Abstract
Over the past 40 years, Denmark has established a world reputation for the comprehensive nature and excellence of its headache research. Advances have been made in epidemiology, genetics, pathophysiology and treatment across the whole spectrum of headache entities. Moreover, the IHS classification of headache, the guidelines for clinical trials and text books on the basic mechanisms and management of headaches were initiated from Denmark. These achievements are a tribute to all those who have participated and to the continuing leadership of Jes Olesen.
Keywords
Introduction
As the representative of a country on the other side of the world to Denmark, I am most appropriately situated to comment on the global impact of the work done in this delightful country and the ripples that wash up on the shores of the Pacific Ocean, remote from their origins in the North Sea.
Early days
I suspect that there must have been two converging streams of thought that provided the genesis of the outstanding contributions that have made Denmark a world leader in headache research. The first is the pioneering work of Niels A. Lassen on cerebral blood flow (1) and the second is the interest of clinicians in the treatment of migraine, exemplified by the study of a monoamine oxidase inhibitor in prophylaxis by Dalsgaard-Nielsen in 1962 (2). The Danish Migraine Society was formed in 1968 with T. Dalsgaard Nielsen as President and B. de Fine Olivarius, Axel Klee, Erik Skinh⊘j and C. Sorensen as founding members.
A symposium held in Copenhagen in 1969 included a presentation by Dalsgaard-Nielsen (3) of his study of 2027 school children and 390 adults, finding that the prevalence of migraine rose from about 3% at the age of 7 years to about 9% for the 15–17 age group In adult life the prevalence in males increased slightly to 11%, while in females it rose to about 19%, conclusions similar to those in many publications since. In the same symposium Erik Skinh⊘j (4) recorded a cerebral blood flow study in a patient experiencing aphasia and sensory loss in his right upper limb as part of a migraine aura. Regional blood flow was diminished by 50% in the appropriate brain areas during the aura, although cerebral angiography appeared normal. One of the organisers of this symposium was Axel Klee, who contributed a paper on the relation between the severity of aura symptoms and the duration of migraine headache (5). Klee had previously written with Willanger on disturbances of visual perception such as metamorphopsia in migraine (6) and had published a comprehensive monograph on clinical aspects of migraine in 1968 (7).
The Danish Migraine Society joined with the American Association for the Study of Headache in 1971 in organizing an International Headache Symposium held at Elsinore in 1971. Here Jes Olesen and Erik Skinh⊘j (8) combined in the study of vasoactive amines on cerebral blood flow using the intra-arterial 133Xenon method without finding any significant change after the injection of noradrenaline and serotonin into the internal carotid artery. Skinh⊘j (9) spoke of the potential of regional cerebral blood flow studies and concluded by saying:
Combined with pharmacological studies—as illustrated in Dr Jes Olesen's paper—we hope that this method, however, may yield some information in the final solution of ‘The Problem of Migraine!’.
And so it has proved to be. In the 30 years since this symposium there is no aspect of headache that has not been explored and illuminated by the outstanding sustained efforts of research in Denmark.
Migraine
Where do we start? Jes Olesen, whom we honour today, has written some 250 original articles in refereed journals and several hundred in other publications, as well as writing or editing many books. The results of his studies on regional cerebral blood flow in migraine with aura, in association with Larson, Lauritzen, Skyhoj Olsen, Lassen, Paulson, Friberg, Iversen and others (10–12) burst on the headache world, clearly documenting for the first time phenomena that had been suspected clinically and demonstrated partially by others. In the 1990 paper (12), the decrease in regional cerebral blood flow that accompanied the onset of the aura was shown to persist into the headache phase. The subsequent increase in flow took place without apparent change in headache. Because the headache most commonly originated on the side giving rise to the aura, it was tempting to assume that the cortical events could initiate headache by stimulating local vascular receptors. However, a prospective clinical study from this team (13) had shown that headache often occurred on the side inappropriate for this explanation to be generally valid, in that aura symptoms were recorded as being ipsilateral to the headache in 19 patients and contralateral in 18.
