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Pathophysiology of cluster headache: A trigeminal autonomic cephalgia

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Pathophysiology of cluster headache: A trigeminal autonomic cephalgia

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Abstract

Cluster headache is a form of primary neurovascular headache with the following features: severe unilateral, commonly retro-orbital, pain accompanied by restlessness or agitation, and cranial (parasympathetic) autonomic symptoms, such as lacrimation or conjunctival injection. It occurs in attacks typically of less than 3 h in length and in bouts (clusters) of a few months during which the patient has one or two attacks per day. The individual attack involves activation of the trigeminal-autonomic reflex; thus, such headaches can be broadly classified with the other trigeminal-autonomic cephalgias, such as paroxysmal hemicrania and the syndrome of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Observations of circadian biological changes and neuroendocrine disturbances have suggested a pivotal role for the hypothalamus in cluster headache. Functional neuroimaging with PET and anatomical imaging with voxel-based morphometry have identified the posterior hypothalamic grey matter as the key area for the basic defect in cluster headache.

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... Consequences are lacrimation, conjunctival injection, nasal congestion, and dilation of the ophthalmic and carotid arteries. 103 The latter likely causes compression of sympathetic nerve fibres, leading to Horner's syndrome and, in some cases, Harlequin syndrome. 63,104,105 The increased parasympathetic innervation modulates nociception in trigeminal nerve endings, releasing neurotransmitters, such as the vasoactive intestinal polypeptide. ...
... 63,104,105 The increased parasympathetic innervation modulates nociception in trigeminal nerve endings, releasing neurotransmitters, such as the vasoactive intestinal polypeptide. 103 Thus, the reflex arc is not just an epiphenomenon but relevant to the pathophysiology of the attacks. 103 Accordingly, researchers soon modulated the activity of the ganglion through electric stimulation and achieved pain relief and a reduction in the attack frequency in many patients. ...
... 103 Thus, the reflex arc is not just an epiphenomenon but relevant to the pathophysiology of the attacks. 103 Accordingly, researchers soon modulated the activity of the ganglion through electric stimulation and achieved pain relief and a reduction in the attack frequency in many patients. 106 Others successfully infiltrated the sphenopalatine ganglion, using, in contrast to Sluder (see above), onabotulinumtoxin A. 107,108 Let it be emphasised that unilateral and bilateral cranial autonomic symptoms may occur during migraine attacks as well. ...
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Objective To summarise the history of cluster headache evolving concepts and growing insights. Background Excruciating pain, activation of the parasympathetic nervous system, and circadian rhythmicity characterise cluster headache attacks. Results We find the oldest descriptions of patients suffering from the disorder in case reports of the 17th and 18th centuries. Only in the 19th and early 20th centuries did physicians start hypothesizing its cause. Initially, many researchers suspected the origin of the pain in peripheral nerves or blood vessels. However, eventually, they understood that the cause of the disease lies in the brain. In 1998, Positron emission tomography studies revealed increased activity of the posterior hypothalamus, whose role remains incompletely understood. Only recently have researchers realised that being diseased implies more than dysfunction. Recent studies analysed the consequences of cluster headache for each patient. Many struggle to deal with the disorder even in the absence of pain. Conclusion Physicians have been aware of this type of pain for at least 300 years. Only when researchers studied pathological anatomy and physiology did knowledge accrue. A more comprehensive picture of the disease severity emerged when they also considered its consequences.
... One of the three patients who were treated with repeat GKRS developed facial numbness and paresthesia. Trigeminal sensory disturbances or deafferentation pain were observed in Ford, 1998 [21] Excellent-free of cluster headache and took minimal or no medication Good-CHs were reduced in severity and frequency by 50% and preventive and abortive medications were continued Fair-improvement of 25% or less, with continued use of preventive and abortive medications Failure-no relief at all McClelland, 2006 [2] Excellent-free of cluster headache and took minimal or no medication Good-CHs were reduced in severity and frequency by 50% and prophylactic medications were continued Fair-improvement of 25% or less, with continued use of prophylactic medications Failure-no relief at all Donnet, 2006 [1] Excellent-free of cluster headache and took minimal or no medication Good-CHs were reduced in severity and frequency by 50% and prophylactic medications were continued Fair-improvement of 25% or less, with continued use of prophylactic medications Failure-no relief at all Ott, 2010 [12] NS Kano, 2011 [4] BNI score: Grade I (pain free, no use of medication), grade II (occasional pain but off medication), grade IIIa (no pain and continued use of medication required), grade IIIb (some pain, controlled with medication), grade IV (pain improved but not adequately controlled on medication), grade V (no pain relief whatsoever) BNI grades I-IIIb representing favorable pain relief, whereas BNI grades IV and V were defined as treatment failures Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... Ford et al. first investigated GKRS targeting the TN for the treatment of CH. The TN was targeted to interrupt the afferent branch of the trigeminal-autonomic reflex, which is thought to trigger and mediate the pain attacks of CH patients [12]. All six patients treated in their study had considerable pain reduction, which persisted in five patients after a median follow-up period of 11.5 months. ...
... Some authors have proposed that this excessive trigeminal damage may be related to an abnormal radiation sensitivity of the TN in CH patients [14]. A dysfunctional trigeminal-autonomic system, which is thought to be the pathophysiology of CH, may be the basis of such excessive radiation sensibility of the trigeminal pathways [12]. In patients treated with combined targeting of the TN and SPG, the simultaneous ablation of two different points along the trigeminal pathways may also have had a role in causing these excessive sensory disturbances. ...
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Cluster headache (CH) is a severe trigeminal autonomic cephalalgia that, when refractory to medical treatment, can be treated with Gamma Knife radiosurgery (GKRS). The outcomes of studies investigating GKRS for CH in the literature are inconsistent, and the ideal target and treatment parameters remain unclear. The aim of this systematic review is to evaluate the safety and the efficacy, both short and long term, of GKRS for the treatment of drug-resistant CH. A systematic review of the literature was performed to identify all clinical articles discussing GKRS for the treatment of CH. The literature review revealed 5 studies describing outcomes of GKRS for the treatment of CH for a total of 52 patients (48 included in the outcome analysis). The trigeminal nerve, the sphenopalatine ganglion, and a combination of both were treated in 34, 1, and 13 patients. The individual studies demonstrated initial meaningful pain reduction in 60–100% of patients, with an aggregate initial meaningful pain reduction in 37 patients (77%). This effect persisted in 20 patients (42%) at last follow-up. Trigeminal sensory disturbances were observed in 28 patients (58%) and deafferentation pain in 3 patients (6%). Information related to GKRS for CH are limited to few small open-label studies using heterogeneous operative techniques. In this setting, short-term pain reduction rates are high, whereas the long-term results are controversial. GKRS targeted on the trigeminal nerve or sphenopalatine ganglion is associated to a frequent risk of trigeminal disturbances and possibly deafferentation pain.
... The temporal and circadian aspects support a central theory, and the trigeminovascular-autonomic reflex has been widely accepted as part of the peripheral theory. 4 A few hypotheses could be postulated for the localized TMJ pain based on the peripheral theory. ...
... Sympathetic neurons from the superior cervical ganglion reach the TMJ along the vessels and play a role in pain reception and monitoring of blood volume. 4 During a CH attack, patients may also experience miosis or ptosis related to disruption to the sympathetic neurons. Fibers from the superior cervical ganglion destined to innervate the eye are compromised by carotid dilatation as they traverse the carotid canal and may sustain neuropraxic injury. ...
... Fibers from the superior cervical ganglion destined to innervate the eye are compromised by carotid dilatation as they traverse the carotid canal and may sustain neuropraxic injury. 4 During a CH attack, there is an activation of the trigeminovascular-autonomic reflex with the release of calcitonin gene-related peptide (CGRP), and if CGRP is administered to a CH patient in an active disease phase, it triggers a CH attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. 5 This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. ...
Article
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A cluster headache attack with ipsilateral temporomandibular joint pain: a case report - Tommy Lik Hang Chan, David Dongkyung Kim, Werner J. Becker
... While pain in cluster headache is the sentinel symptom, the cranial autonomic features are also key symptoms in the classification of cluster headache [1] and that as a TAC [58]. The trigeminal and parasympathetic pathways form the reflex arc, which contribute to these observed symptoms [58,59]. ...
... While pain in cluster headache is the sentinel symptom, the cranial autonomic features are also key symptoms in the classification of cluster headache [1] and that as a TAC [58]. The trigeminal and parasympathetic pathways form the reflex arc, which contribute to these observed symptoms [58,59]. Electrical stimulation of the parasympathetic pathway via the sphenopalatine ganglion has been shown to induce attacks [60] as well as treat or prevent cluster attacks [61,62]. ...
Article
Introduction Current treatment options for the prevention of cluster headache are largely unsatisfactory. The therapies have a limited evidence base and often significant side effects issues. The involvement of the calcitonin gene-related peptide (CGRP) pathway in primary headache disorders, especially migraine, had led to recent success in the development of new migraine therapies. The CGRP pathway also plays a role in the pathophysiology of cluster headache, so CGRP pathway monoclonal antibodies have been studied in the prevention of cluster headache attacks. Areas covered This review will outline the trials of fremanezumab and galcanezumab, the only two CGRP pathway monoclonal antibodies that have undergone trials in cluster headache prevention thus far. This review will highlight key efficacy and safety outcomes from the trials. Expert opinion Galcanezumab was shown to be efficacious in reducing the frequency of attacks in episodic cluster headache, while fremanezumab failed its primary endpoint in episodic cluster headache. Both fremanezumab and galcanezumab trials in chronic cluster headache were terminated after futility analysis predicting failure of both trials to fulfil their primary endpoint. The role of CGRP in cluster headache supports ongoing trials of the remaining CGRP pathway monoclonal antibodies and gepants for preventive and acute treatment. A Panglossian view would include targeting neuropeptides involved in parasympathetic signalling in cluster headache, such as pituitary adenylate cyclase-activating peptide (PACAP); such targets warrant exploration in the search of new cluster headache treatments.
