A. Bahra

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.

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.

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.

PET and MRA findings in cluster headache and MRA in experimental pain

Background: Cluster headache (CH), like migraine, is still regarded as a vascular headache although in both conditions a CNS cause has been suggested. Objective: To examine neurovascular mechanisms in CH. Methods: The authors used functional imaging with PET to investigate 18 CH patients (25 to 62 years old). Ten were in the active period (nine patients with induced attacks and one with spontaneous attack) and eight were out of their bout. In addition, the authors studied spontaneous CH and experimental pain in volunteers using MR angiography. Results: When an acute CH attack was triggered with nitroglycerin (NTG), activation occurred in the ipsilateral posterior inferior hypothalamic gray, the contralateral ventroposterior thalamus, the anterior cingulate cortex, the ipsilateral basal ganglia, the right anterior frontal lobe, and both insulae. In patients out of the bout who experienced only a mild NTG headache, activation was seen bilaterally in the insulae and frontal cortices, the anterior cingulate cortex, the right thalamus, and the left basal ganglia, but not in the hypothalamic gray area. In addition, the authors found a significant activation (vasodilatation) in the region of the major basal arteries that was caused in part by NTG but was also observed in the spontaneous case and could be induced by capsaicin injection into the forehead. Therefore, the vasodilatation is likely to be mediated by neural mechanisms involved in the acute CH attacks that are present in every human being. Conclusions: Dilatation of cranial vessels is not specific to any particular headache syndrome but generic to cranial neurovascular activation, probably mediated by the trigeminoparasympathetic reflex. These data confirm that CH is a CNS disorder best considered as a form of neurovascular headache.

Functional magnetic resonance imaging in spontaneous attacks of SUNCT: Short‐lasting neuralgiform headache with conjunctival injection and tearing

A 71‐year‐old woman presented with a short history of episodes of severe left‐sided orbital and temporal pain in paroxysms lasting 60 to 90 seconds, and accompanied by ipsilateral lacrimation of the eye, rhinorrhea, and conjunctival injection. Results of clinical examination and structural imaging were normal and a clinical diagnosis of SUNCT (short‐lasting unilateral neuralgiform pains with conjunctival injection and tearing) was made. The patient had a BOLD contrast–magnetic resonance imaging study in which significant activation was seen in the region of the ipsilateral hypothalamic gray, comparing the pain to pain‐free state. The region of activation was the same in this patient as has been reported in acute attacks of cluster headache.

Does Chronic Daily Headache Arise De Novo in Association With Regular Use of Analgesics

Background.—The prevalence of chronic daily headache in association with regular use of analgesics is about 2%. Whether regular use of analgesics has a causal or consequential relationship to daily headache has not been established. A causal relationship has been suggested consequent to the observation of improvement or resolution of headache following analgesic withdrawal in patients attending headache clinics, but this observation has not been validated by controlled trials.

Intranasal sumatriptan in cluster headache: Randomized placebo-controlled double-blind study

Background: Current evidence-based acute treatments of cluster headache are limited to oxygen inhalation and subcutaneous sumatriptan. Intranasal sumatriptan is a new formulation with better tolerability than the subcutaneous route. Two open-label studies suggested efficacy of intranasal sumatriptan in cluster headache. Methods: In a double-blind placebo-controlled randomized trial, patients with episodic or chronic cluster headache whose attacks lasted at least 45 minutes each treated one attack with 20 mg sumatriptan nasal spray and another one, at least 24 hours later, with matching placebo. They scored their headache on a five-point scale (very severe, severe, moderate, mild, or none) at 5, 10, 15, 20, and 30 minutes. The primary outcome measure was headache response (a decrease in pain from very severe, severe, or moderate to mild or none) at 30 minutes. Secondary outcome measures included pain-free rates, relief of associated symptoms, and rates of adverse events. Multilevel multivariate analysis was used for statistical analysis. Results: Five study centers enrolled 118 patients in whom 154 attacks were treated: 77 with sumatriptan and 77 with placebo. The responder rates at 30 minutes were 57% for sumatriptan and 26% for placebo (p = 0.002). Pain-free rates at 30 minutes were 47% for sumatriptan and 18% for placebo (p = 0.003). Sumatriptan was also superior to placebo considering initial response, meaningful relief, and relief of associated symptoms. There were no serious adverse events. Conclusion: Sumatriptan nasal spray is effective and well tolerated in the acute treatment of cluster headache attacks of at least 45 minutes’ duration.

