Pathophysiology Of Cluster Headache Research Articles

Cluster Headache: Diagnosis and Treatment

Cluster headache is a rare yet exquisitely painful primary headache disorder occurring in either episodic or chronic patterns. The unique feature of cluster headache is the distinctive circadian and circannual periodicity in the episodic forms. The attacks are stereotypic--they are of extreme intensity and short duration, occur unilaterally, and are associated with robust signs and symptoms of autonomic dysfunction. Although the pathophysiology of cluster headache remains to be fully understood, there have been a number of recent seminal observations. To exclude structural mimics, patients presenting with symptoms suggestive of cluster headache warrant at least a brain magnetic resonance imaging (MRI) scan in their work-up. The medical treatment of cluster headache includes acute, transitional, and maintenance prophylaxis. Agents used for acute therapy include inhalation of oxygen, triptans, such as sumatriptan, and dihydroergotamine. Transitional prophylaxis refers to the short-term use of fast-acting agents. This typically involves either corticosteroids or an occipital nerve block. The mainstay of prophylactic therapy is verapamil. Yet, other medications, including lithium, divalproex sodium, topiramate, methysergide, gabapentin, and even indomethacin, may be useful when the headache fails to respond to verapamil. For medically refractory patients, surgical interventions, occipital nerve stimulation, and deep brain stimulation remain an option. As the sophistication of functional neuroimaging increases, better insight into the pathophysiological mechanisms that underlie cluster headache is expected.

Levels of nitric oxide metabolites in cerebrospinal fluid in cluster headache

The pathophysiology of cluster headache (CH) is only partly understood. Nitric oxide (NO), a potent vasodilator, has been suggested to be involved, and increased plasma levels of nitrite, a stable product on NO degradation, have been identified in the active period and in remission. The aim of our study was to investigate the role of NO in CH by measuring its oxidation products, nitrite and nitrate, in the cerebrospinal fluid (CSF), a biological compartment closer to the supposed focus of the disorder. We collected CSF from 14 episodic CH patients. Lumbar puncture (LP) was performed at two occasions: in active period between headache attacks, and in remission, not earlier than three weeks after the last CH attack. Eleven healthy volunteers served as controls. To estimate NO production, we determined the levels of NO-oxidation end products (NOx), that is, the sum of nitrite and nitrate, by using capillary electrophoresis. CH patients in the active period had significantly increased NOx levels (mean 9.3, 95% confidence interval [CI] 8.5-10.1) compared with those in remission (mean 7.6, 95% CI 6.9-8.2; p < 001) and control subjects (mean 6.2, 95% CI 4.9-7.5; p < 0.001). CH patients also had statistically significant enhanced NOx levels in remission compared with those of control subjects (p = 0.034). CSF was also analysed with regard to inflammatory parameters and protein content. CSF showed signs of pleocytosis or oligoclonal bands or albumin increase in 43% of CH patients although these results were not conclusive. We suggest that CH patients have a generally raised NO tonus, both in the active period and in remission. We interpret these results as indications of a basal hyperfunction of the L-arginine-NO pathway, possibly as an expression of inflammatory activity, and sensitization of pain pathways. This is the first study analysing NOx in CSF in CH, and the results support NO involvement in the pathogenesis of CH.

Role of Sphenopalatine Ganglion Neuroablation in the Management of Cluster Headache

Cluster headache is a primary neurovascular headache. It is a strictly unilateral head pain that is associated with cranial autonomic symptoms and usually follows circadian and circannual patterns. Chronic cluster headache, which accounts for about 10% to 15% of patients with cluster headache, lacks the circadian pattern and is often resistant to pharmacological management. The sphenopalatine ganglion (SPG), located in the pterygopalatine fossa, is involved in the pathophysiology of cluster headache and has been a target for blocks and other surgical approaches. Percutaneous radiofrequency ablation of the SPG was shown to have encouraging results in those patients with intractable cluster headaches.

Genetics of Cluster Headache

Cluster headache (CH) is a rare, excruciating primary headache disorder. A genetic basis has been suggested by family and twin studies, but the mode of transmission seems to vary and the amount of heritability is unclear. The number of genetic association studies investigating variants implicated in the pathophysiology of CH is limited. The HCRTR2 1246G > A and the ADH4 925A > G polymorphisms have been associated with CH. The former has been confirmed and may affect the hypothalamic hypocretin system. However, it only appears to account for a part of the genetic susceptibility for CH, and additional genetic and environmental factors are likely implicated. Pharmacogenetic studies have suggested that the GNB3 825C > T polymorphism may modify treatment response to triptans among CH patients by altering the signal transduction cascade via G protein-coupled receptors. Genetic studies in CH are notoriously difficult due to the complex nature of the disorder and the low prevalence of CH.

Cluster Headache

Event Abstract Back to Event Cluster Headache Frederick G. Freitag1* 1 Diamond Headache Clinic, United States Learning Objectives: Review the current understanding of the pathophysiology of cluster headache Be able to recognize the clinical features of cluster headache Be able to develop a strategy for treatment of cluster headache Cluster headache is divided into multiple subtypes under the IHC classification criteria. The vast majority of patients present with episodic cluster headache (3.1.1). This will be the focus of the presentation. The syndrome is characterized by repeated attack of severe unilateral headache in the orbit and temporal areas lasting 15 to 180 minutes. The attack is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, eyelid edema, forehead and facial sweating, miosis, ptosis (partial Horner’s syndrome), and a sense of restlessness or agitation. The attacks may be up to 8 per day and may occur daily for several weeks to several months. There are both circadian and circannual features to the disorder. The pathogenesis of Cluster headache is poorly understood Treatment of Cluster Headache includes abortive treatment with Oxygen at 100% concentration, sumatriptan (SC, IN), dihydroergotamine mesylate (SC, IN), Zolmitriptan (IN), ergotamine tartrate (SL) and 4 % aqueous lidocaine (IN). Preventive treatment is the mainstay of therapy and includes a variety of agents acting on serotonin receptors such as Methylergonovine, Ergotamine tartrate, Naratriptan, and Frovatriptan. Corticosteroids are especially helpful at 2x physiologic doses at the onset of a series of attacks. Other preventative medicines include Cyproheptadine, lithium carbonate, Verapamil, Nimodipine, Divalproex sodium, Topiramate, Indomethacin, and melatonin. Other approaches include Greater Occipital Nerve blocks, psychedelics including peyote mushroom tea among others. In patients refractive to medical therapy traditionally use revival of the technique of Horton from Mayo Clinic with parenteral administration of histamine may prove useful. Other approaches include repetitive IV DHE, and surgical therapies. Conference: Paroxysmal Neurology Symposium, Chicago, United States, 7 Apr - 7 Apr, 2010. Presentation Type: Oral Presentation Topic: Abstracts Citation: Freitag FG (2010). Cluster Headache. Front. Neurol. Conference Abstract: Paroxysmal Neurology Symposium. doi: 10.3389/conf.fneur.2010.07.00002 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Apr 2010; Published Online: 07 Apr 2010. * Correspondence: Frederick G Freitag, Diamond Headache Clinic, Chicago, IL, United States, dhcdoc@aol.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Frederick G Freitag Google Frederick G Freitag Google Scholar Frederick G Freitag PubMed Frederick G Freitag Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Cluster Headache and Alpha 1-antitrypsin Deficiency

Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin (alpha(1)-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. alpha(1)-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any association between CH and a genotype that does not match the homozygous wild type for alpha(1)-AT. Interestingly, there is a significant difference of CH attack frequency in patients who are heterozygous or homozygous M allele carriers. We conclude that the presence of an S or Z allele is associated with higher attack frequency in CH.

The electrophysiology of cluster headache

Cluster headache (CH) is a neurovascular headache disease characterized by recurrent, strictly unilateral, severe pain attacks. Despite its typical clinical features, including circadian rhythm of the attacks and ipsilateral autonomic dysfunction, the underlying pathophysiology of CH is still unclear. Electrophysiological data point to central disinhibition of the trigeminal nociceptive system as one of the key mechanisms of CH pain. Therefore, altered habituation pattern and changes within trigeminal-facial neuronal circuits due to central sensitization seem to be involved. One biochemical correlate is probably represented in dysfunctions of serotonergic raphe nuclei-hypothalamic pathways. Structural and functional imaging data show an alteration of hypothalamic structures in CH patients, supporting the hypothesis that the hypothalamus, according to its function as a circadian pacemaker, plays a pivotal role in CH pathology. Cortical and brainstem reflexes are reviewed to illuminate the pathophysiology of CH.

Cluster headache, hypothalamus, and orexin

Cluster headache (CH) is a highly disabling condition resulting in severe, recurrent unilateral bouts of pain and accompanying autonomic symptoms. This review describes some current views regarding the underlying pathophysiology covering the pain and cranial autonomic (parasympathetic) activation, and highlights the potential importance of the hypothalamus in CH. The hypothalamus is known to modulate many functions and has been shown to be involved in the pathophysiology of a variety of primary headaches, including CH. Hypothalamic structures are likely to underlie the circadian and circannual periodicity of attacks and contribute to the pain and autonomic disturbances. We discuss the hypothalamic involvement in CH and modulation of trigeminovascular processing and examine the emerging involvement of the hypothalamic orexinergic system as a possible key pathway in CH pathophysiology.

Cluster headache: pharmacological treatment and neurostimulation

Cluster headache is a primary headache syndrome that is characterized by excruciatingly severe, strictly unilateral attacks of orbital, supraorbital or temporal pain, which last 15-180 min and are accompanied by ipsilateral autonomic manifestations (e.g. lacrimation and rhinorrhea). The attacks typically occur with circadian rhythmicity, being experienced at fixed hours of the day or night. In episodic cluster headache, attacks usually occur daily in 6-12-week bouts (cluster periods) followed by remission periods. In chronic cluster headache there is no notable remission. Cluster headache attacks reach full intensity very quickly and abortive agents need to be administered without delay. The pathophysiology of cluster headache is imperfectly understood and treatment has so far been mainly empirical. However, neuroimaging studies have prompted the successful use of hypothalamic stimulation to treat the condition. More recently, the less invasive technique of occipital nerve stimulation has shown promise in drug-refractory chronic cluster headache. This Review discusses both acute and preventive treatments for cluster headache and includes suggestions of how to use the available medications. The rationale, study results and selection criteria for neurostimulation procedures are also summarized, as are the disadvantages of these procedures.

Myofascial trigger points in cluster headache patients: a case series

Active myofascial trigger points (MTrPs) have been found to contribute to chronic tension-type headache and migraine. The purpose of this case series was to examine if active trigger points (TrPs) provoking cluster-type referred pain could be found in cluster headache patients and, if so, to evaluate the effectiveness of active TrPs anaesthetic injections both in the acute and preventive headache's treatment. Twelve patients, 4 experiencing episodic and 8 chronic cluster headache, were studied. TrPs were found in all of them. Abortive infiltrations could be done in 2 episodic and 4 chronic patients, and preemptive infiltrations could be done in 2 episodic and 5 chronic patients, both kind of interventions being successful in 5 (83.3%) and in 6 (85.7%) of the cases respectively. When combined with prophylactic drug therapy, injections were associated with significant improvement in 7 of the 8 chronic cluster patients. Our data suggest that peripheral sensitization may play a role in cluster headache pathophysiology and that first neuron afferent blockade can be useful in cluster headache management.

Reduced Habituation of Trigeminal Reflexes in Patients with Episodic Cluster Headache During Cluster Period

A growing body of evidence supports the pivotal role of the hypothalamus in the pathophysiology of cluster headache (CH). On the basis of animal studies, it has been suggested that a hypothalamic dysfunction can lead to a habituation deficit of brainstem reflex responses, as result of a stress-like condition. Taking into account these findings, we tested the hypothesis that habituation of brainstem reflexes may be impaired in CH patients. The habituation phenomenon of the late components (R2 and R3) of the blink reflex was studied in 27 CH patients during the cluster period, in 22 migraine patients interictally and in 20 control subjects. A significant habituation deficit in the R2 and R3 components was found in CH compared with both controls and migraineurs. The lack of habituation in CH, more pronounced than in migraine, points to abnormal processing of sensory stimuli at the trigeminal level that could be driven by hypothalamic dysfunction during the cluster period.

Cluster headache: from treatment to pathophysiology

This key note lecture illustrates the role of clinical developments in stimulating research and discovery in the area of the pathophysiology of cluster headache (CH) and other trigeminal autonomic cephalalgias (TACs), reviewing the physiological, biochemical and neuroimaging data that have suggested involvement of the hypothalamus in CH pathogenesis. These findings suggested the use of deep brain stimulation as a treatment for chronic drug-resistant CH. The typical circadian and circannual periodicity of CH attacks were the fundamental clinical characteristics that shifted focus from peripheral hypotheses to the idea of central origin for this headache form. Functional neuroimaging demonstrated that TACs are associated with activation of the posterior hypothalamus and there is clinical evidence that patients who suffer from CH have altered biological rhythms. Furthermore, the principal seat of biorhythm regulation - the hypothalamus - is known to have a modulatory role on nociceptive and autonomic pathways, specifically trigemino-vascular nociceptive pathways. Future research will elucidate why neuromodulatory approaches are effective in CH and other TACs, determine whether the hypothalamus is itself the generator of CH attacks, or whether it is activated in response to a generator situated elsewhere, and identify pharmacological treatments that directly target the hypothalamus.

Trigemino‐Cervical Reflex Abnormalities in Patients With Migraine and Cluster Headache

Head pain arises within the trigeminal nociceptive system. Current theories propose that the trigeminal system is intimately involved in the pathogenesis of migraine. Short-latency responses can be recorded in sternocleidomastoid muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex could be a suitable method to evaluate the trigeminal system in migraine and CH. The aim of the present study was to further elucidate the pathophysiology of migraine and cluster headache (CH) with special reference to the involvement of the central trigeminal system in the different forms of primary headache. The trigemino-cervical reflex was investigated in 15 healthy subjects, in 15 patients having migraine with aura, in 15 patients with migraine without aura, and in 10 patients with CH. Significant abnormalities were observed in a great number of patients with both types of migraine and CH during the headache attacks, but only in migraine patients during the interictal period. The alterations are bilateral in migraine, unilateral in CH. Our results further support the relevance of brainstem mechanisms in the pathogenesis of migraine rather than of CH. These data, taken together with that from experimental head pain and functional imaging studies, demonstrate that primary headache syndromes may be distinguished on a functional basis by areas of activation specific to the clinical syndrome.

CGRP-Receptor Antagonism in Migraine Treatment

Primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. Associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment by administration of a triptan (5-HT(1B/1D) agonist) results in alleviation of the headache and normalization of the elevated CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of the trigeminal sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists, which would predictably have less cardiovascular side effects as compared to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reported to be efficacious in the relief of acute attacks of migraine.

Cluster headache: A review of neuroimaging findings

Classified as a trigeminal autonomic cephalalgia, cluster headache is characterized by recurrent short-lived excruciating pain attacks, which are concurrent with autonomic signs. These clinical features have led to the assumption that cluster headache's pathophysiology involves central nervous system structures, including the hypothalamus. In the past decade, neuroimaging studies have confirmed such clinically derived theory by uncovering in vivo neuronal changes located in the inferior posterior hypothalamus. Using a variety of neuro-imaging techniques (functional , biochemical , and structural ) in patients with cluster headache, we are making improvements in our understanding of the role of the brain in this disorder. This article summarizes neuroimaging findings in cluster headache patients, describing neuronal changes that occur during attacks and remission, as well as during hypothalamic stimulation.

Cluster headache and head trauma: Is there an association?

This article discusses what is known of and written regarding the possible association of cluster headache and head trauma. There is additional discussion of conditions other than direct head trauma that are also seen in association with cluster headache. These conditions bring into question the concept of primary versus secondary cluster headache and raise the possible need to expand the category of secondary cluster headache. With increasing knowledge of the pathophysiology of cluster headache, the potentially causative role of head trauma in the development of cluster headache may become better defined.

Gene Expression Profiling in Cluster Headache: A Pilot Microarray Study

Cluster headache (CH) is a primary neurovascular headache disorder characterized by attacks of excruciating pain accompanied by ipsilateral autonomic symptoms. CH pathophysiology is presumed to involve an activation of hypothalamic and trigeminovascular systems, but inflammation and immunological mechanisms have also been hypothesized to be of importance. To identify differentially expressed genes during different clinical phases of CH, assuming that changes of pathophysiological importance would also be seen in peripheral venous blood. Blood samples were drawn at 3 consecutive occasions from 3 episodic CH patients: during attacks, between attacks and in remission, and at 1 occasion from 3 matched controls. Global gene expression was analyzed with microarray tehnology using the Affymetrix Human Genome U133 2.0 Plus GeneChip Set, covering more than 54,000 gene transcripts, corresponding to almost 22,000 genes. Quantitative RT-PCR on S100P gene expression was analyzed in 6 patients and 14 controls. Overall, quite small differences were seen intraindividually and large differences interindividually. However, pairwise comparisons of signal values showed upregulation of several S100 calcium binding proteins; S100A8 (calgranulin A), S100A12 (calgranulin C), and S100P during active phase of the disease compared to remission. Also, annexin A3 (calcium-binding) and ICAM3 showed upregulation. BIRC1 (neuronal apoptosis inhibitory protein), CREB5, HLA-DQA1, and HLA-DQB1 were upregulated in patients compared to controls. The upregulation of S100P during attack versus remission was confirmed by quantitative RT-PCR analysis. The S100A8 and S100A12 proteins are considered markers of non-infectious inflammatory disease, while the function of S100P is still largely unknown. Furthermore, upregulation of HLA-DQ genes in CH patients may also indicate an inflammatory response. Upregulation of these pro-inflammatory genes during the active phase of CH has not formerly been reported. Data from this pilot microarray study provide a basis for further studies in CH.

Quantitative Sensory Testing in Cluster Headache: Increased Sensory Thresholds

To determine if recently reported changes in sensory thresholds during migraine attacks can also be seen in cluster headache (CH), we performed quantitative sensory testing (QST) in 10 healthy subjects and in 16 patients with CH. Eight of the patients had an episodic CH and the other eight a chronic CH. The tests were performed on the right and left cheeks and on the right and left side of the back of the hands to determine the subjects' perception and pain thresholds for thermal (use of a thermode) and mechanical (vibration, pressure pain thresholds, pin prick, von Frey hairs) stimuli. Six patients were examined in the attack-free period. Three were also willing to repeat the tests a second time during an acute headache attack, which was elicited with nitroglycerin. The healthy subjects performed the experiments in the morning and evening of the same day to determine if sensory thresholds are independent of the time of day. If they were, this would allow estimation of the influence of the endogenous cortisone concentration on these thresholds. The control group showed no influence of the time of day on the thresholds. There was a significant difference in pain sensitivity between the back of the hands and the cheeks (P<0.05): higher thresholds were found on the back of the hands. The thresholds generally exhibited little intersubject variability, indicating that QST is a reliable method. There was also a significant difference between the test areas in the patient group (P<0.001): the cheeks were also more sensitive than the back of the hands. In comparison with reference data of healthy volunteers, the detection thresholds were increased in the patients on both test areas. These were statistically significant for warmth, thermal sensory limen (TSL), heat and pressure on the back of the hands (P<0.04) and for the warmth and TSL thresholds on the cheeks (P<0.05). There were no differences in the thresholds regardless of whether the patients were examined in or outside of a cluster bout. Furthermore, we found no cutaneous allodynia in the three patients tested during an attack. The increased sensory thresholds on the cheeks as well as on the back of the hands are in agreement with an increased activation of the patients' antinociceptive system. The seasonal variation and the temporal regularity of single attacks as well as the findings in imaging studies indicate that the hypothalamus is involved in the pathophysiology of CH. In view of the strong connectivity between the hypothalamus and areas involved in the antinociceptive system in the brainstem, we hypothesize that this connection is the reason for the increased sensory thresholds in CH patients found in our study.

Impaired thermal perception in cluster headache

Cluster headache is characterized by attacks of severe periorbital pain. Repetitive burst activity in afferent fibers may induce plastic alterations in somatosensory synaptic processing as a prerequisite for recurring and chronic pain. This psychophysical study addressed hypothesized dysfunctions in craniofacial somatosensory processing in cluster headache disease. Thermal and mechanical sensory functions in the periorbital region were assessed by quantitative sensory testing (QST) in 25 cluster headache patients and 60 healthy volunteers. Perception of warmth (p<0.01), cold (p<0.000001), and pressure pain (p<0.05) was reduced on the cluster side as compared with the contralateral asymptomatic side. In contrast to healthy volunteers, warm detection threshold (WDT) and thermal sensory limen (TSL) on one side did not positively correlate with the other side. WDT and TSL negatively correlated with the elapsed time since last attack. All patients showed QST abnormalities on the headache side in comparison to healthy controls. Loss of sensory functions strongly preponderated gain. Several lines of evidence indicate a pivotal role of the hypothalamus in cluster headache pathophysiology. The impairment of warm and cold perception in patients may be based upon a dysfunction of the hypothalamus which is strongly involved in thermosensory control.

Opioidergic changes in the pineal gland and hypothalamus in cluster headache: A ligand PET study

Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.