Pathogenesis Of Cluster Headache Research Articles

Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks.

Despite advances in neuroimaging and electrophysiology, cluster headache's pathogenesis remains unclear. This review will examine clinical neurophysiology studies, including electrophysiological and functional neuroimaging, to determine if they might help us construct a neurophysiological model of cluster headache. Clinical, biochemical, and electrophysiological research have implicated the trigeminal-parasympathetic system in cluster headache pain generation, although the order in which these two systems are activated, which may be somewhat independent, is unknown. Electrophysiology and neuroimaging have found one or more central factors that may cause seasonal and circadian attacks. The well-known posterior hypothalamus, with its primary circadian pacemaker suprachiasmatic nucleus, the brainstem monoaminergic systems, the midbrain, with an emphasis on the dopaminergic system, especially when cluster headache is chronic, and the descending pain control systems appear to be involved. Functional connection investigations have verified electrophysiological evidence of functional changes in distant brain regions connecting to wide cerebral networks other than pain. We propose that under the impact of external time, an inherited misalignment between the primary circadian pacemaker suprachiasmatic nucleus and other secondary extra- suprachiasmatic nucleus clocks may promote disturbance of the body's internal physiological clock, lowering the threshold for bout recurrence.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

BackgroundCluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan.MethodsWe conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition.Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed.ResultsWe enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10–16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10–13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10–8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache.ConclusionsThis study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

Dopaminergic system abnormalities in chronic cluster headache patients

Various evidences implicated diencephalic-mesencephalic structures in the pathogenesis of cluster headache, in particular, the hypothalamus. We previously reported in patients with chronic cluster headache (CCH) an altered connectivity between posterior hypothalamus and structures of the midbrain monoaminergic systems, such as the ventral tegmental area (VTA), substantia nigra and subthalamic nucleus. The VTA is a pivotal center of the mesocorticolimbic dopaminergic system, a functional network involved in reward processing, avoidance, and chronic pain.

Alterations of the structural covariance network in the hypothalamus of patients with cluster headache.

The hypothalamus is one of the key structures involved in the pathophysiology of cluster headaches. This study aimed to analyze the volume of hypothalamic subunits and structural covariance networks in the hypothalamus of patients with cluster headache. We retrospectively enrolled 18 patients with episodic cluster headache and 18 age- and sex-matched healthy controls. We calculated individual structural volumes in ten hypothalamic subunits using three-dimensional T1-weighted imaging and the FreeSurfer program, which conducted an automated segmentation based on deep convolutional neural networks. We also performed an analysis of the structural covariance network in the hypothalamus using graph theory and the BRAPH program. We compared the volumes of hypothalamic subunits and structural covariance networks in the hypothalamus of patients with cluster headache versus those of healthy controls. There were no significant differences in the structural volumes of the whole hypothalamus and hypothalamic subunits between patients with cluster headache and healthy controls. However, patients with cluster headache had significant alterations of the structural covariance network in the hypothalamus compared to that of healthy controls. The network measure of small-worldness index in patients with cluster headache was lower than that in healthy controls (0.844 vs. 0.955, p = 0.004). We demonstrated a significant difference in the structural covariance network in the hypothalamus of patients with cluster headache versus those of healthy controls. These findings could be related to the pathogenesis of cluster headache.

Can the effects of the mitochondrial DNA mutations found in Leber’s hereditary optic neuropathy be protective against the development of cluster headache in smokers?

Is it possible that some mitochondrial DNA (mtDNA) mutations enhance the risk of developing a headache disorder while other mutations actually confer a protective effect? Mitochondrial disorders have been linked to migraine but very rarely to cluster headache (CH). The true pathogenesis of CH is unknown but a linkage to cigarette smoking is irrefutable. Leber’s hereditary optic neuropathy is a syndrome of bilateral vision loss that typically manifests in a patient’s 20s and 30s, is male predominant, and its sufferers are heavy smokers and heavy drinkers. Tobacco exposure is so linked to the condition that only smokers appear to develop vision loss while nonsmokers remain unaffected carriers of their mutations. In essence, the Leber’s hereditary optic neuropathy population is the CH population but at present there have been no reported cases of CH in this mitochondrial subgroup. Thus, could the effects of the mtDNA mutations found in Leber’s hereditary optic neuropathy, which involve complex I of the electron transport chain, actually confer a protective effect against the development of CH? This article will delve into this theory.

Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment.

In spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown. Here, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug. We report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/D receptors, and in the range of those able to inhibit neurotransmitter release invivo. Our findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

Modern ideas about cluster headache. Literature review

The article presents a review of the literature where, starting with the publication of Ekbom K. (1947), the history of the allocation of cluster headache into a separate form of primary head pain is described, modern diagnostic criteria are presented, the pathogenesis, clinical features of the disease are described. It is shown that due to the rarity of this type of headache and low awareness of doctors, the delay in diagnosis is on average 6–7 years. Patients are prescribed a lot of unnecessary examinations and expert consultations: oculists, ENT doctors, neurosurgeons, psychiatrists, etc. Favorite incorrect diagnoses are migraine and trigeminal neuralgia. The evidence of the leading role of the hypothalamus in the pathogenesis of cluster headache is presented. The principles of therapy are discussed: for the relief of acute attacks, triptans are used as in migraine, the leader of prophylactic therapy is a calcium channel blocker verapamil. In chronic forms and attacks resistant to pharmacological treatment, neurostimulation methods are used.

Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators.

To describe the role of biochemical anomalies of tyrosine (TYR), tryptophan (TRP), and arginine (ARG) metabolism in patients suffering from episodic and chronic cluster headache (CCH). The pathogenesis of cluster headache (CH) and the process that transforms the episodic into the chronic form are unknown. However, the accompanying symptoms suggest a dysfunction of the sympathetic system and hypothalamus along with anomalies of metabolism of catecholamines, elusive amines, and nitric oxide (NO) metabolism. We describe the results obtained from the last papers published on this issue. The level of metabolites were analyzed by different high-performance liquid chromatography methods. In both episodic and CH patients, the levels of dopamine and elusive amines are very elevated. The only biochemical difference found in studies between episodic and chronic cluster was that norepinephrine levels were significantly lower in episodic cluster in comparison to control and chronic subjects. In addition, the levels of ARG, homoarginine, and citrulline, precursors of synthesis of NO, were significantly lower in chronic cluster. All these results suggest that TYR, TRP, and ARG metabolism is abnormal and may constitute a biochemical fingerprint of CH patients. The increased levels of norepinephrine in chronic cluster constitute a possible cause of chronicity of this primary headache. The high levels of tryptamine and its activity on the central serotoninergic system may explain why the length of CH is brief in comparison to migraine and tension-type headache. The low levels of ARG, homoarginine, and citrulline may be the consequence of high circulating levels of α1 -agonists, such as epinephrine and norepinephrine, and their biochemical interaction with endothelial trace amine-associated receptor 1 that induces activation of NO synthase, resulting in NO synthesis in the circulation, NO release, intense vasodilation, and as a result, the cluster attack.

The role of neurotransmitters and neuromodulators in the pathogenesis of cluster headache: a review.

The pathogenesis underlying cluster headache remains an unresolved issue. Although both the autonomic system and the hypothalamus play a central role, the modality of their involvement remains largely unknown. It is, also, unknown why the duration of the pain attacks is so brief and why their onset and termination are abrupt and extremely painful. This review summarizes the evidence to date accumulated in favor of a possible role of anomalies in the metabolism of tyrosine, tryptophan, and arginine in these unresolved issues.

