Episodic Cluster Headache Research Articles

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study.

ObjectiveTo evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment.BackgroundMany patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments.MethodsOne hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double‐blind phase; completers could enter a 3‐month nVNS open‐label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15‐60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified.ResultsThe intent‐to‐treat population comprised 133 subjects: 60 nVNS‐treated (eCH, n = 38; cCH, n = 22) and 73 sham‐treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS‐treated subjects and 15.1% of sham‐treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double‐blind phase and 18/128 subjects in the open‐label phase. No serious ADEs occurred.ConclusionsIn one of the largest randomized sham‐controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well‐tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

The anterior hypothalamus in cluster headache.

Objective To evaluate the presence, localization, and specificity of structural hypothalamic and whole brain changes in cluster headache and chronic paroxysmal hemicrania (CPH). Methods We compared T1-weighted magnetic resonance images of subjects with cluster headache (episodic n = 24; chronic n = 23; probable n = 14), CPH ( n = 9), migraine (with aura n = 14; without aura n = 19), and no headache ( n = 48). We applied whole brain voxel-based morphometry (VBM) using two complementary methods to analyze structural changes in the hypothalamus: region-of-interest analyses in whole brain VBM, and manual segmentation of the hypothalamus to calculate volumes. We used both conservative VBM thresholds, correcting for multiple comparisons, and less conservative thresholds for exploratory purposes. Results Using region-of-interest VBM analyses mirrored to the headache side, we found enlargement ( p < 0.05, small volume correction) in the anterior hypothalamic gray matter in subjects with chronic cluster headache compared to controls, and in all participants with episodic or chronic cluster headache taken together compared to migraineurs. After manual segmentation, hypothalamic volume (mean±SD) was larger ( p < 0.05) both in subjects with episodic (1.89 ± 0.18 ml) and chronic (1.87 ± 0.21 ml) cluster headache compared to controls (1.72 ± 0.15 ml) and migraineurs (1.68 ± 0.19 ml). Similar but non-significant trends were observed for participants with probable cluster headache (1.82 ± 0.19 ml; p = 0.07) and CPH (1.79 ± 0.20 ml; p = 0.15). Increased hypothalamic volume was primarily explained by bilateral enlargement of the anterior hypothalamus. Exploratory whole brain VBM analyses showed widespread changes in pain-modulating areas in all subjects with headache. Interpretation The anterior hypothalamus is enlarged in episodic and chronic cluster headache and possibly also in probable cluster headache or CPH, but not in migraine.

Release of PACAP-38 in episodic cluster headache patients - an exploratory study.

BackgroundActivation of the trigeminal-autonomic reflex, involving the trigeminal ganglion, the superior salivatory nucleus and the sphenopalatine ganglion (SPG) is crucial in the pathophysiology of cluster headache (CH). Since pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is present both in the SPG and the trigeminal ganglion (TG) and its role in migraine has been described, our aim was to determine the plasma PACAP-38 levels in different phases of episodic CH (ECH).Peripheral cubital fossa blood samples were taken during the ictal and inter-bout periods of male ECH patients and from age-matched healthy controls (n = 9). Plasma PACAP-38-like immunoreactivity (LI) was measured with specific and sensitive radioimmunoassay.FindingsSignificantly lower plasma PACAP-38-LI was detected in the inter-bout period of ECH patients than in healthy controls. However, PACAP-38 was significantly elevated in the plasma during CH attacks as compared to the inter-bout phase in the same subjects (n = 5).ConclusionsThis exploratory study suggests that PACAP-38 may be released during the attacks of ECH. Further patients and long-term follow-up are necessary to reveal its function.

Patrones de bloqueo anestésico de nervios pericraneales en el paciente con cefalea

Anaesthetic blocks, whether used alone or combined with other treatments, are a therapeutic resource for many patients with headaches. However, usage patterns by different professionals show significant heterogeneity. Material and methodsThe Headache Study Group of the Spanish Society of Neurology (GECSEN) designed a self-administered cross-sectional survey and sent it to all group members through the SEN's scientific area web platform in February 2016. The objective was to ascertain the main technical and formal aspects of this procedure and compare them with data obtained in a similar survey conducted in 2012. ResultsA total of 39 neurologists (mean age 41.74 years; SD: 9.73), 23 men (43.7 years; SD: 9.92) and 16 women (38.94 years; SD: 9.01) participated in this survey. Of these respondents, 76.9% used anaesthetic block in their clinical practice (79.16% in a tertiary-care hospital). The main indications were diagnosis and treatment of neuralgia (100%), prevention of chronic migraine (61.7%), episodic cluster headache (51.3%), and chronic cluster headache (66.7%). AB was used by 31% of the respondents to block only the lateral occipital complex, 13% also infiltrated the supraorbital nerve, and another 13% infiltrated the auriculotemporal nerve as well. ConclusionsThe indications for anaesthetic blocks and the territories most frequently infiltrated are similar to those cited in the earlier survey. However, we observed increased participation in this latest survey and a higher percentage of young neurologists (35.89% aged 35 or younger), indicating that use of this technique has entered mainstream clinical practice.

