genesis of some syndromes, and has recently been refined, implying that the observed activation in migraine (brainstem) and in several trigeminal-autonomic headaches (hypothalamic grey) is involved in the pain process in either a permissive or triggering manner rather than simply as a response to first-division nociception per se. Using the advanced method of voxel-based morphometry, it has been suggested that there is a correlation between the brain area activated specifically in acute cluster headache – the posterior hypothalamic grey matter – and an increase in grey matter in the same region. No structural changes have been found for migraine and medication overuse headache, whereas patients with chronic tension-type headache demonstrated a significant grey matter decrease in regions known to be involved in pain processing. Modern neuroimaging thus clearly suggests that most primary headache syndromes are predominantly driven from the brain, activating the trigeminovascular reflex and needing therapeutics that act on both sides: centrally and peripherally.     

Evaluation of acute headaches in adults

Classifying headaches as primary (migraine, tension-type or cluster) or secondary can facilitate evaluation and management A detailed headache history helps to distinguish among the primary headache disorders. "Red flags" for secondary disorders include sudden onset of headache, onset of headache after 50 years of age, increased frequency or severity of headache, new onset of headache with an underlying medical condition, headache with concomitant systemic illness, focal neurologic signs or symptoms, papilledema and headache subsequent to head trauma. A thorough neurologic examination should be performed, with abnormal findings warranting neuroimaging to rule out intracranial pathology. The preferred imaging modality to rule out hemorrhage is noncontrast computed tomographic (CT) scanning followed by lumbar puncture if the CT scan is normal. Magnetic resonance imaging (MRI) is more expensive than CT scanning and less widely available; however, MRI reveals more detail and is necessary for imaging the posterior fossa. Cerebrospinal fluid (CSF) analysis can help to confirm or rule out hemorrhage, infection, tumor and disorders related to CSF hypertension or hypotension. Referral is appropriate for patients with headaches that are difficult to diagnose, or that worsen or fail to respond to management     

Headache Attributable to Disorders of the Eye

Sensory innervation to the eye and periocular area arises from the ophthalmic branch of the trigeminal nerve. Thus, ocular, orbital, and systemic disorders may produce head pain with ocular signs and symptoms. Whereas some of these entities have characteristic diagnostic features, others mimic primary headache disorders such as migraine and cluster headache. This article reviews common ocular and neuro-ophthalmic conditions that are accompanied by pain in or near the eye.     

Somatostatin infusion withdrawal: a study of patients with migraine,cluster headache and healthy volunteers

Migraine and cluster headache are the most common disabling primary headache syndromes and are typically episodic. A reliable method of triggering such headache attacks facilitates the study and treatment of these disorders. There is sufficient clinical and laboratory evidence to suggest that somatostatin withdrawal may be a useful way of triggering headache. We studied 15 subjects, eight migraineurs, four cluster headache sufferers and three healthy controls. Each subject had a standard somatostatin infusion, 250 microg/h for 3.5h. Subjects were followed for 24h post-infusion. Growth hormone was suppressed in each subject demonstrating a biologically active infusion of somatostatin. None of the non-headache sufferers had pain. Seven of eight migraine sufferers had no immediate headache and no delayed headache. One migraineur experienced short lasting headache with no migrainous features. Three of four patients with cluster headache had no significant pain with the infusion, while one had pain after 1h. The results suggest that somatostatin infusion is not a reliable way to produce headache in experimental settings in either migraine or cluster headache. The data do not exclude a role for somatostatinergic mechanisms in primary headache.     

The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache

The most important primary headaches (i.e. independent disorders that are not caused by another disease) are migraine, tension-type headache and cluster headache. All primary headaches are in need of better treatments. Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc). Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.     

Das Fenster zur Kopfschmerzforschung

Current functional neuroimaging studies in headache patients have demonstrated that changes in vascular function are not the primary cause for the pain in migraine. Especially in headache research, functional imaging revealed for the first time important information on the pathophysiology of idiopathic syndromes beyond mere anatomical attribution. Several independent studies have reinforced the crucial role of the brainstem in migraine resulting in primary dysfunction of the endogenous antinociceptive systems, including the periaqueductal grey and the dorsal raphe nucleus (DRN) in the midbrain as well as areas involved in the neuronal regulation of cerebral blood flow (DRN and locus coeruleus). The hypothalamus on the other hand is involved in the fundamental processes leading to the acute attacks of cluster headache. These data have been repeatedly replicated by several groups and led to a new understanding of the pathophysiology of these syndromes and specifically the central role of the brain. The recent studies investigating the structural changes in migraine, chronic tension-type headache and cluster headache are not yet clear in their relevance but raise important questions and promise increasing knowledge of one of the most frequent symptoms in humans.