Advances in the understanding of headache Peter J. Goadsby Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

Primary headache disorders account for a substantial part of the morbidity seen in medical practice and so advances in their understanding and management are of general importance. The classification of headache disorders has recently been revised, and the importance of frequent migraine, chronic (transformed) migraine and some important, albeit rarer, conditions that were previously not included has been recognized. Identification of the first genes for a migraine syndrome, namely familial hemiplegic migraine, and their classification as channelopathies opens up new understanding of these disorders and their possible pathophysiology. Functional brain imaging of migraine and cluster headache has placed the pathophysiology of these disorders firmly and clearly in the brain. As our understanding of migraine and related syndromes has increased, new therapies have been developed which reduce the significant disability associated with these important neurological disorders.

Introduction

Accepted: August 30, 2005 Correspondence to: Professor P.J. Goadsby, Headache Group, Institute of Neurology, Queen Square, London WC1N 3BG UK. E-mail: [email protected]

Headache dominates neurology outpatient appointments1 and is one of the most common disorders presenting to doctors. The World Health Organization considers a day with severe migraine to be as disabling as a day spent as a quadriplegic.2 Therefore it is necessary to understand headache disorders and to know about the considerable opportunities that exist to alleviate the suffering of many patients. Traditionally, headache has been assigned too little time in the medical school teaching curriculum because of the pressures of ever-increasing knowledge in world of increasing patient expectations. However, it seems curious to arm doctors with information about rare and unexpected illnesses and not prepare them for common disabling conditions such as headache. Many developments in recent times in headache have particular relevance to clinical practice and clinicians should be aware of these changes in order to optimize patient care. In this article some developments that cut across the neurobiology of headache and its clinical management are highlighted. Emphasis is also given to frequent headache since it presents often and can be difficult to manage. Interested readers are referred to

British Medical Bulletin 2005; 73 and 74: 83–92 DOI: 10.1093/bmb/ldh052

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P. J. Goadsby

recent monographs for more detailed accounts of the management of a broader range of headache disorders.3,4

Classification of headache The development and promulgation of the International Headache Society (IHS) diagnostic criteria in 1988 was perhaps one of the great advances in the study of headache in the late twentieth century. These criteria provided clear definitions which allowed homogenous populations to be selected for clinical studies. The IHS system formed the basis of all the important studies in the 1990s. The definitions did not suffer from the vagueness of the 1962 Ad Hoc Classification, but the research strength of the classification also proved to be its clinical ‘Achilles’ heel’. While it is essential to define clear populations for research, this can force artificial distinctions in clinical practice. Many biological properties lie on a continuous distribution. One might expect headache presentations to be on a clinical continuum and therefore it can be difficult to make diagnoses and define appropriate management at certain points in time. In this light it is not surprising that in the clinic patients have sometimes been difficult to classify using the new system, although it works very well for most cases. In the second edition of the classification5 the migraine classification has been fine tuned and some important headache types not previously dealt with have been included. The classification of migraine has been modified for paediatric populations by acknowledging attacks are shorter and have less associated features. In addition, some further thought has been given to the childhood periodic syndromes of cyclical vomiting, abdominal migraine and benign paroxysmal vertigo of childhood, which so often portend migraine in adolescence and adulthood. In IHS 2004, Section 3 on Cluster and Related Headaches has been altered to accommodate the range of phenotypes of what have been termed the trigeminal autonomic cephalalgias (TACs).6 These syndromes share the pathophysiological feature of pronounced activation of the cranial parasympathetic autonomic outflow in association with pain.7 In this section, ‘chronic’ and ‘episodic’ headache has been standardized, so that ‘chronic’ means the form of the disorder that does not have breaks of at least 1 month and ‘episodic’ is the form that has breaks of ≥1 month. Both cluster headache8 and paroxysmal hemicrania9 have episodic forms, and this is now recognized. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) has been included.10 Other headaches not previously recognized in the 1988 classification include hemicrania continua, hypnic headache and primary thunderclap 84

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headache. These are important, as the first two respond well to therapy and the latter has important management implications. Hemicrania continua is very sensitive to indomethacin9 and hypnic headache usually responds to lithium.11

Chronic daily headache

The most controversial issue in headache classification, indeed in some respects in all headache clinical practice, is how to deal with the problem of frequent daily or near-daily headache. Approximately 5% of North American and Western European populations have headache on ≥15 days/ month for, on average, ≥4 h/day. If headaches lasting for shorter periods are included, chronic daily headache is simply a syndrome defined by frequent headache.12 It is often incorrectly equated with the concept of ‘transformed migraine’, which is a subset of chronic daily headache (Table 1). Similarly, although IHS now includes a narrowly defined new daily persistent headache,5 I use it in the syndromic sense13 which helps me remember to look for the important secondary causes (Table 2). The concept that migraine sufferers may have a less severe daily headache is not new at all, as it was recognized by luminaries of the nineteenth century including Gowers.14 In the revised IHS criteria the term ‘chronic Table 1 Classification of chronic daily headache (headache on ≥15 days/month that may be due to a range of underlying mechanisms and may be complicated by or caused by medication overuse) Secondarya