The cavernous sinus in cluster headache - a quantitative structural magnetic resonance imaging study.

Background It has been hypothesized that a constitutionally narrow cavernous sinus might predispose individuals to cluster headache. Cavernous sinus dimensions, however, have never been assessed. Methods In this case-control study, we measured the dimensions of the cavernous sinus, skull base, internal carotid and pituitary gland with high-resolution T2-weighted magnetic resonance imaging in 25 episodic, 24 chronic and 13 probable cluster headache patients, 8 chronic paroxysmal hemicrania patients and 22 headache-free controls. Dimensions were compared between groups, correcting for age, sex and transcranial diameter. Results On qualitative inspection, no relevant pathology or anatomic variants that were previously associated with cluster headache or chronic paroxysmal hemicranias were observed in the cavernous sinus or paracavernous structures. The left-to-right transcranial diameter at the temporal fossa level (mean ± SD) was larger in the headache groups (episodic cluster headache: 147.5 ± 7.3 mm, p = 0.044; chronic cluster headache: 150.2 ± 7.3 mm, p < 0.001; probable cluster headache: 146.0 ± 5.3 mm, p = 0.012; and chronic paroxysmal hemicrania: 145.2 ± 9.4 mm, p = 0.044) compared with controls (140.2 ± 8.0 mm). After adjusting for transcranial diameter and correcting for multiple comparisons, there were no differences in the dimensions of the cavernous sinus and surrounding structures between headache patients and controls. Conclusion Patients with cluster headache or chronic paroxysmal hemicrania had wider skulls than headache-free controls, but the proportional dimensions of the cavernous sinus were similar.

Living With Cluster Headache: A Qualitative Study of Patients' Perspectives.

Our aim was to explore the views and experiences of a group of Spanish men suffering from cluster headache (CH). CH has considerable effects on patients' quality of life, impairs everyday activities, and can modify lifestyle. This is the first time the experience of patients with CH is examined in a clinical study using a qualitative, phenomenological approach. We conducted a qualitative phenomenological study exploring how 20 male patients with CH, followed at the Headache Unit of a Spanish hospital, perceived their disease. Data were collected through in-depth interviews, researchers' field notes and patients' personal letters. A systematic text condensation analysis was performed following appropriate guidelines for qualitative research. Mean age was 41.15 years (standard deviation, 11.25). Seventeen patients had episodic CH and three patients had chronic CH. Five main themes describing the significance of suffering CH emerged: (a) meaning of disease, (b) experience of attacks, (c) meaning of treatment, (d) healthcare, and (e) social and family interaction. Patients with CH often live in fear and uncertainty because of their condition. Intensity and frequency of attacks, the use of ineffective treatments, skepticism perceived from social and workplace environments and physician unawareness play a significant role. Qualitative research offers insight into the way CH patients experience their disease, and may be helpful in establishing a fruitful relationship with these patients.

Efficacy and safety of a single occipital nerve blockade in episodic and chronic cluster headache: A prospective observational study.

Background Treatment options for cluster headache (CH) include acute, transitional and prophylactic strategies. We assessed the efficacy and safety of a single occipital nerve block (ONB) in patients with episodic (eCH) and chronic CH (cCH). Methods In this prospective, observational study 101 CH were treated with a single ONB using triamcinolone 10 mg and bupivacaine. Attack frequency, pain intensity and side effects were assessed at days 1 and 7 after ONB and thereafter weekly for 60 days until recurrence of attacks. Results Baseline mean daily attack frequency was 2.9 ± 2.5 (eCH) and 3.3 ± 2.9 (cCH), which was reduced to 0.7 ± 1.2 (eCH) and 1.1 ± 1.4 (cCH) after one day ( p = 0.08 for group difference) and to 1.1 ± 1.6 (eCH) and 1.9 ± 2.3 (cCH) after seven days ( p = 0.01 for group difference). In patients with eCH the pain-free period lasted longer compared to cCH ( p = 0.004). There was no association between the presence of local anesthesia and treatment response ( p = 0.88). No serious adverse events occurred. Conclusion ONB is an easy, safe and effective transitional treatment option in case of insufficient response of CH to treatment both in patients with eCH and cCH. Patients with eCH have a better and more sustainable treatment response.

Age of onset of episodic and chronic cluster headache - a review of a large case series from a single headache centre.

BackgroundIn the largest case series of cluster headache (CH) published in the literature, age of onset varies between 29.6 and 31.6 years. Differences in onset age based on gender and subtype diagnosis are reported, while there are only few data on patients with childhood and elderly onset. We therefore deemed it useful to review our own large case series of CH patients.MethodsThe age of onset of cluster headache was investigated in a consecutive case series of 808 patients (585 men and 223 women), including 686 (503 men and 183 women) with episodic cluster headache (ECH), 103 (66 men and 37 women) with chronic cluster headache (CCH), and 19 with an indeterminate form of CH (16 men and three women).ResultsThe mean age of onset was 30.2 ± 13.8 years (30.1 ± 13.0 in men and 30.4 ± 15.7 in women). The women with primary CCH had a mean onset age of 42.8 ± 21.7 years, while the women with secondary CCH did not differ much from those with ECH. Distribution of the study subjects by decades of onset age showed a peak in the third decade both in men and in women, but when only CCH patients were considered it displayed a more marked bimodal pattern in women (with peaks in the second and the sixth decade) than men (with peaks in the third and the fifth decade). The clear male predominance in cases with onset in the central age groups became attenuated in the extreme age groups. In patients with onset between ≤ 15 years and ≥ 50 years, the traditional male-to-female ratio was actually inverted in CCH.ConclusionsBased on these epidemiological findings, it would be important to investigate the possible role, causative or protective, played by hormonal factors in CH pathogenesis.

Ketamine i. v. for the treatment of cluster headaches : An observational study

Cluster headaches have an incidence of 1-3 per 10,000 with a 2.5:1 male-to-female gender ratio. Although not life threatening, the impact of the attacks on the individual patient can result in tremendous pain and disability. The pathophysiology of the disease is unclear, but it is known that the hypothalamus, the brainstem, and genetic factors, such as the G1246A polymorphism, play arole. A distinction is made between episodic and chronic cluster headaches. In acontrolled setting, we treated 29patients with cluster headaches (13 with chronic cluster and 16 with the episodic form), who had been refractory to conventional treatments, with alow dose of ketamine (an NMDA receptor antagonist)i.v. over 40min to one hour every 2weeks or sooner for up to fourtimes. It was observed that the attacks were completely aborted in 100 % of patients with episodic headaches and in 54 % of patients with chronic cluster headaches for aperiod of 3-18months. We postulated neuroplastic brain repair and remodulation as possible mechanisms.

Altered serum levels of kynurenine metabolites in patients affected by cluster headache.

BackgroundThe reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls.MethodWe assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded.ResultsLC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH.ConclusionThe reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

Pain processing in primary headaches, from spinal sensitisation to cortical modulation.

In primary headaches, such as migraine and cluster headache, an abnormal processing of pain stimuli at trigeminal, as well as at spinal level, has been demonstrated. As in other pain conditions, also primary headaches are accompanied by central sensitisation of pain pathways at cephalic and extra-cephalic level. Interestingly, in primary headaches the facilitation in pain processing has been detected during either the attack or active phase, as well as during the interictal period[1–3]. The interictal facilitation in pain processing in patients with episodic migraine or cluster headache during the active phase but outside the attack, reflects a generalised defective function of the pain system, probably as a consequence of a genetic substrate. This chronic hyperexcitability may contribute to their susceptibility to develop recurrent pain attacks. In the chronic form of migraine, as well as in cluster headache during the active phase of the disease, the hypersensitivity of the pain system is related to a dysfunction in central supraspinal antinociceptive pathways modulating pain processing[2, 4, 5]. In migraineurs, a high frequency of migraine attacks coupled with an overexposure to symptomatic medication contributes to a further impairment in nociceptive control, leading to the progression from episodic to chronic form of migraine and medication-overuse headache. This hypothesis is supported by a recovery to a normal functioning of both the supraspinal antinociceptive system and pain sensitivity after withdrawal treatment or clinical improvement. In cluster headache, the state-dependent facilitation in pain processing is linked to a state-dependent defective supraspinal control of pain, which is normally operating during the remission phase of the disease. On these bases, an imbalance of excitatory and inhibitory systems supports the development of episodic, remittent and chronic pain conditions in subjects with a pro-nociceptive profile. Interestingly, a series of studies demonstrated morphologic and metabolic abnormalities in pain-related brain areas in subjects with chronic form of migraine and cluster headache. Our recent data have demonstrated that the facilitation in pain processing and the related defective supraspinal control of pain are linked to a dismodulation of the default mode network.

O047. The sound-induced flash illusions reveal visual cortex hyperexcitability in cluster headache.

Objectives Pathophysiology of cluster headache (CH) is not wellknown. Although posterior hypothalamus has been suggested to play a pivotal role, evidence exists of a more diffuse involvement of the central nervous system including brainstem and cerebral cortex. In this regard, we recently observed increased motor cortical excitability in episodic CH patients both outside and inside bout [1]. The sound-induced flash illusions (SIFI) represent an example of multisensory integration, and provide a tool to indirectly explore the excitability state of the visual cortex [2]. SIFI are classified as “fission” and “fusion” illusions. When one visual stimulus (flash) is accompanied by two or more auditory stimuli (beeps), it is often perceived as multiple flashes (fission illusion). Conversely, fusion illusion occurs when subjects perceive less number of flashes when these are presented with only one beep. On such bases, here we used SIFI to explore excitability of visual cortex in CH patients.

High-Dose Verapamil in Episodic and Chronic Cluster Headaches and Cardiac Adverse Events: Is It as Safe as We Think?

Cluster headache (CH) is a primary headache disorder with relatively effective treatments. Although few sufficiently controlled trials are available, verapamil is recommended as the first-line prophylactic drug for CH by the French Headache Society (with a low level of evidence, level B) and by the EFNS (European Federation of Neurological Societies, level A). Daily doses of more than 480 mg (and up to 1200 mg daily) are frequently used off-label, while 360 mg daily is the only dosage to have demonstrated its effectiveness in a double-blind trial against placebo, and the usual label posology used by cardiologists is 240 mg daily in hypertension. We report the case of a 19-year-old man who was self-reported to our cardiology consultation for dyspnea and asthenia for 18 months. His medical history consisted of CH crisis for 4 years treated by verapamil 720 mg/day for 18 months with relatively good efficiency. His electrocardiogram (ECG) showed a sinus bradycardia at 40 bpm with a first-degree atrio-ventricular block. Evolution was favorable after progressive verapamil discontinuation. Analysis performed on the French Pharmacovigilance Database between July 1, 2000 and December 1, 2014 found four other cases of cardiac adverse events related to high-dose verapamil used in CH prevention (two cases of syncope with complete atrio-ventricular block with verapamil 1200 and 240 mg daily, respectively, one syncope related to sick sinus syndrome with verapamil 360 mg daily, and one case of sinus bradycardia with verapamil 720 mg daily). Although available studies seem to demonstrate an apparent good tolerance, this off-label practice should not be considered as standard of care and requires strict cardiac monitoring, as suggested by the Agence Nationale de Sécurité du Médicament (ANSM) in a recent re-evaluation of the benefit/risk ratio of high-dose verapamil used in CH prevention.

Cluster headache.

Cluster headache.

Blunted autonomic response in cluster headache patients.

Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (-2.86 vs. -13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, -0.05 vs. -0.17, p < 0.05). CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.

The neuropsychology of cluster headache: cognition, mood, disability, and quality of life of patients with chronic and episodic cluster headache.

BackgroundCluster headache (CH) is commonly regarded as one of the most disabling headache conditions, and referred to as one of the most painful conditions known to humankind. Although there has been some research indicating the severe impact of CH, there is little comprehensive evidence of its impact on quality of life, disability, mood, and cognitive function in both its episodic (ECH) and chronic (CCH) variants.MethodsThis cross-sectional study investigates various aspects of cognitive function including intelligence, executive function, and memory, and mood, disability, and quality of life in 22 patients with ECH and CCH compared with age-matched healthy controls.ResultsThe results showed that intelligence and executive functions are intact in patients with CH, but that patients with CH perform significantly worse than healthy controls on tests of working memory and (all P < .05) report greater cognitive failures (P < .05). Around one third of both the ECH and CCH groups achieved “caseness” for depression, while self-reported anxiety was higher in those with CCH than the ECH patients, with 75% of the former compared with 38% of the latter groups achieving “caseness” on the measure of anxiety. Patients with CH reported high levels of disability, which was not significantly different between the 2 groups (P > .05). The patients with CH reported poor quality of life compared with healthy controls; however, this difference was not statistically significant.ConclusionPatients with CH show worse working memory, disturbance of mood, and poorer quality of life compared with healthy controls. The differences between patients with ECH and CCH, and the implications of these findings for the management of CH are discussed.