Alterations of structural connectivity in episodic cluster headache: A graph theoretical analysis

We evaluated structural volumes and connectivity using graph theoretical analysis in patients with cluster headache. Ten patients with episodic cluster headache were recruited, who had a normal brain MRI on visual inspection. We also enrolled a control group of 20 healthy volunteers. All of the participants underwent 3-D volumetric T1-weighted imaging. We obtained the structural volumes using FreeSurfer image analysis and performed structural global and local connectivity analysis using BRAPH. The volumes of the left caudal anterior cingulate and postcentral gyrus were decreased in the patients with cluster headache compared to healthy individuals. In addition, in the measures of local structural connectivity, there was significant hub re-organization in the patients with cluster headache; the strength of the right frontopolar, left pericalcarine, and left posterior cingulate gyrus, the betweenness centrality of the right precentral and left pericalcarine gyrus, and the closeness centrality of the left pericalcarine and left posterior cingulate gyrus were decreased. Whereas the betweenness centrality of the right rostral middle frontal and left inferior temporal gyrus were increased in the patients with cluster headache. However, the measures of global structural connectivity were not different between the patients with cluster headache and healthy individuals. We demonstrate that the structural volumes and connectivity in patients with cluster headache are significantly different from those in healthy controls, especially revealing hub re-organization. These alterations are implicated in the pathogenesis of cluster headache and suggest that cluster headache is a network disease.

Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory.

To propose a hypothesis theory to establish a linkage between cigarette smoking and cluster headache pathogenesis. Cluster headache is a primary headache syndrome grouped under the trigeminal autonomic cephalalgias. What distinguishes cluster headache from all other primary headache conditions is its inherent connection to cigarette smoking. It is undeniable that tobacco exposure is in some manner related to cluster headache. The connection to tobacco exposure for cluster headache is so strong that even if an individual sufferer never smoked, then that individual typically had significant secondary smoke exposure as a child from parental smoking behavior and in many instances both scenarios exist. The manner by which cigarette smoking is connected to cluster headache pathogenesis is unknown at present. If this could be determined this may contribute to advancing our understanding of cluster headache pathophysiology. Hypothesis statement. The hypothesis theory will include several principles: (1) the need of double lifetime tobacco exposure, (2) that cadmium is possibly the primary agent in cigarette smoke that leads to hypothalamic-pituitary-gonadal axis toxicity promoting cluster headache, (3) that the estrogenization of the brain and its specific sexually dimorphic nuclei is necessary to develop cluster headache with tobacco exposure, and (4) that the chronic effects of smoking and its toxic metabolites including cadmium and nicotine on the cortex are contributing to the morphometric and orexin alterations that have been previously attributed to the primary headache disorder itself.

Efficacy of transdermal rotigotine in chronic cluster headache: A case series

Cluster headache (CH) is one of the most severe forms of headache, but the number of effective treatments is still limited. Recently, we reported the case of a drug-resistant CH patient responsive to the rotigotine transdermal patch, which is used in the treatment of Parkinson’s disease. This report formed the basis for a case series where other drug-resistant CH patients were treated with rotigotine. Here are the results of this study. Twenty-two CH patients underwent the treatment. Eight were episodic cluster headache (ECH) patients and 14 were chronic cluster headache (CCH) patients. Of the eight ECH patients, four reported that their CH had been stopped by the treatment. Of the 14 CCH patients, 11 were considered responders to the treatment (5 experienced a full resolution of headache, and 6 had a headache reduction of at least 50% in terms of mean monthly number of attacks). Our case series confirms the previous observation that rotigotine could be helpful in the treatment of CH. It may even influence the monoaminergic system that has a key role in the pathogenesis of CH.

Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis.

Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts.

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

BackgroundCluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.MethodsWe have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.ResultsAlthough no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 × 10−6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 × 10−5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.ConclusionsOur study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-016-0705-y) contains supplementary material, which is available to authorized users.

57. Botulinum toxin type-A therapy in cluster headache: Two clinical cases

Cluster headache (CH) is a primary chronic disabling form with autonomic symptoms, that often does not respond satysfactorily to prophylactic treatment. Botulinum toxin type A is an effective therapy for chronic migraine. We describe 2 clinical cases of CH examining the role of Onabotulinum-toxin-A on this form of primary headache. We treated with Onabotulinum-toxin-A two men (46 and 65 years-old) with refractory CH, with a periodicity of 3–4 months, in the muscles of the head and neck following a Blumenfeld treatment paradigm. The first patient has undergone six applications of Onabotulinum-toxin-A (total dosage of 155 U-31 sites) with a follow-up of two years. The second patient has undergone ten applications of Onabotulinum-toxin-A (total dosage between 105 and 195 U-31-39 sites), with a follow-up of three years. Symptoms improvement appeared after the second infiltrative treatment in both case with persistence of effectiveness until seven treatment, with intensity and frequency attack reduction. The first patient reported rare episodes of temporo-mandibular joint tension. The second case showed a total cessation of attacks. Interleukin-1 is a potent prototypical pro-inflammatory cytochine implicated in the pathogenesis of CH, and botulinum toxin inactivate interleukin-1.Onabotulinum-toxin-A can represent a valid alternative prophylactic therapy in CH.

