Peter J. Goadsby

Hypothalamic activation in cluster headache attacks

BACKGROUND Cluster headache, one of the most severe pain syndromes in human beings, is usually described as a vascular headache. However, the striking circadian rhythmicity of this strictly half-sided pain syndrome cannot be readily explained by the vascular hypothesis. We aimed to assess changes in regional cerebral blood flow (rCBF) in patients with cluster headache. METHODS We used positron emission tomography (PET) to assess the changes in rCBF, as an index of synaptic activity, during nitroglycerin-induced cluster headache attacks in nine patients who had chronic cluster headache. Eight patients who had cluster headache but were not in the bout acted as a control group. FINDINGS In the acute pain state, activation was seen in the ipsilateral inferior hypothalamic grey matter, the contralateral ventroposterior thalamus, the anterior cingulate cortex, and bilaterally in the insulae. Activation in the hypothalamus was seen solely in the pain state and was not seen in patients who have cluster headache but were out of the bout. INTERPRETATION Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache. We suggest that a radical reappraisal of this type of headache is needed and that it should in general terms, be regarded as a neurovascular headache, to give equal weight to the pathological and physiological mechanisms that are at work.

New appendix criteria open for a broader concept of chronic migraine.

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.

Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials

BACKGROUND The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice. METHOD We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials. RESULTS 53 clinical trials (12 unpublished) involving 24089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post dose); and 67% (63-70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12.5 mg almotriptan showed similar efficacy at 2 h but better other results; 2.5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2.5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy. INTERPRETATION At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success.

Brainstem activation specific to migraine headache

Findings from functional imaging studies have shown activation of the brainstem during migraine without aura (MWOA) and activation of the hypothalamus during cluster headache. We assessed a patient with cluster headache and migraine by positron emission tomography during an active cluster headache after he had taken 1.2 glyceryl trinitate. The patient developed a typical MWOA, during which we saw activation in the dorsal rostral brainstem. There was no activation in the region of the hypothalamus. Our findings provide evidence that migraine involves the brainstem, and show several areas involved in cluster headaches. Our data show the potential for objective distinction between primary headache syndromes with functional imaging, in disorders hitherto distinguished on clinical grounds.

Correlation between structural and functional changes in brain in an idiopathic headache syndrome

Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.

EFNS guideline on the drug treatment of migraine – revised report of an EFNS task force

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients’ quality of life. To give evidence‐based or expert recommendations for the different drug treatment procedures of the different migraine syndromes based on a literature search and an consensus in an expert panel. All available medical reference systems were screened for all kinds of clinical studies on migraine with and without aura and on migraine‐like syndromes. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A,B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non‐steroidal anti‐inflammatory drugs (NSAIDs) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAIDs and triptans, oral metoclopramide or domperidon is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. A status migrainosus can probably be treated by steroids. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis are amitriptyline, naproxen, petasites, and bisoprolol.

Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the ‘raw patient data’ of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24 089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h postdose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.

The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation.

Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.

Premonitory symptoms in migraine An electronic diary study

Background: Migraine is frequently associated with nonheadache symptoms before, during, and after the headache. Premonitory symptoms occurring before the attack have not been rigorously studied. Should these symptoms accurately predict headache, there are considerable implications for the pathophysiology and management of migraine. Methods: Electronic diaries were used in a 3-month multicenter study to record nonheadache symptoms before, during, and after migraine. The authors recruited subjects who reported nonheadache symptoms in at least two of three attacks that they believed predicted headache. Symptoms were entered in the diaries by patient initiation and through prompted entries at random times daily. Entries could not be altered retrospectively. Data recorded included nonheadache symptoms occurring during all three phases of the migraine, prediction of the attack from premonitory symptoms, general state of health, and action taken to prevent the headache. Results: One hundred twenty patients were recruited: 97 provided usable data. Patients correctly predicted migraine headaches from 72% of diary entries with premonitory symptoms. A range of cognitive and physical symptoms was reported at a similar rate through all three phases of the migraine. The most common premonitory symptoms were feeling tired and weary (72% of attacks with warning features), having difficulty concentrating (51%), and a stiff neck (50%). Subjects who functioned poorly in the premonitory phase were the most likely to correctly predict headache. Conclusions: Using an electronic diary system, the authors show that migraineurs who report premonitory symptoms can accurately predict the full-blown headache.

Cluster headache A prospective clinical study with diagnostic implications

BackgroundCluster headache, when compared with migraine or tension-type headache, is an uncommon form of primary neurovascular headache. However, with a prevalence of approximately 0.1% and a lengthy history of disabling and distressing episodic pain, cluster headache is an important neurologic problem. MethodsPatients (n = 230) were recruited from our specialist clinic (24%) or from support groups (76%). All patients had a detailed history taken by at least two physicians and were assigned diagnoses according to the International Headache Society Diagnostic Guidelines. ResultsThe pain characteristics were of a strictly unilateral, predominantly retro-orbital (92%) and temporal pain (70%). Of the cranial autonomic features, lacrimation (91%) was the most common. Nausea (50%), photophobia (56%), and phonophobia (43%) often were noted, as was a sense of agitation or restlessness in 93% of patients. Typical migrainous aura was noted in 14% of this cohort. Most patients (79%) had episodic cluster headache, which was largely the same clinically as chronic cluster headache except for the persistence of attacks over time. The overall male-to-female ratio in this sample was 2.5:1, and this has decreased with time. Neither oral contraceptive use, menses, menopause, nor hormone replacement therapy had any consistent effect on cluster headache in women. Less than half of the patients had tried injectable sumatriptan, and many had not tried high-flow oxygen. Several unproven preventative agents that usually are used in migraine and an array of alternative therapies had been used; none of the latter was consistently effective. ConclusionPatients with cluster headache offer a population of primary headache patients with devastating acute attacks of pain. The syndrome is stereotyped with effective evidence-based treatments that are prescribed in only half of patients having cluster headache.