Oral zolmitriptan is effective in the acute treatment of cluster headache

Objective: To evaluate the efficacy and tolerability of oral zolmitriptan 5 mg and 10 mg and placebo in cluster headache. Methods: A multicenter, double-blind, randomized, three-period, crossover, outpatient study. Adult patients received placebo and zolmitriptan 5 mg and 10 mg orally for the acute treatment of episodic or chronic cluster headache. Headache intensity was rated by a five-point scale: none, mild, moderate, severe, or very severe. Patients only treated moderate to very severe headaches. The primary efficacy measure was headache response (two-point or greater reduction from baseline in the cluster headache rating scale) at 30 minutes. Secondary efficacy measures included proportion of patients with initial headache relief within 15 and 30 minutes, mild or no pain at 30 minutes, meaningful headache relief, and use of escape medication. Results: A total of 124 patients took at least one dose of study medication, with 73% having episodic and 27% chronic cluster headache. For the primary endpoint, there was a treatment-by-cluster-headache-type interaction (p = 0.0453). Therefore, results are presented separately for chronic and episodic cluster headache. In patients with episodic cluster headache, the difference between zolmitriptan 10 mg and placebo at 30 minutes reached significance (47% versus 29%; p = 0.02). Mild or no pain at 30 minutes was reported by 60%, 57%, and 42% patients treated with zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo (both p ≤ 0.01 versus placebo). For all other secondary endpoints, zolmitriptan 10 mg was significantly superior to placebo in episodic cluster headache patients, whereas zolmitriptan 5 mg was significantly superior to placebo for three of the four secondary endpoints. In patients with chronic cluster headache, response rates following zolmitriptan 5 mg or 10 mg were not significantly different from placebo at any endpoint. Zolmitriptan 5 mg and 10 mg were well tolerated. Conclusion: Oral zolmitriptan is efficacious in episodic cluster headache.

Medication-overuse headache in patients with cluster headache

Objective: Medication-overuse headache (MOH) in cluster headache (CH) patients is incompletely described, perhaps because of the relatively low prevalence of CH. Methods: The authors describe a retrospective series of 17 patients (13 men, 4 women) with CH who developed MOH in association with overuse of a wide range of monotherapies or varying combinations of simple analgesics (n = 9), caffeine (n = 1), opioids (n = 10), ergotamine (n = 3), and triptans (n = 14). The series includes both episodic (n = 7) and chronic (n = 10) CH patients. Results: A specific triptan-overuse headache diagnosis was made in 3 patients, an opioid-overuse headache diagnosis was made in 1 patient, and an ergotamine-overuse headache diagnosis was made in 1 patient. In approximately half of the patients (n = 8), the MOH phenotype was a bilateral, dull, and featureless daily headache. In the other 9 patients, the MOH was characterized by at least one associated feature, most commonly nausea (n = 6), exacerbation with head movement (n = 5), or throbbing character of the pain (n = 5). The common denominator in 15 patients was a personal or family history, or both, of migraine. The 2 other patients gave a family history of unspecified headaches. Medication withdrawal was attempted and successful in 13 patients. Conclusions: Medication-overuse headache is a previously underrecognized and treatable problem associated with cluster headache (CH). CH patients should be carefully monitored, especially those with a personal or family history of migraine.

No change in the structure of the brain in migraine: A voxel-based morphometric study

Migraine is a common, disabling form of primary neurovascular headache. For most of the twentieth century it was regarded as a vascular headache whose primary pathophysiology lay in the cranial vasculature. Functional brain imaging using positron emission tomography has demonstrated activation of the rostral brain stem in acute migraine. Voxel‐based morphometry is a new fully automated whole brain technique that is sensitive to subtle macroscopic and mesoscopic structural differences between groups of subjects. In this study 11 patients suffering from migraine with aura (10 females, one male: 23–52 years, mean 31); 11 controls (10 females, one male: 23–52, mean 31); 17 patients with migraine without aura (16 females, one male: 24–57, mean 34); 17 controls (16 females, one male: 24–57, mean 34) were imaged with high resolution volumetric magnetic resonance imaging. There was no significant difference in global grey or white matter volumes between either patients with migraine and controls, or patients with aura and without aura. This study did not show any global or regional macroscopic structural difference between patients with migraine and controls, with migraine sufferers taken as homogenous groups. If structural changes are to be found, other methods of phenotyping migraine, such as by genotype or perhaps treatment response, may be required to resolve completely whether there is some subtle structural change in the brain of patients with migraine.