Ipsilateral Alteration of Resting State Activity Suggests That Cortical Dysfunction Contributes to the Pathogenesis of Cluster Headache.

The pathomechanism of cluster headache (CH) is not entirely understood, but central and peripheral components were suggested. A recent report showed that transcranial magnetic stimulation measured cortical excitability was increased in the hemisphere ipsilalteral to the pain. In the current study we set out to investigate the amplitude of resting brain fMRI activity to find signatures of the increased excitability. High resolution T1 weighted and resting state functional MRI images were acquired from seventeen patients with CH in pain free period and from twenty-six healthy volunteers. Patients' data were normalized (e.g. inverted along the midsagittal axis) according to the headache side. Independent component analysis and a modified dual regression approach were used to reveal the differences between the resting state networks. Furthermore, the timecourses were decomposed into five frequency bands by discrete wavelet decomposition and were also re-regressed to the original data to reveal frequency specific resting activity maps. Two of the identified resting state networks showed alterations in CH. When the data were inverted to have patients' headaches on the left, the ipsilateral attention network showed increased connectivity in 0.08-0.04Hz frequency band in the in CH group. In the same dataset, cerebellar network showed higher functional connectivity in 0.02-0.01Hz range in the ipsilateral cerebellum. When the data of patients having headache on the left were inverted to the right, similar increased signal was found in the ipsilateral attention network in 0.08-0.04Hz band. The cerebellar network showed increased connectivity in the cerebellum in 0.02-0.01Hz band in patients. The Fourier analysis of these area revealed increased power in CH at all cases. Our results showed alterations of brain functional networks in CH. The alterations of resting state activity were found in the hemisphere ipsilateral to the pain, signifying the altered cortical processing in the pathomechanism of CH.

Bout-associated intrinsic functional network changes in cluster headache: A longitudinal resting-state functional MRI study.

Background Previous imaging studies on the pathogenesis of cluster headache (CH) have implicated the hypothalamus and multiple brain networks. However, very little is known regarding dynamic bout-associated, large-scale resting state functional network changes related to CH. Methods Resting-state functional magnetic resonance imaging data were obtained from CH patients and matched controls. Data were analyzed using independent component analysis for exploratory assessment of the changes in intrinsic brain networks and their relationship between in-bout and out-of-bout periods, as well as correlations with clinical observations. Results Compared to healthy controls, CH patients had functional connectivity (FC) changes in the temporal, frontal, salience, default mode, somatosensory, dorsal attention, and visual networks, independent of bout period. Compared to out-of-bout scans, in-bout scans showed altered FC in the frontal and dorsal attention networks. Lower frontal network FC correlated with longer duration of CH. Conclusions The present findings suggest that episodic CH with dynamic bout period shifts may involve bout-associated FC changes in multiple discrete cortical areas within networks outside traditional pain processing areas. Dynamic changes in FC in frontal and dorsal attention networks between bout periods could be important for understanding episodic CH pathophysiology.

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.

Evidence-based treatments for cluster headache.

Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. The brief duration and severity of the attacks command the use of rapid-acting pain relievers. Inhalation of oxygen and subcutaneous sumatriptan are the two most effective acute therapeutic options for sufferers of CH. Several preventive medications are available, the most effective of which is verapamil. However, most of these agents are not backed by strong clinical evidence. In some patients, these options can be ineffective, especially in those who develop chronic CH. Surgical procedures for the chronic refractory form of the disorder should then be contemplated, the most promising of which is hypothalamic deep brain stimulation. We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition.

Physiopathologie de l’algie vasculaire de la face (AVF)

The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache.