Early ReportHypothalamic activation in cluster headache attacks
Introduction
The pain of cluster headache is perhaps the most severe known to human beings. Women who have such headaches describe each attack as being worse than childbirth. The syndrome is clinically well defined1 and despite its recognition in published work for more than two centuries2 its pathophysiology is poorly understood.
The excruciatingly severe one-sided pain is likely to be mediated by activation of the first (ophthalmic) division of the trigeminal nerve, whereas the autonomic symptoms are a result of activation of the cranial parasympathetic outflow from the VIIth cranial nerve.3 The relapsing- remitting course,4 its seasonal variation,4 and the clockwise regularity5 are characteristic but unexplained features of the disorder.
The striking circadian rhythmicity of cluster headache has led to the suggestion of a central origin for its initiation.6, 7 Substantially lowered concentrations of plasma testosterone during the cluster headache period in men provided the first evidence of hypothalamic involvement in cluster headache.8 This finding was further supported by a reduced response to thyrotropin-releasing hormone9 and a range of other circadian irregularities that have been reported in patients who have cluster headaches.10 Melatonin is a marker of the circadian system and a blunted nocturnal peak melatonin concentration and complete loss of circadian rhythm have been reported in patients who have cluster headache.10 The endogenous circadian rhythm is run by an oscillator in the suprachiasmatic nuclei in the ventral hypothalamus and reacts to temporal environmental cues of light conditions via a retino-hypothalamic pathway. The hypothalamus, or a closely related structure, is a candidate site for triggering the acute attack of cluster headache.
Positron emission tomography (PET) is probably the best technique for visualising in-vivo changes in regional cerebral blood flow (rCBF) in human beings. Modern high-resolution PET allows the detection of subtle changes in rCBF during defined behavioural tasks and provides an index of synaptic activity relating networks of regions to tested brain functions.11
Cluster headache attacks can be elicited with nitroglycerin during the active period without significant side effects.5 Nitroglycerin-provoked and spontaneous cluster attacks are comparable3, 12 and nitroglycerin does not substantially alter rCBF.13 The headache can be rapidly and effectively aborted with sumatriptan. This approach was therefore used to detect brain regions with increased blood flow during nitroglycerin-induced cluster attacks, focusing our interest on the hypothalamic region.
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Methods and patients
Nine right-handed men (age 25–62 years, mean 43 years) with active chronic cluster headache, according to the Headache Classification Committee of the International Headache Society,1 were studied during an induced acute headache attack (study group). Acute cluster headache was provoked by inhalation of nitroglycerin (1·0–1·2 mg).5 All patients studied were not treated prophylactically for cluster headache and were otherwise healthy. Eight patients with a history of cluster headache but who
Results
Of the nine patients in the bout, five experienced a cluster headache attack on the left side and four patients on the right side after nitroglycerin spray. Typical concurrent autonomic symptoms such as ipsilateral miosis, lacrimation, and rhinorrhoea confirmed the presence of a classic cluster headache attack. All patients described the provoked attack as being similar to spontaneous attacks. In the nine patients who had attacks of acute cluster headache, significant activations in the acute
Discussion
We observed areas of activation in acute cluster headache that fall into two broad groups: areas known to be involved in pain processing or response to pain, such as cingulate and insula cortex and thalamus; and areas activated specifically in cluster headache but not in other causes of head pain, notably the hypothalamic grey areas. These data suggest that primary headache syndromes share some processing pathways but equally can be distinguished on a functional neuroanatomical basis by areas
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