... The clinical features of CH are its trigeminal distribution of the pain, its associated autonomic symptoms, and its episodic pattern, the latter being arguably the most important in distinguishing it from migraine [5]. Localizing this disease process has proved to be difficult. ...
... Blood vessel dilation, mediated by vasodilator peptides such as calcitonin gene-related peptide (CGRP) released by the trigeminal nerve fibers, and parasympathetic symptoms including lacrimation, nasal congestion, or miosis implicate this theory. Additionally, imaging findings have shown the ipsilateral, posterior hypothalamus to be activated during CH attacks, further solidifying its postulated role in the CH's circadian rhythmicity and neuroendocrine changes, including elevated testosterone levels during active cluster periods [5]. ...
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Purpose of Review The treatment of cluster headache has evolved to include a handheld neuromodulation device and a monoclonal antibody in addition to more traditional agents. Recent Findings Galcanezumab is an approved treatment for episodic cluster headache. The non-invasive vagal nerve stimulator has been shown to be effective as a treatment for episodic cluster headache. Dedicated pituitary imaging may not be necessary with a normal MRI of the brain. Summary Cluster headache is the most common trigeminal-autonomic cephalalgia, characterized by unilateral, frequent, debilitating attacks associated with ipsilateral autonomic symptoms. Attacks have a circadian and, often, seasonal pattern with periods of remission that can last months to years in episodic patients. Though a rare disease, an increasing number of studies have revealed novel targets for treatment. Treatment in cluster headache should focus on early intervention to reduce frequency of attacks and the length of the cycle, which improves outcomes and disability. Acute therapy is used to treat attacks, while bridging and preventive therapies are combined to reduce cycle length. Case 1: A 43-year-old man presents with the chief complaint of severe headaches. Upon general examination, he seems uncomfortable, agitated, and exhausted. He states that he hasn’t “slept in over a week because of debilitating headaches.” His headaches start around the same time every night: when he lays down to go to sleep. The pain is described as sharp, like a “hot poker” to his left eye. His partner has noticed that his eye droops and turns red when the pain starts. The attacks come on abruptly and prevent him from sleeping. The severe pain lasts 30 to 45 min, but he has mild-to-moderate pain that lingers for the rest of the night. He has seen his primary care physician, an allergist, and an ear, nose, and throat (ENT) specialist before coming to see a neurologist. Similar headaches occurred last year during the month of October as well. On further questioning, he reports that these headache attacks have been occurring almost yearly for the past 7 years. Each year, these headaches come on as the weather is changing and occur on a nightly basis for about 3 to 4 weeks.
... The pathophysiology of cluster headache remains unclear. However, previous studies have revealed that the cause of cluster headache may be both peripheral and central in origin [1,4]. One of the assumptions concerning the pathophysiology of cluster headache is the activation of the trigemino-vascular system, the parasympathetic nervous system, and the hypothalamus. ...
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Objective 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. Methods 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. Results 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). Conclusion 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.
... While the pathophysiology of cluster headache has not been entirely dissected, there are several proposed mechanisms described. These include a genetic predisposition [2], involvement of the trigeminovascular and cranial parasympathetic nervous systems and the role of the central nervous system and particularly of the hypothalamic region, which is thought to have a key role in the genesis of the attacks [12][13][14]. ...
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Purpose of review Among the spectrum of pain conditions, cluster headache represents one of the most severe. Targeted therapies for cluster headache are evolving thus improving the available therapeutic armamentarium. A better understanding of the currently available therapies, as well as new and emerging options, may aide physicians to manage affected sufferers better by evolving treatment guidance. Recent findings While classic first-line medications are useful in some patients with cluster headache, they are often accompanied by significant side effects that limit their use. Recently, novel treatments with better tolerability and decreased medication interactions have proven to be effective. A remarkable example of this is the blockage of the calcitonin gene-related peptide pathway with monoclonal antibodies, which may be a key element in the future treatment of cluster headache. The sphenopalatine ganglion and vagus nerve perform a critical role in the regulation of pain and the trigeminal autonomic reflex. Neuromodulation therapies targeting these structures have shown excellent tolerability and few significant adverse events, constituting a promising form of treatment. Finally, several potential therapeutic targets are examined in this review, such as small molecule CGRP receptor antagonists, known as gepants, and serotonin receptor 5-HT1F receptor agonists: ditans. Summary In summary, a deepening of the understanding of cluster headache mechanisms in recent years has driven the evolution of sophisticated therapeutic approaches that could allow a new era in the treatment of this difficult condition.
... For its innervation, both sympathetic and parasympathetic, the SPG is believed to play a part in the headache pain and cranial autonomic symptoms associated with cluster headache, which is a result of activation of the trigeminal-autonomic reflex. In cluster headache, post-ganglionic parasympathetic fibres from the SPG that innervate the cerebral and meningeal blood vessels are activated releasing neuropeptides that cause vessel dilation and/or activation of the trigeminal nociceptor fibres in the meninges, which is perceived as referred pain from the head by the sensory cortex [3]. ...
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Background In 1908 Sluder described a clinical picture of unilateral facial pain, lachrymation, rhinorrhea and mucosal congestion deriving from the Sphenopalatine Ganglion (SPG) irritation. We described a case of monolateral xerophthalmia, dry palate and mouth, deriving from SPG lesion after septoplasty that we called “SPG Deficit Syndrome”. Methods In our study a woman complaining functional nasal disorders and Computer Tomography (CT) images of a huge condro-vomerian septal spur in right nasal cavity, was underwent to septoplasty. After surgery she complained monolateral xerophthalmia, xerostomia and migraine. Results We formulated hypothesis of parasympathetic postgangliar nerve transmission interruption due to a lesion of effector fibers, supported by post-operative CT images of posterior wall of maxillary sinus lesion and by endoscopic evaluation of dryness of palatal mucosa and right nasal cavity. Conclusion To the best of our knowledge this is the first case of this kind of symptomatology reported as complication after septoplasty.
... The trigeminal cranial nerve and the trigeminovascular system rank among the cardinal peripheral structures that are involved in CH attacks pathogenesis. Moreover, the physiological trigeminal autonomic reflex with the corresponding parasympathetic nerve fibers synapsing in the SPG [25], seems to contribute to the genesis of CH attacks [26]. As a result of the parasympathetic system activation, there is evidence of intracranial vessels' dilation, plasma protein extravasation, local dural release of inflammatory mediators, and clinical evidence of ipsilateral facial autonomic symptoms [27]. ...
Article
Introduction: Although it causes a huge burden to sufferers, cluster headache (CH), remains an undertreated condition, partly due to the absence of established acute and prophylactic treatment options. New therapeutic approaches providing fast and safe relief from CH are needed. Areas covered: A systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendation on recently published (last 5 years) papers on CH treatment. The authors also collected preliminary results from ongoing trials on emerging therapeutic/preventive pharmacological and interventional approaches for CH. Studies and results are reviewed and discussed. Expert opinion: The complexity of CH pathophysiology prevents the definition of reliable acute and preventive treatments. In the real-world clinical setting, several treatments are combined to provide relief to patients and increase their quality of life. Drugs targeting neuropeptides or their receptors within the trigeminovascular network are of particular interest to prevent CH attacks. Calcitonin gene-related peptide (CGRP) blockade seems attractive and promising, but studies on anti-CGRP monoclonal antibodies indicated rather modest or even absence of a prophylactic effect. A deeper insight into CH pathophysiology, and combined approaches may lead the path to new, more effective and personalized CH therapies.
... 31,32 Desuden aktiveres den trigemino-autonome refleks, hvilket kan forklare smerteudbredelsen og de autonome symptomer. 33 ...
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Guidelines from the Danish Headache Society for treatment of headache disorders
... Transient stimulation of the spheno-palatine ganglion (SPG), chronic occipital nerve stimulation (ONS), and stimulation of retro-hypothalamic area by DBS are currently listed as invasive stimulation techniques [38]. Spheno-palatine ganglion stimulation (SPGS) has been proposed to work through several mechanisms, one of which is targeting the parasympathetic nervous system involved in the pathophysiology of trigeminal autonomic cephalalgias [64]. Pulsante® is a medical device, developed for SPGS to abort CH attacks in patients with chronic CH (CCH). ...
Article
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Deep Brain Stimulation (DBS) has been introduced as an innovative treatment for several neurological disorders, including Parkinson’s disease, essential tremor, and dystonia and it has been proven effective in helping individuals affected by these disorders; hence, enhancing their quality of life. DBS has also been investigated for the treatment of cluster and other primary headaches. Electrodes are surgically implanted into brain structures, for example the posterior hypothalamus in case of cluster headache. Hypothalamic DBS has been successfully used to treat patients with cluster headache and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). In these headache conditions, DBS may reduce headache frequency by half, however, some side effects have also been reported that are mainly related to infection where the electrodes are placed, syncope, and diplopia. Hypothalamic DBS is proposed to modulate neuronal structures that are directly or indirectly involved in detection or transmission of painful stimuli or in the processing of this information. Reports of the use of DBS for chronic migraine are not found in the literature. This commentary explores the medical hypothesis that DBS could be considered as a therapeutic option for intractable chronic migraine. This hypothesis is based on the commonalities between cluster headache and migraine in terms of some shared symptoms, and potential overlap of underlying mechanisms. However, due to the absence of clinical evidence supporting the use of DBS in CM, the fact that disease-specific optimization of DBS parameters must be considered carefully, and considering the optimal CNS structures to target are currently unknown, it is concluded that this interventional and invasive technique should be avoided for CM for the present time.