Other contributions to headache were not neglected in the 1980s. Blood flow in the temporal muscles (14) and in the subcutaneous tissue of the temples (15) did not vary significantly in migraine headache, although the lumen of the superficial temporal artery was found to be wider on the affected side during unilateral migraine headache (16). In Basic Mechanisms of Headache, edited by Jes Olesen and Lars Edvinsson, published in 1988 (17), Jes contributed chapters on tension headache, experimental headaches and migraine mechanisms, while no fewer than 16 of the 40 chapters came from the Danish school. In the same year, the first edition of the IHS Classification of Headache (18) appeared under Jes Olesen's chairmanship, restoring some measure of order to a chaotic field.
The 1990s have proved to be equally productive. The epidemiological work of Rasmussen demonstrated the general applicability of the IHS criteria for the distinction between migraine and tension-type headache (19). A broader study of the life-time prevalence of headache in 1000 people (20) showed a life-time prevalence of migraine to be 15% and of chronic tension headache to be 3%, ending with benign cough, exertional and sexual activity headaches each scoring 1%. Vascular studies were extended by the use of transcranial Doppler sonography that showed that flow velocity in the middle cerebral artery slowed during migraine headache, although regional cerebral blood flow in the territory supplied by that artery remained constant, implying that the artery dilated by about 20% (21). After the infusion of sumatriptan 2 mg intravenously, arterial flow velocity returned to normal as the headache subsided. Nitric oxide has since become a prime suspect as a mediator of vascular dilatation and possibly of vascular pain in headache (22).
Tension headache
The difficult subject of tension headache has also been investigated. A strong correlation between tenderness of the pericranial muscles and tension-type headache became apparent without any alteration of pressure-pain threshold (23). Thirty minutes of sustained jaw clenching caused 69% of patients and 17% of controls to develop a tension-type headache (24). In those patients who did not, the pressure–pain threshold increased, indicating that they were able to combat pain by activating their endogenous pain control system. The beneficial effect of amitriptyline (in contrast to a specific serotonin inhibitor) in treating this condition was confirmed (25).
Genetics
Turning now to genetics, the mode of inheritance of migraine was studied in a population of 4000 people (26). Compared with the general population, the first-degree relatives of patients with common migraine had a 1.9-fold risk of migraine, whereas the relatives of those patients having migraine with aura had a 4-fold risk of having the same condition. One spin-off from this study is particularly helpful for those clinicians dealing with post-traumatic migraine, the validity of which may be challenged in the law courts. The first-degree relatives of patients whose migraine without aura followed head injury had a lower risk of having migraine than the relatives of migrainous patients without a history of trauma (27). It was therefore probable that head injury could cause migraine even in those without any pre-existing susceptibility.
The familial occurrence of cluster headache was assessed in 421 patients (28). A positive family history of cluster headache was found in 7% of the 370 responders. Compared with the general population, the first-degree relatives of patients had a 14-fold risk of having cluster headache, indicating a genetic contribution to the problem. The findings implicate in some families an autosomal dominant gene with a penetrance of 0.30–0.34 in males and 0.17–0.21 in females (29). A genetic factor is presumably also involved in chronic tension-type headache as first-degree relatives have a 2.1–3.8-fold increased risk of this disorder compared with the general population (30). Twin studies have shed light on the inheritance of migraine with aura (31). Monozygotic twins had a concordance rate of 34%, significantly higher than in dizygotic twins (12%). The recurrence risk of migraine with aura was 50% in monozygotic twins and 21% in dizygotic twins, much the same as in non-twin siblings. Nevertheless, environmental factors must play a part in the development of migraine with aura, as the concordance rate was less than 100%. These findings are similar to those gained from the Swedish and Australian twin registries.
Clinical Trials
Sometimes negative clinical trials can be as important as those with positive results. When CP-122 288 proved to be highly effective in blocking the neurogenic inflammation model in animals, the clinical trial of its efficacy in migraine became crucial in testing the validity of the model. The report of two negative trials (32) made it clear that caution must be observed in applying laboratory results to the clinic. The master of clinical trials is Peer Tfelt-Hansen who chaired the committee that prepared the Guidelines for Controlled Trials of Drugs in Migraine (33). In initiatives like this, the Headache Classification Committee and the editing of The Headaches, now in its second edition (1999), and the International Headache Society itself, Denmark has led the way.
Conclusion
Who knows what the future holds? Perhaps further exploration of nitric oxide as a vasodilator transmitter agent, perhaps greater knowledge of central pathways, perhaps more clinical wisdom and better treatments. Whatever transpires, I am confident that Denmark will be one of the world leaders and that Jes Olesen will be carrying the banner for a long while yet.