Ramelteon in the Prophylaxis of Chronic Cluster Headache- Case Report

Cluster headache is a primary headache characterized by severe pain with most attacks occurring during sleep. This is a case report on the use of ramelteon as a treatment for chronic cluster headache. A 42-year-old businessman, who had been experiencing episodic cluster headaches for 10 years, was diagnosed with chronic cluster headache in the past year during which time his activities of daily living had been greatly reduced because of daily cluster headache attacks. We initiated treatment with ramelteon (8 mg/day) prophylactically before sleep, and his average attack frequency per day after taking the drug was less than that before taking the drug. The elimination half-life of ramelteon is typically under 2 h, whereas that of melatonin is typically 30 min. This difference in the elimination half-life may have caused the better response to ramelteon treatment than to melatonin. We conclude that ramelteon may be useful as a new agent in both the prevention and prophylaxis of chronic cluster headache, when attacks occur at the same time during the night and that cluster headache is related to circadian rhythm.

A rare cause of symptomatic cluster headache

Cluster headache (CH) is characterized by recurrent attacks of short-lasting excruciating pain accompanied by signs of autonomic dysfunction. Although neuroimaging results are usually normal in primary headaches, rarely structural lesions may be associated with CH like presentation. Most symptomatic CH is due to pituitary tumors and less commonly due to arteriovenous malformations (AVM) and aneurysms. Here we describe a case of 44-year-old male who presented to us with new onset episodic CH with headache features typical. Initially, headache responded to treatment, but later the headache became continuous, severe in intensity and refractory to treatment. Since magnetic resonance imaging was normal, he was subjected to digital substraction angiography (DSA) to rule out aneurysm or AVM. DSA revealed indirect carotid-cavernous fistula (CCF). Once the fistula was obliterated with onyx embolization, headache subsided completely. MRI brain is often routinely performed in CH to rule out secondary causes. When MRI brain is normal, detailed vascular imaging with DSA must be performed in patients with CH with especially in those with atypical features. Like continuous pain refractory to treatment, sudden increase in severity in the first episode, minimal or absent autonomic features and abnormal physical findings like persistent ptosis in the headache-free period. Although many cases of symptomatic CH have been reported in literature we report the first case of CCF presenting as CH. Early identification is essential as it is completely curable with endovascular treatment.

Markers of endothelial function in migraine patients: Results from a bi-center prospective study.

Numerous studies suggest an increased vascular risk in patients with migraine, in particular in those with aura. A possible link between both conditions might be a dysfunction of the vascular endothelium. This observational study analyzed the endothelial markers angiopoietin-1, angiopoietin-2, Tie-2, sFlt-1 and NT-proBNP for the first time in migraineurs, patients with other primary headache disorders and healthy controls. Patients with episodic migraine with and without aura, episodic cluster headache, tension-type headache and healthy controls were included. Blood samples were obtained during migraine attacks and headache-free periods in migraineurs, in and out of bout in cluster headache and during headache-free periods in tension-type headache and healthy individuals to analyze markers of endothelial function. No significant difference in endothelial markers between migraine, other headache disorders and healthy controls was detected. There was no significant difference between migraine attacks and headache-free intervals. Additionally, no distinction could be found between migraine with and without aura. The endothelial markers analyzed do not display a characteristic pattern in different headache disorders especially migraine compared to healthy controls. The novel findings of our study indicate that factors other than endothelial dysfunction seem to be responsible for the at least statistical association of migraine with vascular disease.

Reduced CSF hypocretin-1 levels are associated with cluster headache.

Cluster headache (CH) is a debilitating disorder characterized by unilateral, severe pain attacks with accompanying autonomic symptoms, often waking the patient from sleep. As it exhibits strong chronobiological traits and genetic studies have suggested a link with the hypocretin (HCRT) system, the objective of this study was to investigate HCRT-1 in CH patients. Cerebrospinal fluid HCRT-1 concentration was measured in 12 chronic and 14 episodic CH patients during an active bout, and in 27 healthy controls. The patients were well characterized and clinical features compared to the HCRT concentration. We found significantly lower HCRT levels both in chronic (p = 0.0221) and episodic CH (p = 0.0005) patients compared with controls. No significant relationship was found with other clinical features. This is the first report of significantly reduced HCRT concentrations in CH patients. We speculate that decreased HCRT may reflect insufficient antinociceptive activity of the hypothalamus. The mechanism of the antinociceptive effect of HCRT is not known and requires further investigation. This study supports the hypothesis of a connection between arousal regulation and CH.