... CH has a lifetime prevalence of approximately 1/1000 [2], and it affects young adults, predominantly males [3,4]. The exact cause of CH is currently unknown [5,6], but it is thought to involve a synchronized abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system [7]. As some epidemiological studies revealed familial clustering, a genetic alteration has also been proposed [8][9][10][11]. ...
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Objective Cluster headache (CH) is a primary headache characterized by strictly unilateral, short-lasting severe headache attacks accompanied by at least one ipsilateral autonomic symptom. Our study aimed to determine whether CH patients had olfactory dysfunction and to correlate it with clinical characteristics.Materials and methodsTwenty patients and 57 healthy volunteers were included in the study. All participants were examined in the otorhinolaryngology outpatient clinics to exclude other clinical problems causing olfactory dysfunction. The Sniffin’ Sticks test was performed, and threshold (T), discrimination (D), identification (I) scores, and TDI global olfactory score were evaluated.ResultsThe CH patients had significantly lower threshold scores than healthy controls (6.9 ± 1.70 vs. 7.8 ± 1.08, p = 0.007). The mean threshold scores of CH patients during in-bout (n = 9) were significantly lower than CH patients during out-of-bout (n = 11) in subgroup analysis (5.9 ± 1.16 vs. 7.6 ± 1.76, p = 0.038). CH patients with left-sided headache had significantly lower discrimination scores compared to CH patients with right-sided headache (12.8 ± 1.24 vs. 14.4 ± 1.51, p = 0.03).Conclusion There is marked impairment in olfactory function in CH patients compared to healthy controls.
... Parasympathetic activation mediated by the trigeminal-autonomic reflex has been ascertained as the mechanism for the presentation of CAS in CH 31 . The trigeminal-autonomic reflex is a brainstem connection between the trigeminal nerve and facial cranial parasympathetic nerve outflow, which is activated by the stimulation of the trigeminovascular system 32 . ...
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Although cranial autonomic symptoms (CAS) are typical in cluster headache (CH), some individuals with CH show no CAS during their headache attacks. Probable cluster headache (PCH) is a subtype of CH that fulfils all but one criterion of CH. This study aimed to investigate the frequency and clinical features of CH and PCH without CAS in comparison to those with CAS. We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals. Of the 216 participants with CH and 26 with PCH, 19 (8.8%) and 7 (26.9%), respectively, did not have CAS. Participants with CH without CAS exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0–6.0] vs 8.0 [3.0–12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0–7.0] vs 7.0 [3.0–11.0], p = 0.042) than those with CAS. Among participants with PCH, headache intensity was less severe in participants without CAS than in those with CAS (numeric rating scale, 8.0 [7.0–8.0] vs 9.5 [8.0–10.0], p = 0.015). In conclusion, a significant proportion of participants with CH and PCH did not have CAS. Some clinical features of CH and PCH differed based on the presence of CAS.
... Cluster headache (CH) is an excruciating form of primary headache that is characterized by recurrent unilateral headache attacks accompanied by ipsilateral autonomic features. 1,2 Salient features of CH are its male predominance, circadian rhythmicity, and trigeminal autonomic features. CH is significantly associated with cigarette smoking, which is unique among all primary headache disorders, 3-6 but a satisfactory explanation for this relationship or pathogenetic association has not been established. ...
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Background and purpose: Epidemiologic data suggest that cluster headache (CH) is significantly associated with cigarette smoking. The aim of this study was to determine differences in features between patients with a smoking history and those who are never-smokers, using data from a prospective multicenter registry. Methods: Data used in this study were obtained from the Korean Cluster Headache Registry that collected data from consecutive patients diagnosed with CH. We compared clinical and demographic features between ever-smokers (current or former smokers) and never-smokers. Results: This study enrolled 250 patients who were diagnosed with CH, of which 152 (60.8%) were ever-smokers and 98 (39.2%) were never-smokers. The age at CH onset was significantly lower in the never-smoker group than in the ever-smoker group [27.1±12.9 years vs. 30.6±10.9 years (mean±standard deviation), p=0.024]. Seasonal rhythmicity (58.1% vs. 44.7%, p=0.038) and triptan responsiveness (100% vs. 85.1%, p=0.001) were higher in never-smokers, while other clinical features such as pain severity, duration, attack frequency, and associated autonomic symptoms did not differ significantly between the groups. The male-to-female ratio was markedly higher in ever-smokers (29.4:1) than in never-smokers (1.7:1). Conclusions: Most of the clinical features did not differ significantly between patients with a smoking history and never-smokers. However, the age at CH onset, sex ratio, and seasonal rhythmicity were significantly associated with smoking history.
... Imaging studies support this theory [36,37]. In addition, it is known that the trigemino-autonomic reflex is activated during attacks, which explains the pain distribution and the presence of autonomic symptoms [38]. ...
Article
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Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.
... Pain occurs from triggering of the trigeminothalamic system. Trigeminal activation starts from orofacial cutaneous impulses or neck musculature [15,16]. Whiplash injuries can activate cervicotrigeminal convergence mechanisms [17]. ...
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Postconcussion syndrome (PCS) is a complex set of symptoms occurring in a small percentage of patients following concussion. The condition is characterized by headaches, dizziness, cognitive difficulties, somatosensory issues, and a variety of other symptoms with varying durations. There is a lack of objective markers and standard treatment protocols. With the complexity created by premorbid conditions, psychosomatic issues, secondary gains, and litigations, providers often find themselves in a tough situation in the care of these patients. This article combines literature review and clinical insights with a focus on the underlying pathophysiology of PCS to provide a roadmap for evaluating and treating this condition.
... substance P) induce neurogenic inflammation and dilation of the meningeal blood vessels, which leads to pain perception [24]. The activation of the trigeminal nerve additionally triggers the physiological trigeminal autonomic reflex, which leads to the activation of the parasympathetic system with subsequent ipsilateral facial autonomic symptoms [25]. ...
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Introduction Cluster headache (CH) is the most common trigeminal autonomic cephalalgia with a significant need for novel treatment options. While the use of most of the acute CH medications is supported by clinical trials and based on a pathophysiological concept for the generation of pain, the scientific evidence for preventive CH medications is very limited. Areas covered This article reviews acute and preventive substances for the pharmacological treatment of CH with a focus on the mode of action of these drugs. We also summarized the clinical trial evidence and discuss future research directions. Expert opinion Recommendations for current pharmacological CH therapies, in particular for CH prevention, are often based on small open label studies with inconclusive results. Larger trials are missing. A shared pathophysiological mechanism of action of these preventatives does not exist. Future studies with CGRP(R) antibodies and novel substances with specific actions are needed and will thereby help to understanding the pathophysiology of CH.
... The results of this clinical trial have been previously published [16]. The sphenopalatine ganglion is located at the terminal end of the vidian canal, which contains the greater and lesser petrosal nerves that are preganglionic parasympathetic afferents synapsing in the sphenopalatine ganglion, which are shown to be involved in inducing the trigeminal autonomic reflex onset of cluster headaches [17]. Thus, stimulating the sphenopalatine ganglion would intercept this interaction and terminate the cluster headache. ...
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Background: The trigeminocardiac reflex (TCR) is a brainstem reflex following stimulation of the trigeminal nerve, resulting in bradycardia, asystole and hypotension. It has been described in maxillofacial and craniofacial surgeries. This case series highlights TCR events occurring during sphenopalatine ganglion (SPJ) neurostimulator implantation as part of the Pathway CH-2 clinical trial "Sphenopalatine ganglion Stimulation for Treatment of Chronic Cluster Headache". Methods: This is a case series discussing sphenopalatine ganglion neurostimulator implantation in the pterygopalatine fossa as treatment for intractable cluster headaches. Eight cases are discussed with three demonstrating TCR events. All cases received remifentanil and desflurane for anesthetic maintenance. Results: Each patient with a TCR event experienced severe bradycardia. In two cases, TCR resolved with removal of the introducer, while the third case's TCR event resolved with both anticholinergic treatment and surgical stimulation cessation. Conclusion: Each TCR event occurred before stimulation of the fixed introducer device, suggesting the cause for the TCR events was mechanical in origin. Due to heightened concern for further TCR events, all subsequent cases had pre-anesthesia external pacing pads placed. Resolution can occur with cessation of surgical manipulation and/or anticholinergic treatment. Management of TCR events requires communication between surgical teams and anesthesia providers, especially during sphenopalatine ganglion implantation when maxillary nerve stimulation is possible.
... The pathophysiology remains unclear; a neurovascular process involving the trigeminovascular system, trigeminal autonomic reflex, and posterior hypothalamus is hypothesized. 7 Functional imaging studies observed activation of the ipsilateral inferior hypothalamic gray matter in CH attacks. 8 These findings, together with the circadian periodicity of CH, influenced selection of candidate genes. ...
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Objective To identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model, for each cohort. The two cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified two replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10⁻¹⁷, OR [95%CI] = 1.51 [1.37–1.66]) and rs4519530 (p = 6.98 x 10⁻¹⁷, OR = 1.47 [1.34–1.61]) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10⁻⁸, OR = 1.36 [1.22–1.52]) and rs11153082 (p = 1.85 x 10⁻⁸, OR = 1.30 [1.19–1.42]) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome-wide-significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to e.g. treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. This article is protected by copyright. All rights reserved.
... limiting the exploration to glucose metabolism or cerebral blood flow, respectively (306). As a main result, both PET and MRI demonstrated the implication of posterior hypothalamic region and anterior cingular cortex in critical phase (307,308). ...