Primary >4 h daily Chronic migraine Transformed migrainec

4 h/day. This syndrome is included here is to emphasize that, in general, the attacks themselves last for 10 days/month) since this problem needs to be addressed if treatment with a preventive is to be successful

migraine’ has been adopted for patients who experience migraine without aura on ≥15 days/month. It appears logical to include probable migraine patients as well, and in my clinical practice I use the term transformed migraine, in the sense developed by Silberstein and Lipton (Table 3), to indicate migraine or probable migraine on ≥15 days/month. It appears to make more biological sense as we see similarities in, for example, functional brain imaging in episodic migraine15–17 and chronic migraine.18 It is likely that the IHS Committee will also soon move to the term transformed migraine when expressing the idea that some patients have frequent headache that is biologically based on migraine.

Genetics of headache At present the genetics of headache is the genetics of migraine. It seems logical to assume that all primary headaches have a predisposition that is in some way activated by physiological and other life events, such as puberty. Clinically, cluster headache, paroxysmal hemicrania and 86

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SUNCT can be seen to run in families. Overall, it seems to be a good way of understanding primary headache. The description of mis-sense mutations in the CaV2.1 subunit of the P/Q voltage-gated Ca2+ channel gene on chromosome 19 in families with familial hemiplegic migraine (FHM) was a milestone in the field.19 This effort was further boosted by the description of mutations in ATP1A2 that encodes the α2 subunit of the Na+/K+ pump20 and mutations in the neuronal voltage-gated sodium channel SCN1A, each again in familial hemiplegic migraine.21 Some families with more routine forms of migraine can be linked to chromosome 19 or the X chromosome, and migraine is part of the phenotype of mitochondrial cytopathies. However, the genotype–phenotype correlations remain disappointing. Clearly, a time will come when the known syndromes can be checked by DNA analysis of apparently affected patients and it is hoped that this may even guide therapy.

Pathophysiology of migraine: studying the brain Classical neurology as promulgated by Gowers sought to provide anatomical answers to clinical questions. In many ways Sherington changed this and sought a physiological approach. The anatomical approach has been very successful, but the problems of primary headache will need a ‘physiological approach to clinical neurology’ (after J.W. Lance). To some extent human functional imaging is beginning to do this. In the 1960s and 1970s migraine was considered a vascular phenomenon, and is still often referred to incorrectly as a vascular headache. In his classical book, Wolff 22 summarized the referral patterns of intracranial painproducing structures, taking the view that migraine aura was due to vasoconstriction and the subsequent headache was due to a reactive vasodilatation. Olesen et al.23 debunked this link. The spreading depression theory24 points out that the flow changes follow metabolic demand; this is known as vasoneuronal coupling. When considering features of the attack, such as photophobia and phonophobia, and yawning or diuresis in the premonitory phase,25 the vascular hypothesis seems unattractive. Looking at the totality of the attack one might ask what parts of the brain, indeed the brainstem or diencephalon, were likely to be the sites of the lesion? Neuroimaging has supplied some of the answers. Positron-emission tomography (PET) scanning in acute migraine demonstrated activation in the rostral brainstem that persisted after the successful treatment of the attack but are not present interictally26 (Fig. 1). These changes are not seen in experimentally induced ophthalmic division pain27 or in cluster headache.28 We observed a patient during a bout of cluster headache who had a phenotypic migraine in the PET scanner and brainstem changes consistent with migraine and not with cluster British Medical Bulletin 2005;73 and 74

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Fig. 1 PET findings in (A) migraine,15 (B) cluster headache28 and (C) experimental head pain.27 Activation of rostral brainstem structures in migraine and posterior hypothalamic grey matter in cluster headaches seems relatively specific for the syndromes, as neither are seen in experimental ophthalmic (first) division head pain. The findings support the view that primary neurovascular headaches, migraine and cluster headache are fundamentally disorders of the nervous system.

headache.15 Imaging further spontaneous attacks appears to show that the dorsal rostral pons is a crucial area which activated consistently in migraine attacks.16 In chronic migraine, which is defined as migraine without aura on ≥15 days/month for >6 months,5 the same area of the dorsolateral pons is activated on PET,18 suggesting that infrequent and frequent migraine have a similar basis. Blood oxygen level dependent (BOLD) contrast functional MRI (fMRI) is a promising technique for the further study of single patients and determination of the site of abnormal activation.29 Magnetic resonance angiography has demonstrated that flow changes seen in migraine15 and cluster headache28 are simply a result of ophthalmic division pain.30,31 Another recent finding with neuroimaging that further supports the importance of the brainstem, particularly the dorsolateral pons, in migraine is the demonstration that the changes lateralize with the attack. By studying attacks of typical migraine triggered by nitroglycerin it can be shown that patients with left-sided attacks have left-sided brain activation and patients with right-sided attacks have right-sided activation, while patients with bilateral pain have bilateral activation.17 These data suggest that the dorsolateral pons is pivotal in the phenotypic expression of migraine as a lateralized syndrome. These changes persist after resolution of the pain with a triptan, and are not present interictally. They were not seen in a control group scanned using the same protocol but in whom migraine did not develop. Moreover, the pontine change is not seen in either controls or migraineurs during the dull bilateral headache phase induced by nitroglycerin.17 Understanding the candidate areas in the pons, such as the nucleus locus coeruleus (the major noradrenergic 88

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nucleus of the brain) may provide further insights and provide new directions for preventive management.

Advances in management Triptans (serotonin 5-HT1B/1D receptor agonists), first in the form of sumatriptan, were the greatest single advance in migraine and cluster headache therapy in the twentieth century. Sumatriptan was followed by zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan,32 with donitriptan just finished preclinical development. Ergotamine, the mainstay of specific acute treatment for most of the early twentieth century after its initial description in the nineteenth century, now has few indications in which it is the treatment of choice.33 It is clear that patients want rapid, complete and consistent pain relief. However, it is not clear how they choose between the available treatments. What is established is that, when asked, most patients have preferences for individual triptans Table 4 lists some situations in which the various triptans may be helpful.

New treatments

Three important unmet treatment needs can easily be identified. First, there is a considerable need for the development of preventive medications. On average, two-thirds of patients will have a 50% reduction in headache frequency with most preventive therapies. They can then choose between sleepiness, exercise intolerance, erectile impotence, nightmares, dry mouth, weight gain, tremor, hair loss or the potential for fetal deformities as possible side effects. It is an important statement about the level of disability experienced by migraineurs that they do make such choices. The recent reporting of positive clinical trials with topiramate has established its utility in migraine.34–36 Secondly, non-vascular treatments of acute attacks are required for those patients who cannot be given triptans and ergot derivatives. A clinical trial has shown that BIBN4096BS, a potent specific calcitonin gene-related peptide antagonist, was effective compared with placebo in acute migraine.37 This study helped to answer the pressing pathophysiological issue of the primacy of the importance of the ‘neurogenic theory’ over the ‘vascular theory’ and provides the beginning of a crucial advance in therapy. It is useful to observe that the advance was predicted by laboratory work more than a decade ago,38,39 and the translation of experimental work to clinical practice illustrates the importance of basic neurobiology in advancing clinical practice. It is now clear that vasoconstriction (vascular British Medical Bulletin 2005;73 and 74

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Table 4 Clinical Stratification of Acute Specific Migraine Treatments Clinical situation

Treatment options

Failed analgesics/NSAIDS

First tier Sumatriptan 50 mg or 100 mg orally Rizatriptan 10 mg orally Almotriptan 12.5 mg Eletriptan 40 mg orally Zolmitriptan 2.5 mg orally Slower effect/better tolerability Naratriptan 2.5 mg Frovatriptan 2.5 mg Infrequent headache Ergotamine 1–2 mg orally Dihydroergotamine nasal spray 2 mg Sumatriptan 20 mg nasal spray Zolmitriptan 5 mg nasal spray Rizatriptan 10 mg MLT wafer Zolmitriptan 2.5 mg dispersible Ergotamine 2 mg (perhaps most effective p.r./usually with caffeine) Naratriptan 2.5 mg orally Eletriptan 80 mg Naratriptan 2.5 mg Frovatriptan 2.5 mg Sumatriptan 25 mg p.r. Sumatriptan 6 mg s.c. Prevention Ergotamine at night Oestrogen patches Treatment Triptans Dihydroergotamine nasal spray Sumatriptan 6 mg s.c. Dihydroergotamine 1 mg i.m.

Early nausea or difficulties taking tablets

Headache recurrence

Tolerating acute treatments poorly Early vomiting Menstrually related headache

Very rapidly developing symptoms

NSAIDs, non-steroidal anti-inflammatory drugs; p.r., per rectum; s.c., subcutaneously; i.m., intramuscularly

theory) is not necessary for aborting acute migraine. Indeed, it has recently been demonstrated that sildenafil, a phosphodiesterase inhibitor, will induce migraine without changes in cerebral vessel diameter.40 This provides perhaps the last nail in the coffin of the vascular theory. From a therapeutic viewpoint the development of non-vasoconstrictor treatments of migraine offers an important advance in terms of safety that will be welcomed by clinicians and patients alike.

Conclusion It is no exaggeration to say that the future of headache is bright: a better classification in IHS 2004,5 a new understanding of the basic cause in terms of genetics, observing pathophysiology from functional brain 90

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imaging and new therapies are very promising. Headache is the most common of human maladies, which is also perhaps its greatest limitation. Familiarity is a major limitation to the interrogation of a subject, as is the case with headache. It is a clinical necessity for the physician to understand headache. It is it is a major cause of disability in our patients and a major burden of cost on the community. Our aim is to understand our patients, reduce their disability and reduce the cost to society.

Acknowledgements The author’s work has been supported by the Wellcome Trust.

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