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Background Converging evidence suggests that anatomical and functional mesocorticolimbic abnormalities support the chronicization of pain disorders. Methods We mapped structural and functional alterations of the mesocorticolimbic system in a sample of chronic cluster headache patients (n = 28) in comparison to age and sex-matched healthy individuals (n = 28) employing structural MRI and resting-state functional MRI. Results Univariate logistic regression models showed that several of the examined structures/areas (i.e., the bilateral nucleus accumbens, ventral diencephalon, hippocampus, and frontal pole, and the right amygdala) differentiated chronic cluster headache patients from healthy individuals (p Conclusion Our results showed that chronic cluster headache patients present anatomical and functional maladaptation of the mesocorticolimbic system, with functional data indicating a possible prefrontal areas' failure to modulate the mesolimbic structures. These results were opposite to what we hypothesized based on the previous literature on chronic pain conditions. Future studies should assess whether the observed mesocorticolimbic abnormalities are due to the neuroprotective effects of the assumed medications, or to the frequent comorbidity of CH with neuropsychiatric disorders or if they are a genuine neural signature of CH and/or chronic cluster headache condition.

Introduction Deep brain stimulation (DBS) of the posterior hypothalamus (pHyp) has been reported as an effective treatment for primary, drug-refractory and chronic cluster headache (CCH). We here describe the use of such a procedure for the treatment of secondary CCH due to a neoplasm affecting the soft tissues of the right hemiface. Methods A 27-year-old man affected by infiltrating angiomyolipoma of the right hemiface who subsequently developed drug refractory homolateral CCH underwent DBS of the right pHyp region at the Fondazione IRCCS Istituto Nazionale Neurologico Carlo Besta. Results After surgery, the patient presented a significant reduction in frequency of pain bouts. However, because of a subsequent infection, the entire system was removed. After re-implantation of the system, successful outcome was observed at 2 years follow-up. Discussion This brief report shows the feasibility of pHyp DBS in secondary drug-refractory CCH syndromes; future reports are needed in order to confirm our positive result.

This study validates the method of interviewing only the first-degree relatives indicated by the proband as possible cluster headache sufferers. We interviewed essentially all the first-degree relatives (93%) of 87 probands with cluster headache. We found only one new first-degree relative with cluster headache (1/ 40 = 2.5%). The selective interview may be used with confidence as a means of investigating the hereditary component of cluster headache.

We report two cases of cluster headache sine headache occurring in a family of cluster headache sufferers. A 54-year-old female, suffered for 15 years from short-lasting, right-sided attacks of eye reddening, lacrimation, rhinorrea, palpebral oedema and miosis, seven to eight times per day, in periods of 20-30 days. She did not experience headache, either with or without these phenomena. Her son suffers from periorbital, short-lasting, right-sided painful attacks accompanied by eye reddening, lacrimation, rhinorrea and nasal stiffnesss, occurring in periods of 30-35 days. Soon after the end of the current cluster period he still had daily attacks lasting 10-15 min, with the oculo-nasal autonomic phenomena only. The occurrence of cluster headache sine headache and cluster headache in the same family strongly suggests that the first condition is related to the cluster headache syndrome. Cluster headache sine headache should be considered as a subtype of the cluster headache syndrome.

The case of a young woman presenting with repeated headache episodes associated with right eye midriasis is described. CT scan, MR of the brain and selective cerebral angiography were unremarkable. Tyramine eyedrop response suggested parasympathetic hypofunction on the affected side. The diagnosis of ophthalmoplegic migraine is proposed.

Hypothalamic involvement has been invoked to explain the periodicity of the cluster periods and rhythmicity of the pain attacks in cluster headache. To explore this hypothesis the ovine corticotrophin-releasing hormone (o-CRH) and the insulin tolerance test were administered to a group of episodic cluster headache sufferers during both cluster period and remission. A group of low back pain patients and healthy subjects comprised the control populations. For the o-CRH test, 7 healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 12 in cluster period were studied. Five healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 9 in cluster period were administered the insulin tolerance test. Significantly increased basal cortisol levels were found in cluster headache patients in both illness phases ( p < 0.0001), but not in low back pain patients. Significantly reduced cortisol response to the o-CRH test was observed in cluster headache patients in both phases compared to healthy controls ( p < 0.02.). A blunted ACTH and cortisol response ( p < 0.0001 and p < 0.003 respectively) to the insulin tolerance test was present in cluster headache patients in both phases of the illness compared to healthy subjects and low back pain patients. On the contrary, the ACTH surge after insulin induced hypoglycemia was significantly increased in the low back pain patient group ( p = 0.02). These results suggest that the altered hypothalamic-pituitary-adrenal axis responsiveness in cluster headache patients is not a consequence of the pain, and point to a central, probably hypothalamic derangement in this pathology.

The cause of cluster headache remains to be determined. The involvement of peripheral neurovascular structures can explain the pain and autonomic signs of a cluster attack, but not its rhythmicity. The central theory of cluster headache attributes the cyclic recurrence to involvement of the hypothalamus. To evaluate hypothalamic dysfunction a number of hormone studies have been carried out on cluster headache patients. Alterations in plasma melatonin, cortisol, testosterone, gonadotrophins, prolactin, growth hormone and thyrotropin have been documented, some only in the cluster period but others in the remission phase of the illness. We believe that the hormonal abnormalities in cluster headache support disorders of hypothalamic function.

Cluster headache is a disorder of unknown origin. Some studies have focused their attention on neuroendocrine derangement, others on immunity. To probe central alterations in cluster headache (CH), immune parameters were investigated in cluster headache patients in comparison to low back pain patients and healthy controls. Increases in peripheral blood monocytes found in remission cluster headache patients may be attributable to chronic central nervous system (hypothalamic?) noradrenergic dysfunction or altered b-endorphin. Alterations in NK+, CD3+and CD4+levels found in cluster period cluster headache and low back pain patients are probably pain or stress-related.

Levels of b-endorphin in peripheral blood mononuclear cells have been studied as a new approach to investigating opioid tone in migraine and tension-type headache. Sixty-one patients with migraine without aura, 39 with migraine with aura and 23 with episodic tension-type headache were compared with 37 healthy controls. Peripheral blood samples were taken from patients not enduring headache attacks and not undergoing prophylactic treatment. A significant reduction in peripheral blood mononuclear cell b-endorphin concentrations was observed in migraine patients with and without aura, but not in tension-type headache patients. Altered transmitter modulation to peripheral blood mononuclear cells may be the cause of this alteration, which could be part of a more diffuse opioid system derangement in migraine subjects.

Clinical observations indicate a central nervous system, probably hypothalamic, involvement in cluster headache pathogenesis. In order to investigate the supposed hypothalamic involvement in cluster headache, we followed the hypothalamic-pituitary-adrenal axis and autonomic responses to the insulin tolerance test and the ovine corticotrophin-releasing hormone test in episodic cluster headache patients, both during remission and during the cluster period. The study revealed increased basal cortisol levels in all cluster patients. A blunted cortisol response to ovine corticotrophin-releasing hormone, in spite of a normal ACTH surge, was subsequently found in both illness phases. These findings suggest hypo-thalamic-pituitary-adrenal axis hyperactivity in both cluster phases. Furthermore, reduced ACTH and cortisol responses after insulin challenge were also observed in both remission and cluster period patients; a reduced norepinephrine surge was seen only in the cluster period. Taken together, these results suggest a hypothalamic involvement in the altered neuroendocrinological and autonomic responses found in our patients.