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Les radiotraceurs en TEP sont des outils de neuropharmacologie pour l’exploration des récepteurs couplés aux protéines G. L’une de leurs applications souhaitée est la mesure des taux de neurotransmetteurs endogènes dans la synapse. Aucun radiotraceur n’est validé pour mesurer indirectement les taux basal de neurotransmetteur. Si le développement des premiers radiotraceurs dopaminergiques a pu montrer leur sensibilité à la libération de dopamine lors de défi pharmacologique aux amphétamines, le modèle ligand récepteur a montré ses limites. Autrement dit, certains phénomènes jusque-là inexpliqués par le modèle sont été observés in vivo. Des hypothèses ont été formulées à l’aide des données obtenues in vitro pour repenser ce modèle. Elle indiquent notamment l’existence de 2 types de sites de liaison sur les récepteurs couplés au protéines G. Un agoniste se lie aux sites de haute affinité situés sur les récepteurs fonctionnels couplés aux protéines G. Un antagoniste se fixe sur les sites de basse affinité présents à la fois sur les récepteurs couplés et non couplés aux protéines G. Il semblerait que la propriété agoniste du radiotraceur soit plus favorable pour assurer une sensibilité au neurotransmetteur endogène de par sa compétition sur les même sites que ce dernier. A ce jour, la majorité des radiotraceurs TEP sont antagonistes. Cela pourrait expliquer le nombre important d’échec pour montrer leur sensibilité aux neurotransmetteur endogène. Dans ce travail de thèse, nous montrons en quoi le statut de radiotraceur agoniste TEP repense la neuropharmacologie au moyen d’une revue de la littérature. Par ailleurs, les expériences précliniques avec le nouveau radiotraceur agoniste 5-HT1A, le [18F]F13640, montrent de façon inédite sa sensibilité à la libération de sérotonine alors que ses homologues antagonistes indiquent des résultats plus contrastés. Ces éléments montrent l’importance de comparer l’imagerie des radiotraceurs agonistes et antagonistes. Ils promeuvent le développement du [18F]F13640 et des radiotraceurs agonistes pour alimenter l’approche fonctionnelle de la pharmacologie en TEP
... Cluster headache (CH) is a primary headache disorder and represents the most common type of the trigeminal autonomic cephalalgias (TACs) (Vikelis and Rapoport 2016; Headache Classification Committee of the International Headache Society IHS 2018). The pathophysiology of CH is still not completely understood, even though its clinical presentation is well characterized (Goadsby 2002;May 2005). CH is presumably a complex disease with genetic and environmental inputs (Schürks 2010). ...
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Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case–control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3′UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.
... Между тригеминоваскулярной системой и вегетативной нервной системой существует связь в виде тригеминовегетативного рефлекса. При этом афферентная часть этого рефлекса представлена тройничным нервом, а эфферентная -лицевым или большим каменистым нервом [15]. Считается, что тригеминовегетативный рефлекс играет важную роль в механизме кластерной головной боли [11]. ...
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Trigeminal autonomic cephalalgias (TACs) are rare but are the most intense primary headaches that severely limit patients’ ability to work and be socially active. This article reviews the modern classification of TACs, based on the International Classification of Headache Disorders-3, and the key differences between TAC types, as well as the pathophysiological mechanisms – the role of the trigeminovascular system, autonomic nervous system, hypothalamus and vagus nerve – and their relation to circadian rhythms. The sleep disturbances that can occur in patients with TACs, exacerbating the course of the disease, and the role of melatonin, hypothalamus and suprachiasmatic nucleus in these conditions are also discussed. In addition, current therapies for cluster headache are described, which include acute therapy and prophylactic therapy, with recommendations regarding the timing of prophylactic therapy discontinuation. The review also includes the available data on melatonin as well as new therapies such as CGRP monoclonal antibodies and neuromodulation, which includes the two most promising techniques: non-invasive vagus nerve stimulation and sphenopalatine ganglion microstimulation. Furthermore, the authors present the clinical case of a patient with chronic cluster headache, which was significantly reduced in frequency and intensity when melatonin was added to the therapy.
... The attacks are of two types -chronic and episodic. Chronic cluster(cCh) headaches are characterized by persistent attacks occurring regularly for more than one year, followed by a headache-free period that lasts for less than one month, whereas episodic cluster headaches(eCH) tend to last anywhere between 7 days to a year, followed by a headache-free period lasting for at least a month or more 23 . ...
Article
Cluster Headaches are one of the most arguably severe forms of primary headache syndrome that affects humans. Although it is relatively uncommon, it has a significant impact on the quality of life. It is a multifactorial disease that has risk factors ranging from seasonal changes, lifestyle habits to genetics. It occurs in 2 forms- Episodic and Chronic, each having its well-defined Diagnostic Criteria. Moreover, Cluster Headache has an exhaustive list of options for both Preventive and Abortive treatment. This article focuses on Cluster Headache, its pathophysiology, risk factors, differentials, and its diverse treatment modalities. In this study, an all-language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till October 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Cluster Headache," "Triptans," "Neuromodulation," and "Migraine." We explored the literature on Cluster Headache for its epidemiology, pathophysiology, the role of various genes and how they bring about the disease as well as its episodic and chronic variants, and treatment options. Although we have a wide variety of options for Preventive and Abortive therapy, newer more effective pharmacological and non-pharmacological interventions are being developed, and must be integrated into new treatment protocols.
... [35] The attacks are thought to be initiated by the hypothalamic activity. [36] Trigeminal neuralgia (TN) TN is a rare neuropathic pain disorder affecting the fifth CN and is characterized by sharp episodes of PAIN A RI paroxysmic pain lasting from a few seconds to minutes. Classical TN is caused by neurovascular compression most frequently by the superior cerebellar artery of the trigeminal nerve roots into the pons. ...
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he autonomic nervous system (ANS) controls the heart rate, blood pressure, digestion, respiration, pupillary reactivity, sweating, urination, sexual arousal, and regulates the functions of internal organs. This system provides the homeostasis of the cells, tissues, and organs throughout the body and protects against the disturbances imposed by the external and internal stressors. The ANS has three main divisions: The sympathetic nervous system (SNS), the parasympathetic nervous system (PNS), and the enteric nervous system. In general, the SNS and PNS have opposing effects. Each region belonging to the 'pain matrix' interacts with ANS. The descending system regulates pain and creates a regulatory effect by the contribution of aminergic neurotransmitters. Hypothalamus, amygdala, and periaqueductal gray are the main structures of this regulatory system. Dysfunction of the ANS is frequently observed in pain patients. The SNS induce, facilitate, or potentiate chronic pain. Increased responsiveness of injured sensory nerves to catecholamines, increased expression of α-1 adrenoreceptors on the primary afferent nociceptors and hyperalgesic skin, central sensitization rendering Aβ mechanoreceptors, enhanced discharge and sympathetic sprouting in dorsal root ganglia, central sensitization, and dysfunction of the pain modulation is proposed mechanisms. In this review, the anatomical, physiological and pathological aspects of ANS and pain, and laboratory tests to evaluate autonomic functions will be discussed. Pathophysiological role of ANS in migraine, trigeminal autonomic cephalgias, trigeminal neuralgia, peripheral nerve injuries, small fiber neuropathies, myofascial pain syndrome, fibromyalgia, painful joint diseases, visceral pain, phantom limb pain, complex regional pain syndrome, and spinal cord injury will be discussed.
Article
Objectives A recent approach to treatment of cluster headaches (CH) employs a microstimulator device for on‐demand neuromodulation of the sphenopalatine ganglion (SPG) during an acute CH attack. A precise anatomical localization of the SPG within the pterygopalatine fossa (PPF) is optimal in order to position the SPG electrode array. This study aims to investigate a novel approach for SPG localization using computed tomography angiographic studies (CTA). Materials and Methods Two independent observers identified the location of the SPG on 54 computed tomography angiographic studies (CTA) and measured its position relative to the vidian canal (VC). The qualitative confidence of identification, morphology, position within the PPF and its relation to vascular structures were also recorded. Results The SPG was detectable in 88% of cases with a variable position. The most frequent positions were superior (56%) and lateral (99%) relative to the VC with a mean (±SD) craniocaudal distance of 0.34 mm (±1.38) and a mean mediolateral distance of 3.04 mm (±1.2). However, in a considerable proportion of cases, the SPG was identified inferiorly to the VC (33%). Interobserver and intraobserver agreement for SPG location were moderate and strong respectively. Conclusions Since localization of SPG on CTAs is feasible and reproducible, it has future clinical potential to aid placement, optimal positioning and individualized programming of the electrode array.
Chapter
Headache is a very common medical complaint and has a long list of potential causes. The two main types of headache are primary or secondary. Cluster headache is the most painful of primary headache disorders and is one of the few headaches that is more prevalent in men. The diagnosis is clinical with imaging done to exclude other causes. It is marked by intermittent episodes of severe unilateral headache accompanied by autonomic symptoms. The exact mechanism is not known, but the discovery of hypothalamic and trigeminovascular dysfunction has guided some of the available treatments for the disease.
Article
Purpose of review: Cluster headache is a neurological disorder that patients consider the most severe pain they experience. Recognizing new treatments provides opportunities to advance current management. Recent findings: In contrast to the classic treatments, new options narrow in on the therapeutic target and are better tolerated. Calcitonin gene-related peptide (CGRP) pathway blockade with monoclonal antibodies (MABs), specifically the CGRP MAB galcanezumab, represents an important advance for episodic cluster headache, reducing the number of attacks during a bout. Neuromodulation strategies aimed at anatomical structures involved in the pathophysiology of cluster headache, such as the sphenopalatine ganglion and the vagus nerve, have proved effective in reducing the pain intensity and the number of attacks, and also to be safe and well tolerated. Summary: Our understanding of the pathophysiology of cluster headache and its management continues to grow. Novel treatments have appeared from research, such as neuromodulation and CGRP monoclonal antibodies. Nonetheless, chronic cluster headache and designing trials that select the correct sham in evaluating devices remain challenging.
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Background: Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified. Methods: We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS. Results: Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed. Conclusion: Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.
Article
Für die Therapie von Clusterkopfschmerzen, die konservativ nicht ausreichend beherrschbar sind, stellt die Stimulation des Ganglion sphenopalatinum (SPG-Stimulation) eine vielversprechende Methode der Therapieoptimierung dar. Sie erfordert allerdings eine enge Zusammenarbeit von Neurologen, die auf Clusterkopfschmerz spezialisiert sind, und erfahrenen Mund-Kiefer-Gesichtschirurgen. Die ersten Ergebnisse sind vielversprechend, bedürfen aber noch der Bestätigung in einer größeren Kohorte.
Article
Objective: To summarize the available evidence on disability, quality of life (QoL), and economic burden on societies of cluster headache (CH), and to present which tools have been used to measure these domains with indications for future research. Background: CH is a rare and severe primary headache. The focus of research on this disorder has historically been on understanding its complex pathophysiological mechanisms, whereas personal and global healthcare impact, disability, and QoL received little attention. Methods: We reviewed the available literature published up to 2019, identifying primary research addressing QoL, disability, impact, or impairment in daily life due to episodic CH (ECH) or chronic CH (CCH), and its societal impact. Results: CH produces a significant impact on sufferers QoL, disability, and work-related aspects, with a stronger impact on CCH than ECH. The CH-related disability appears to be greater than is seen in subjects with other primary headache disorders. Conclusions: Information about patient-reported outcomes is rarely collected in patients with CH. An effort to improve the amount of information on the lived experience of patients with CH is needed and CH-specific disability and QoL measures require development.
Chapter
Cluster headache (CH) is an entity of trigeminal autonomic cephalalgia with a prevalence of 0.1–0.2%. Ten to 15% of patients have a chronic form (CCH), at times intractable to medical therapies. In these patients, peripheral and central neuromodulation can provide another treatment modality. DBS in the ventral tegmental area (VTA) has been shown to be a safe and effective therapy for refractory CCH patients who failed conventional treatments. To date, over 120 patients have been reported in the literature since the first case report in 2001.
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Cluster headache is uniquely rhythmic in its occurrence both diurnally and annually. This has implications for the clinical approach to the patient but also for our understanding of the role of central structures in its pathological basis. Many intrinsic and extrinsic factors seem to influence CH rhythmicity, including genetics. The proclivity for attacks to occur at night and the possible association with particular sleep phenomena, including sleep apnea, have motivated a number of studies which has improved our understanding but many questions remain unanswered. The sleep-headache interaction seems to be bidirectional and possibly both direct and indirect. The latter could involve more disperse networks of homeostatic regulation, which may better encompass recent observations. Treatment of the headache patient with concurrent sleep problems can be particularly challenging, especially considering side-effects and interactions of commonly used medications. While current treatment guidelines do not incorporate chronotherapeutic thinking, some evidence may suggest that application of such principles on an individual level may be beneficial.
Article
There is renewed interest in the central role of the sphenopalatine ganglion (SPG) in cerebrovascular autonomic physiology and the pathophysiology of different primary and secondary headache disorders. There are diverse neural structures (parasympathetic, sympathetic and trigeminal sensory) that convene into the SPG which is located within the pterygopalatine fossa (PPF). This makes the PPF an attractive target to neuromodulatory interventions of these different neural structures. Some experts advocate for the nasal application of local anesthetics as an effective route for SPG block with the belief that the local anesthetic can freely access the PPF. It is time to challenge this historical concept from the early 1900s. In this daring discourse, I will review anatomical studies, CT and MRI reports to debunk this old myth. Will provide anatomical evidence to explain that all these assumptions are untrue and the local anesthetic has to magically ‘travel’ a distance of 4–12 mm of adipose and connective tissue to reach the SPG in sufficient concentration and volume to effectively induce SPG blockade. Future research should focus on assessing a clinical biomarker to confirm SPG blockade. It could be regional cerebral blood flow or lacrimal gland secretion.
Article
Introduction: Cluster headache [CH] is a severely disabling trigeminal autonomic cephalalgia [TAC]. Approximately 1 in 1,000 adults are affected by CH. Calcitonin gene-related peptide [CGRP] is an important mediator in the pathophysiology of CH. Galcanezumab is a monoclonal antibody with an affinity for the CGRP peptide, FDA approved for the prevention of episodic CH. Areas covered: Search words queried were ‘cluster headache,’ ‘cluster headache, and CGRP,’ ‘cluster headache, and galcanezumab.’ Over 99 articles in Pubmed and prescribing information for galcanezumab were reviewed. Some of the data pertaining to CH trials with fremanezumab were reviewed using clinical trials.org. Expert opinion: Galcanezumab has shown benefit in decreasing the weekly frequency of CH attacks across week 1 through week 3 in patients with CH; 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (95% confidence interval, 0.2 to 6.7; P = 0.04). It has a favorable risk-benefit ratio. The prevention of CH with CGRP inhibition represents a novel advance for a condition with a significant unmet need. The negative trial results of galcanezumab for chronic cluster headache [CCH] may be due to the refractory nature and sheds light on the critical need to investigate the underlying biology and therapeutic options.
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Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire.
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Background Cluster Headache (CH) is most painful primary headache sometimes lead to poor quality of life and associated disability. So far not have treatment way to cured the CH. in this study, we introduce the novel and effective surgery for CH. Method Six patients with CH, the diagnosis of CH matched on criteria of Headache Classification Committee of the IHS, third edition (IHCD-III), and six patients eligible for surgical treatment indication and with strongly requirement. All of them underwent temporal craniectomy and transection greater superficial petrosal nerve (GSPN) and deep petrosal nerve (DPN) pathway to the sphenopalatine ganglion (SPG). Result All six patients had performed the surgery for CH and follow-up per three months. Significantly cured the pain and autonomic dysfunction. In the follow-up process none of the patients had re-occurred alacrimia, all of them had reduction of secretion of nasal, oral mucosa and parotid; the six patients satisficed for the surgery. Conclusion The six patients with CH received surgery by transection greater superficial petrosal nerve (GSPN) and deep petrosal nerve (DPN) pathway to the SPG and were completely cured, and adverse event and serious complication did not occur.
Article
Aim: This study aims to evaluate the efficacy of sphenopalatine ganglion block (SPGB) on postoperative edema and ecchymosis for the patients undergoing septorhinoplasty (SRP). Methods: In the study, a total number of 55 participant patients (40% male and 60% female, aged between 18 and 42 years) undergoing hump resection and osteotomies were allocated into 2 groups. The SPGB (+) group consisted of 27 patients who underwent SPGB, while the SPGB (-) group consisted of 28 patients who underwent SRP without SPGB. On the first, third, and seventh postoperative days (POD1, POD3, POD7), the score marks of periorbital edema and ecchymosis of the patients were evaluated. Additionally, postoperative upper eyelid edema and upper eyelid ecchymosis as well as lower eyelid edema, and lower eyelid ecchymosis on POD1, POD3, POD7 were evaluated. A comparison with regard to intraoperative bleeding, surgical field, and operation time between the 2 groups was also conducted. Results: Upper eyelid edema, upper eyelid ecchymosis, lower eyelid edema, lower eyelid ecchymosis on POD 1, 3, 7 were found to be significantly lower in SPGB (+) group in comparison to SPGB (-) group (P < 0.001). Intraoperative blood loss and surgical field were found to be significantly lower in SPGB group (+) than in SPGB (-) group (P < 0.00). The operation time was not found statistically significant between the 2 groups (P = 0.212). Conclusion: Sphenopalatine ganglion block is a safe and effective way of reducing postoperative edema and ecchymosis after SRP. Besides, it provides a better surgical field and reduced bleeding intraoperatively.
Article
Purpose of review: The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. Recent findings: This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. Summary: Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.
Article
Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.
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Background: Indomethacin is a nonsteroidal anti-inflammatory drug whose mechanism of action in certain types of headache disorders remains unknown. The so-called indomethacin-responsive headache disorders consist of a group of conditions with a very different presentation that have a particularly good response to indomethacin. The response is so distinct as to be used in the definition of two: hemicrania continua and paroxysmal hemicrania. Methods: This is a narrative literature review. PubMed and the Cochrane databases were used for the literature search. Results: We review the main pharmacokinetic and pharmacodynamics properties of indomethacin useful for daily practice. The proposed mechanisms of action of indomethacin in the responsive headache disorders, including its effect on cerebral blood flow and intracranial pressure, with special attention to nitrergic mechanisms, are covered. The current evidence for its use in primary headache disorders, such as some trigeminal autonomic cephalalgias, cough, hypnic, exertional or sexual headache, and migraine will be covered, as well as its indication for secondary headaches, such as those of posttraumatic origin. Conclusion: Increasing understanding of the mechanism(s) of action of indomethacin will enhance our understanding of the complex pathophysiology that might be shared by indomethacin-sensitive headache disorders.
Chapter
Intermittent explosive disorder can be described as a severe “affective aggression” condition, for which drugs and other supportive therapies are not fully effective. In the first half of the 19th century, experimental studies progressively increased knowledge of aggressive disorders. A neurobiologic approach revealed the posterior hypothalamic region as a key structure for the modulation of aggression. In the 1960s, patients with severe aggressive disorder, frequently associated with intellectual disability, were treated by bilateral stereotactic lesioning of the posterior hypothalamic area, with efficacy. This therapy was later abandoned because of issues related to the misuse of psychosurgery. In the last 2 decades, however, the same diencephalic target has been selected for the reversible treatment by deep brain stimulation, with success. This chapter presents a comprehensive approach to posterior hypothalamic surgery for the treatment of severely aggressive patients and discusses the experimental steps that allowed this surgical target to be selected. Surgical experiences are reported, together with considerations on target features and related encephalic circuits.
Article
Resumen Introducción La cefalea en racimos fue descrita por B.T. Horton como un fuerte dolor unilateral en la región orbitaria de predominio cíclico, que afecta principalmente a hombres. No se conocen exactamente las anormalidades estructurales y funcionales de su etiología, aunque se relaciona con un gen autosómico. El diagnóstico se basa en la clínica del paciente y el tratamiento en el manejo del dolor y supresión de los factores precipitantes del episodio. Objetivo Desarrollar un plan de cuidados de enfermería para paciente con cefalea en racimos y establecer una conducta promotora de salud. Metodología Se realizó revisión de la literatura sobre la cefalea en racimos. Basados en la taxonomía de valoración por dominios de Nanda Internacional, la clasificación de Resultados de Enfermería (NOC) y la clasificación de Intervenciones de Enfermería (NIC), se desarrolló un plan de cuidados individualizado. Seguidamente se aplicó en el paciente el modelo de promoción de la salud de Nola Pender con el fin de promover conductas promotoras de salud. Resultados Se describe el proceso de enfermería partiendo de los diagnósticos dolor, fatiga y conocimiento y conducta de salud con sus respectivos objetivos, intervenciones y acciones de enfermería. Se evidenció mejoría al administrar al paciente oxígeno venturi al 50% a 15 litros por minuto, por 30 minutos; topiramato cada 12 horas y generación de conductas saludables orientadas desde el modelo de promoción de la salud propuesto por Pender. Conclusiones Se resalta la importancia no solo del abordaje en la severidad del cuadro clínico, sino de la promoción de los estilos de vida adecuados sobre factores de riesgos desencadenantes de la enfermedad.
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Cluster headache is one of the trigeminal autonomic cephalalgias (TACs) and characterized by attacks of excruciating pain, often occurring in clusters of weeks to months. Cluster headache can be divided into an episodic (around 80% of patients) and chronic form in which attacks occur without attack-free periods of at least 3 months. The pain experienced during a cluster headache attack is regarded as one of the most intense forms of pain known to men. Hallmarks are concomitant autonomic features occurring ipsilateral to the pain such as a lacrimation, nasal congestion, miosis and ptosis, and an intrinsic restlessness or agitation. Unfortunately, the pathophysiology of cluster headache has not yet been elucidated. Because of the intense pain experienced during the attacks, fast-acting attack treatment is vital for patients. Attack treatment options are 100% oxygen and/or subcutaneous sumatriptan. Pharmacological prophylactic therapies are verapamil and lithium, among others. The last decade, increasing evidence for efficacy of neuromodulatory options has emerged such as greater occipital nerve modulation, noninvasive vagus nerve stimulation, and sphenopalatine ganglion modulation.
Article
Object The characteristics of cluster headache (CH) patients in many countries and the diagnostic and therapeutic approach have been described in several publications, but so far no clinical data have been published from Turkey. Material methods This is a cross-sectional retrospective study that includes all patients who were diagnosed with CH and referred to our headache clinic, Dokuz Eylül University Faculty of Medicine, Neurology Department from 1991 to January 2018. Results We included 114 patients (24 females and 90 males) in our study. The mean age at onset was 31.68 ± 12.72 (range 13–68). Eighty-six (78.18%) patients had episodic cluster headache (ECH) and 24 (21.82%) patients had chronic cluster headache (CCH). The age at onset was significantly higher in the patients with CCH than with ECH (p = 0.002). The most common location was orbitotemporal for both genders. The most common accompanying symptoms were lacrimation (80.73%). The male:female ratio in all patients was 3:7, 3.8:1 in those with CCH and 4:1 in those with ECH. Eighty-nine (87.25%) patients had prophylactic treatment and 60 of them received verapamil. Conclusion In our study, some clinical features of our patients were similar to those of Europe and America or the Asian countries and some of them not. There are regional differences in cluster headache patients. With more awareness of cluster headache and research from many countries, clinical differences can be revealed more objectively in the future.
Article
Background Endoscopic foreheadplasty surgery (EFS) is a common procedure, however little evidence exists describing the nature or treatment of postoperative headache pain and associated symptoms. Objectives Our objective was to describe the intensity, quality, location, and duration of headache pain in women following EFS. We also compared post EFS symptoms with migraine, described medication use and efficacy, and measured emotional and functional outcomes. Methods This descriptive study used an observational repeated measures design. Forty-two women (age mean±std=59.0±7.9 years) undergoing EFS were prospectively recruited from twelve private cosmetic practices in three California counties. Phone interviews with the Acute Short-Form 12v2, and Headache Questionnaires were conducted on postoperative days (POD) 1, 3, 7, and 30. Results At POD#1, 93% reported at least moderate pain and 64% severe pain. Severe pain was characterized as throbbing (71%), sharp (53%), dull (76%), exploding (41%), imploding (53%), continuous (53%) or intermittent (41%) on POD#1. Moderate pain was most frequent on POD#3 (21%) compared to POD#1 (19%), POD#7 and #30 (12%). Mild pain predominated on POD#3 (40%) and POD#7 (40%), with (20%) remaining on POD#30. The majority (79%) of post EFS symptoms commonly included light sensitivity and nausea, and therefore met most International Classification of Headache Disorders criteria for migraine. Analgesic use provided inconsistent relief. Functional and emotional status did not return to baseline throughout the 30-day postoperative period. Conclusions Immediately following EFS, most women experience moderate to severe headache pain, despite use of medications. Pain persists in many patients for up to a month. Headache is associated with migraine symptoms, including light sensitivity and nausea.
Article
Introduction Cluster headache was described by B.T. Horton as a strong unilateral pain in the orbital region of cyclical predominance, which affects mainly men. The structural and functional abnormalities of its aetiology are not exactly known, although it is related to an autosomal gene. The diagnosis is based on the patient's symptoms and the treatment on pain management and suppression of the precipitating factors of the episode. Objective To develop a nursing care plan for patients with cluster headaches and establish health-promoting behaviour. Methodology A review of the literature on cluster headache was conducted. Based on the Nanda International domain assessment taxonomy, Nursing Outcomes Classification (NOC) and Nursing Interventions Classification (NIC), an individualized care plan was developed. Next, the Nola Pender Health Promotion Model was applied to the patient to promote health-promoting behaviours. Results The nursing process is described starting from the diagnoses of pain, fatigue, knowledge, and health behaviour with their respective objectives, interventions, and nursing actions. Improvement was evidenced when the patient was administered 50% venturi oxygen at 15 L per min, for 30 min; topiramate every 12 h and generation of healthy behaviours based on the Health Promotion Model proposed by Pender. Conclusions The importance of not only addressing the severity of the clinical picture is highlighted, but also the promotion of appropriate lifestyles on risk factors that trigger the disease.
Article
Resumen La cefalea en racimos (CR) se encuadra dentro del apartado 3 de la clasificación de la Sociedad Internacional de Cefaleas (IHS), que es el reservado para las llamadas cefaleas trigémino autonómicas (CTA). Se trata de uno de los procesos de cefalea primaria más frecuentes, dolorosos e incapacitantes. Los tratamientos farmacológicos agudos y preventivos son, en muchos casos, mal tolerados y de efectividad limitada. Debido a la mejora en la comprensión de su fisiopatología de la CR, los dispositivos de neuromodulación se han posicionado como opciones seguras y eficaces de tratamiento preventivo y el tratamiento agudo de la CR. Haremos un recorrido sobre la información disponible hasta el momento y además, exponemos el caso de un paciente con CR incapacitante, muy resistente al tratamiento médico, tratado en nuestra Unidad del Dolor con el implante de un sistema de neuroestimulación de nervio periférico de nervios supraorbitario (SON) y nervio occipital mayor (GON). A continuación revisaremos los criterios diagnósticos que la definen la CR, lo datos que conocemos, a día de hoy, sobre su fisiopatología y la posición que ocupa actualmente la neuromodulación en el abordaje terapéutico de la misma. Con la descripción del caso clínico de un paciente tratado en nuestra Unidad del Dolor con una cefalea especialmente severa y resistente al tratamiento farmacológico.
Chapter
Headache is among the most common of human maladies. So much so that it is generally (and often incorrectly) assumed to be understood, especially by doctors. The classification of headache, with formal definitions of different diagnostic entities, by the International Headache Society into (1) primary—occurring in the absence of external causes, and (2) secondary—some of which may have sinister cause, has greatly simplified the description, understanding, and management of this often challenging symptom. It also allows those headaches with serious or life-threatening consequences to be distinguished from other forms. This chapter examines the various types of headache, from primary headaches and migraine, and tension-type to secondary headache and other forms.
Article
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Background: The present paper describes the immunocytochemical and morphometric characteristics of two major cell groups of the suprachiasmatic nucleus (SCN) in the human hypothalamus: the vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neuronal subdivisions. The dimensions (volume and length) and the number of neurons expressing each peptide in the two subdivisions were obtained, as well as the mean diameter of the cell nuclei. All morphometric parameters were studied in relation to sex and age. Methods: Brains of 42 human subjects (22 males and 20 females) ranging in age from 10 to 92 years were obtained at autopsy. The hypothalamic area containing the SCN was dissected from each brain, dehydrated, and embedded in paraffin. Serial sections of 6 microns were cut in a coronal plane and stained with thionin for general orientation. To determine the architectonic boundaries of the VP- and VIP-expressing cell populations every 25th section was immunocytochemically stained by means of antibodies against arginine VP or VIP using the peroxidase-antiperoxidase method. The VP- and VIP-expressing cell numbers in the SCN of each subject were estimated by unilaterally counting the number of nuclear profiles with the aid of a Zeiss microscope under x 500 magnification, using a deconvolution procedure and a correction for section thickness. Results: The main portion of the VP positive neurons is located in the dorsomedial part of the SCN and is rostrocaudally longer in females than in males (1.76 +/- 0.12 mm and 1.40 +/- 0.10 mm, respectively). The volume of the VP subdivision is 0.244 +/- 0.017 mm3 and contains 6,890 +/- 520 VP-immunoreactive neurons, with a mean density of about 29,000 neurons/mm3. No significant sexual dimorphism or age-related alterations in the population of VP neurons is found. The VIP positive neurons are mainly located in the ventral and central part of the SCN and extend rostrocaudally in a similar way in females and males (1.07 +/- 0.08 mm and 1.02 +/- 0.11 mm, respectively). The volume of the VIP subdivision is 0.034 +/- 0.004 mm3 and contains 1,700 +/- 140 VIP-immunoreactive neurons, with a mean density of about 63,000 neurons/mm3. An age-dependent sexual dimorphism is observed in the number of VIP-expressing neurons in the SCN: young males have about twice as many VIP neurons as females of the same age, whereas in middle-aged subjects this sexual difference is reversed, and less robust, with females now having about 1.7 times as many VIP neurons as males. In old subjects the difference in VIP cell number between men and women disappears. Conclusions: The present study clearly shows that the population of VP neurons in the human SCN is considerably larger than the population of VIP neurons. Furthermore, the age-related sexual differences in the VIP cell number reinforces the idea that the SCN is not only involved in the timing of circadian rhythms but also in the temporal organization of reproductive functions.
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The cyclic nature of cluster headache warranted a study of the 24-hour rhythms of serum cortisol and melatonin. They were both altered during cluster periods as compared with periods of remission and healthy controls. The 24-hour mean and maximal cortisol levels were higher and the timing of the cortisol minimum was delayed as compared to the same patients in remission. Although there was no relation between the cortisol and melatonin levels and headaches, the rise of cortisol following many attacks might in part represent an adaptive response to pain. The nocturnal melatonin maximum was lower during cluster periods than in remission. This finding, and the dysautonomic signs during attacks, may reflect a change of the vegetative tone in a hyposympathetic direction.
Article
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The development of a facial flush during thermocoagulation of the Gasserian ganglion was monitored in 16 patients with pulse recording techniques and in a further 17 patients with thermography. There was a close association between the development of the facial flush in the distribution of one or more divisions of the trigeminal nerve and the subsequent demonstration of postoperative analgesia. In regions where significant changes took place, vascular pulsations increased 25-233% (mean 96%) and facial temperature rose 0.5-2.0 degrees C. The response persisted for up to an hour postoperatively, and was not diminished in patients with pre-operative analgesia from a previous procedure. Possible mechanisms for the facial flush, including stimulation of an active vasodilator system, the antidromic release of vasoactive substances from trigeminal nerve terminals and the release of tonic vasoconstriction are discussed. A practical application of the pulse recording technique used in the present investigation would be to monitor the distribution of vasodilatation at operation to avoid unwanted first division sensory loss.
Article
Histaminic cephalalgia is a distinct clinical entity that usually begins in the later decades of life.1 It is characterized by a unilateral headache of short duration generally lasting less than an hour; it commences and often terminates suddenly. It tends to awaken the patient at night one to two hours after he has gone to sleep, and the severity of the pain makes the patient get out of bed and pace the floor. At its height the pain is associated with watering and congestion of the eye, rhinorrhea or stuffiness of the nostril, sweating, and, often, visible dilatation of the temporal vessels of the involved side of the head. Once observed in its full-blown form, the clinical picture will never be forgotten.Constant, excruciating, burning, and boring pain is the outstanding complaint. It involves the orbital area and the temple and may extend to the upper jaw, occipital region,
Article
Cluster headache is an excruciatingly painful, essentially unilateral headache associated with homolateral autonomic signs. It has a highly distinctive temporal pattern. The attacks occur in cluster periods lasting weeks or months that are separated by remission periods of months or years. The pathogenesis of cluster headache is still unknown, although it is probable that the pain and autonomic manifestations result from the activation of the trigeminovascular system.The periodic nature of cluster headache [i.e. typically, cluster periods begin in spring or autumn (fall) when there is a rapid rate of change of the quantity of daylight, and, often, within a cluster period, the attacks recur on a daily basis with ‘clockwork’ regularity] suggests that activation of the trigeminovascular system could derive from the involvement of the hypothalamus, the site of the biological pacemaker.Since melatonin production is under the control of the hypothalamic pacemaker, the role of melatonin in cluster headache has been investigated. A number of studies have shown that melatonin levels are reduced during cluster periods, suggesting that the disorder is associated with a periodic dysfunction of hypothalamic structures.In this article, some of the biological functions of melatonin are reviewed in light of their possible relevance to the mechanisms that cause cluster headache. These include the role of melatonin in the regulation of circadian rhythms and the possible implications of its effects on -aminobutyric acid (GABA) and serotonin (5-hydroxytryptamine; 5-HT) receptors, intracellular levels of calcium ions and prostaglandin production. Preliminary clinical data on the use of melatonin in the prophylaxis of cluster headache are discussed. In a double-blind, placebo-controlled clinical study, melatonin effectively prevented cluster headache in 50% of patients. This finding suggests the possible utility of melatonin as a second-line prophylactic agent, and provides additional evidence of a periodic central dysfunction in this disease.
Article
SYNOPSIS A large body of evidence points to an inflammatory process in the cavernous sinus and tributary veins as being primarily responsible for cluster headaches. The inflammation obliterates the venous outflow from the cavernous sinus on one side and injures the through-running sympathetic fibers to the eye, upper eye lid, forehead skin, and the intracranial internal carotid artery and its branches. The active period ends when the inflammation is suppressed and the sympathetic fibers partially or fully recover. Evidence is presented that the symptoms suggestive of an enhanced parasympathetic activity during attacks may alternatively be explained as local pain fiber activation or a stasis in the outflow from the cavernous sinus. Vasodilator agents like nitroglycerin induce an attack by enhancing the venous load on the cavernous sinus. Constriction of the proximal intracranial internal carotid artery, spontaneously induced by tressful pain activation of the perivascular sympathetic nerves, or by exogenous administration of serotonin 1 D-like receptor agonists or oxygen, terminates the venous load and thus the pain and associated symptoms.
Article
Objective.–To investigate whether there is clinical or biochemical evidence for a transient systemic inflammation during active periods of cluster headache. Methods.–Twenty-seven male and female consecutively selected patients with episodic cluster headache filled in questionnaires aiming at detecting any concurrent systemic vasculitic or rheumatoid disease. They were physically examined by both a neurologist and a rheumatologist independent of each other. Blood and urine samples were taken one to three times during an active cluster period and once in remission. The following analyses were performed: hemoglobin, erythrocyte sedimentation rate, C-reactive protein, complete blood counts including differential counts, creatinine, albumin, creatine kinase, electrophoreses of serum (with haptoglobin, orosomucoid, IgG, IgM), von Willebrand's factor, antinuclear antibodies, rheumatoid factor, cytoplasmic antineutrophil cytoplasmic autoantibodies, perinuclear antineutrophil cytoplasmic autoantibodies, and routine urinary tests. An age- and sex-matched control group of 99 consecutive patients attending the Outpatient Department of Neurology for symptoms/diseases other than severe headache completed the same questionnaire as the patient group. Results.–Only one patient with cluster headache showed clinical signs (livedo reticularis) that could have been due to an ongoing systemic vasculitis. Most symptoms were equally or even more prevalent in the control group than among the patients with cluster headache. However, cold feet were about twice as prevalent among female patients with cluster headache than in the control group. This was considered due to their smoking habits. Laboratory tests showed no statistically significant differences between the active cluster periods and remission. There were some slightly abnormal values in single laboratory tests, some of which were probably due to concurrent upper respiratory infections. The findings of laboratory tests for one patient could have been due to nephritis. All patients were negative for cytoplasmic antineutrophil cytoplasmic autoantibodies and perinuclear antineutrophil cytoplasmic autoantibodies. Conclusions.–These results were taken as evidence that no systemic inflammation is present during the active cluster headache period. However, whether a local retro-orbital inflammation underlies the pathophysiology of cluster headache remains obscure.
Article
Purpose: Ictal pain is a rare symptom of seizures. Epileptic pain may be experienced unilaterally (lateral/peripheral), cephalically, or in the abdomen. Painful seizures have been associated with seizure origin in both the parietal and the temporal lobes. We report on the different types of epileptic pain and discuss its etiology and possible localizing value. Methods: We reviewed the records of patients referred to our epilepsy program over the last 6 years. Eight (1.4%) of 573 patients had pain as an early prominent symptom of their seizures. Results: Pain was predominantly unilateral in three patients, cephalic in two, and abdominal in three patients. Seizure onset was in or involving the parietal lobe in all patients, and when the painful symptoms were lateralized, they were contralateral to the side of seizure origin. Parietal lobe seizure origin was determined by both intracranial EEG recording and neuroimaging [magnetic resonance imaging (MRI), ictal single photon emission computed tomography (SPECT)] in five patients, and by both scalp EEG and neuroimaging in three patients. Conclusions: We conclude that ictal pain is a rare symptom of parietal lobe seizure origin with lateralizing potential.
Article
SYNOPSIS We report a severe acute headache that occurred in conjunction with a solitary fresh lesion of multiple sclerosis in the periaqueductal gray region of a 16-year-old girl. This unique natural event supports the recent proposition, based on observations of patients with implanted electrodes, that perturbations of the periaqueductal gray region can produce headache. It also suggests that headaches accompanying attacks of multiple sclerosis are due to disturbances in particular regions of the brain.
