Any theory about the cause of cluster headache has to explain the unique clinical features of this disorder, such as the unilateral pain distribution in the territory of the first division of the Vth cranial nerve and the 2nd cervical root, the extreme severity of the pain, the diagnostic local autonomic symptoms, the male preponderance, and the characteristic circadian and circannual rhythms of attacks. In recent years, the cavernous sinus area has attracted attention as a possible site of origin for both the pain and the autonomic signs, because sympathetic (from the pericarotid plexus), parasympathetic (from the greater superficial petrosal nerve), and sensory fibres, including nociceptive peptidergic axons (from the first division of the trigeminal nerve), intersect there. This plexus of fibres can be damaged by episodic local inflammation and venous stasis.1 In support of this peripheral hypothesis is the ability of sumatriptan, the peripherally acting 5-hydroxytryptamine agonist, rapidly to abort most attacks2 and trigeminovascular activation,3 of intranasal capsaicin to reproduce the autonomic symptoms except miosis,4 and of paracavernous structural lesions to mimic typical attacks of cluster headache.5 Another factor supporting the peripheral hypothesis is that the volume of the cavernous sinus loggia may be smaller than normal in patients with cluster headache.6 However, a peripheral generator cannot account for the typical temporal pattern of the disorder or the bilateral changes detected with autonomic and electrophysiological tests.7,8 Hence hypothalamic involvement has long been suspected and indirectly supported by hormonal findings.912
Today's report by Arne May and colleagues provides, for the first time, direct proof that the ipsilateral anteroventral hypothalamus is activated during nitroglycerin-provoked attacks in patients with chronic cluster headache. Hence they conclude that neural mechanisms are the primary factors and vascular changes secondary in cluster headaches, as in other vascular headaches such as migraine. Nevertheless, several questions remain about the precise inter-relations between hypothalamus, autonomic nuclei, and trigeminovascular pain (figure). For instance, the possibility that the hypothalamic activation is secondary to the trigeminal pain cannot be excluded. Somatic sensory information from the trigeminal system may reach the hypothalamus directly or via the nucleus of the solitary tract13 and the finding by May and colleagues that the hypothalamic activation starts but also stops with the pain might favour such an interpretation. The lack of hypothalamic activation after subcutaneous frontal injection of capsaicin in healthy volunteers14 does not preclude the hypothesis because excitability of hypothalamic neurons might well differ between healthy volunteers and cluster headache patients (see below). Interestingly, neuroendocrine changes, similar to those found in cluster headache and compatible with hypothalamic dysfunction, were also described in "idiopathic" trigeminal neuralgia,15 in which a peripheral generator of the pain is now commonly accepted.
If one thinks of the hypothalamus as primary factor in cluster headaches, how might it generate the severe segmental pain, since it projects directly to trigeminal motor, but not to sensory, nuclei?13 Could it do so by activation of autonomic nuclei, which in turn would lead to vascular changes in the cavernous sinus loggia, or by an effect on descending pain-controlling systems? The study by May and colleagues and their interpretation of the results suggest that the nitric oxide donor nitroglycerin is able to provoke cluster headaches by directly activating the hypothalamus, not because of vasodilatation in the middle fossa.16 Nitric oxide is involved in light-induced phase shifts of the function of the supra-chiasmatic nucleus during the night.17 The suprachiasmatic nucleus lies within the area where activation was found on positron emission tomography, and there is evidence that phase shifts of the chrono-biological clock occur in cluster headaches.11 The signalling pathways in the supra-chiasmatic nucleus change with the temporal domain in the circadian rhythm, but the critical gating probably takes place at a molecular level downstream from the second messengers.17 Perhaps these gating mechanisms malfunction in patients with cluster headaches, and perhaps this impairment is related to the abnormal membrane-dependent transduction mechanisms in blood cells of patients with cluster headache,18 and possibly to the therapeutic effect of lithium, which modulates G proteins and the phosphatidylinositol signalling pathway.19 Could a change in excitability of hypothalamic neurons explain why they were not activated during nitroglycerin-induced attacks in a positron-emission tomographic study of patients with episodic cluster headache,20 and why nitroglycerin may be a more effective provoking agent in episodic than in chronic cluster headaches?16 The skewed sex distribution of cluster headaches makes the medial preoptic area of the hypothalamus, including the suprachiasmatic nucleus, also an area of much interest because of its sexual dimorphism.21
Like most pivotal studies in the sciences, that by May and colleagues raises several challenging questions. Having long advocated the crucial role of the central nervous system in migraine and cluster headache, I have no difficulty in accepting their proposal that these disorders are primarily neurovascular in origin. However, the relevant dysfunction in the central nervous system and the cellular and molecular mechanisms by which it leads to trigeminovascular pain and autonomic symptoms have yet to be worked out. Fortunately, thanks to modern technology, knowledge is progressing rapidly, which makes the outlook for patients optimistic.
Jean Schoenen
Department of Neurology, University of Liège, 4000 Liège, Belgium
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