Article
The temporal organization of plasma melatonin. cortisol. growth hormone (GH) and prolactin secretion was examined in healthy rested controls and in patients suffering from episodic cluster headache. Eleven patients with typical cluster headache (10 men, 1 female) and 8 male controls were studied over a 24-h period: blood was collected at 2-h intervals during the day and at l-h intervals at night. Plasma melatonin. cortisol, GH and prolactin levels were determined by radioimmunoassay. Most of the cluster headache patients showed a decrease in nocturnal melatonin secretion and the melatonin rhythm was even completely abolished in one patient. Chronobiological analysis of the cluster headache patients' 24-h plasma melatonin profile showed a significant decrease in amplitude and mesor: these were 58.7 pg/ml and 34.4 pg/ml respectively in control subjects, versus 18.7 pg/ml and 17.6 pg/ml for the patients. In addition. patients showed a significant phase-advance in their melatonin rhythm For cortisol, the rhythm appeared slightly blunted in the cluster headache group and was significantly phase-advanced. The plasma prolactin profile showed no significant alteration, but for plasma GH the nocturnal peak was advanced in some patients: in the absence of sleep recording, however, no conclusion could be drawn. Results from this study suggest a neuroendocrine dysregulation in cluster headache in the endogenous clock which controls the pineal rhythmicity.
Article
At its simplest, voxel-based morphometry (VBM) involves a voxel-wise comparison of the local concentration of gray matter between two groups of subjects. The procedure is relatively straightforward and involves spatially normalizing high-resolution images from all the subjects in the study into the same stereotactic space. This is followed by segmenting the gray matter from the spatially normalized images and smoothing the gray-matter segments. Voxel-wise parametric statistical tests which compare the smoothed gray-matter images from the two groups are performed. Corrections for multiple comparisons are made using the theory of Gaussian random fields. This paper describes the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with nonuniformity artifact. We provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.
Article
Using a positron emission tomography (PET) study it was shown recently that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so called 'migraine generator'. To test this hypothesis we performed an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as in the migraine patients. A small amount of capsaicin was administered subcutaneously in the right forehead to evoke a burning painful sensation in the first division of the trigeminal nerve. Increases of regional cerebral blood flow (rCBF) were found bilaterally in the insula, in the anterior cingulate cortex, the cavernous sinus and the cerebellum. Using the same stereotactic space limits as in the above mentioned migraine study no brain stem activation was found in the acute pain state compared to the pain free state. The increase of activation in the region of the cavernous sinus however, suggests that this structure is more likely to be involved in trigeminal transmitted pain as such, rather than in a specific type of headache as was suggested for cluster headache.
Article
Regional cerebral blood flow was studied in the cat, with and without trigeminal ganglion stimulation, by the intravenous injection of the tracer [14C]iodoantipyrine and subsequent regional brain dissection. Electrical activation of the trigeminal ganglion led to a selective increase in regional blood flow in the frontal and parietal cortex that was bilateral without change in the posterior cortex, deep cerebral nuclei, white matter, or brain stem. Unilateral intracranial section of the facial nerve blocked the response in the ipsilateral frontal and parietal cortex, whereas bilateral facial nerve section blocked the contralateral frontal cortical response. The contralateral parietal cortical increase in blood flow was not affected by facial nerve section and may thus represent the result of metabolic activation of sensory cortex.
Article
SYNOPSIS In a study of 30 cluster headache sufferers compared with 30 men suffering from classical migraine, no significant difference in plasma testosterone levels could be detected. On examination of individual patients it is noted that three patients suffering from chronic cluster headache did have values below the normal range. However, an equal number of sufferers from classical migraine also had low values. All of four female patients suffering from cluster headache had elevated male hormone levels. Speculations are offered as to why hormone variations may be found in these conditions. Further studies will be undertaken in an effort to better understand the underlying mechanisms of this distressing disorder.
Article
Percutaneous radiofrequency ablation of the Gasserian ganglion or posterior root, or both, was performed in 140 patients. Of the 135 patients with trigeminal neuralgia, satisfactory analgesia was achieved in 121. Postoperative complications included unintentional first-division analgesia (10), transient sixth-nerve palsy (1), neuroparalytic keratitis (2), and anesthesia dolorosa (2). The phenomenon of facial blush may be helpful in avoiding unwanted first-division analgesia. In four of five patients with other forms of neuralgia, the procedure did not relieve pain; the fifth patient experienced significant relief from pain due to carcinoma of the mandible.
Article
SYNOPSIS Plasma testosterone values were obtained by the RIA method from two groups of cluster headache male patients in separate laboratories. In each group testosterone levels were compared between controls and cluster patients in active and remission periods. Significantly lower values were found in active cluster patients when compared to either cluster-remission or controls. The results are preliminary and suggest a possible association of lowered plasma testosterone levels with active cluster period in cluster headache male patients.
Article
The resulting changes in the regional cerebral blood flow of 18 patients suffering from idiopathic trigeminal neuralgia and treated by selective thermocoagulation of the trigeminal ganglion were measured by xenon-133 emission tomography. One hour after thermal stimulation, there was an asymmetric increase (P < 0.05) in cerebral blood flow, with a 14.7% mean increase in the ipsilateral cerebral hemisphere (P < 0.001) and a 12.7% mean increase in the contralateral side (P < 0.01). The increase in regional cerebral blood flow was not uniform but was most marked in the ipsilateral middle cerebral artery territory (P < 0.001). There was a slight decrease in cerebellar blood flow, but the reduction in the ipsilateral cerebellar lobe was less than that in the contralateral lobe (P < 0.01). The topography of the most significant changes coincided with that of the innervation of the cerebral vessels by the trigeminal nerve. Several mechanisms are involved in the increase in regional cerebral blood flow, including overall nonspecific activation of the central nervous system and local mechanisms associated with the trigeminal-vascular system.
Article
A patient is described with a 17-year history of intractable left-sided facial pain. The pain occurred daily in 5 sec spasms to a maximum of one every 2-3 min and was restricted to the left upper face. It was associated with rhinorrhoea on the left and often with ipsilateral facial flushing. Conventional therapy, including carbamazepine, baclofen and three posterior fossa explorations, had not provided lasting relief. Local facial stimulation by tapping a painful trigger point led to both pain and flushing of the face ipsilaterally. During this flushing, blood was collected and assayed using sensitive radioimmunoassays for several neuropeptides (neuropeptide Y, substance P, vasoactive intestinal polypeptide and calcitonin gene-related peptide). A marked (119%) increase in calcitonin gene-related peptide was noted in the external jugular vein blood ipsilaterally during the flushing with no change in the other peptides measured. To quantitate the effect of calcitonin gene-related peptide on human extracranial vessels, standard pharmacological procedures were used to examine the potency of the peptide as a vasodilator of human facial artery. The IC50 of calcitonin gene-related peptide for the prostaglandin F2 alpha-precontracted human facial artery was 10(-9) mol/l. The relevance of these observations to the clinical problem of migraine is considered.
Article
The retrograde transneuronal viral cell body labeling method was used to study the CNS nuclei that innervate the parasympathetic preganglionic neurons which project to the pterygopalatine ganglion. Small injections of a suspension of pseudorabies virus (PRV) were made in the pterygopalatine ganglion of rats and after 4 days their brains wer e processed for immunohistochemical detection of PRV. Some of the tissues were stained with a dual immunofluoresence method that permitted the visualization of PRV and neurotransmitter enzyme or serotonin immunoreactivity in the same cell. Retrograde cell body labeling was detected in the ipsilateral ventrolateral medulla oblongata in the region that has been termed the superior salivatory nucleus. This area was the same region that was retrogradely labeled after Fluoro-Gold dye injections in the pterygopalatine ganglion. Retrograde transneuronally infected cell bodies that provide putative afferent inputs to the pytergopalatine parasympathetic preganglionic neurons were mapped throughout the brain. In the medulla oblongata, transneuronally labeled neurons were seen in the nucleus tractus solitarii, dorsomedial part of the spinal trigeminal nucleus and gigantocellular reticular nucleus. In most experiments, some A1 catecholamine cells and serotonin neurons of the raphe magnus, raphe pallidus, raphe obscurus, and parapyramidal nuclei were labeled. In the pons, labeled cells were found in the parabrachial nucleus. A5 catecholamine cell group, and non-catecholamine part of the subcoeruleus region. In the midbrain, cell body labeling was located in the central gray matter and retrorubral field. In the diencephalon, labeling was found mainly in the hypothalamus. The areas included the lateral hypothalamic area, lateral preoptic area, dorsomedial and paraventricular hypothalamic nuclei, and ventral zona incerta. Contralateral second order cell body labeling was seen in the tuberomammillary nucleus of the hypothalamus. Some of these cells were histidine decarboxylase-immunoreactive. In the forebrain, the bed nucleus of the stria terminalis, substantia innominata, and an area of the cerebral cortex called the amygdalopiriform transition zone were labeled.
Article
Current views on cluster headache pathogenesis indicate a primary central nervous system dysfunction, in particular a hypothalamic involvement. To confirm the hypothalamic involvement in cluster headache we evaluated the hypothalamic-pituitary axis responsiveness with the thyrotrophin releasing hormone (TRH) test. A dose of 200 micrograms of TRH was administered i.v. to nine healthy controls, 32 patients with cluster headache during cluster period and 16 in remission period. Delta maximum thyrotrophin (TSH) was significantly lower in patients with cluster headache during cluster period (p less than 0.05 versus healthy controls and cluster headache patients in remission). No difference was observed between healthy controls and cluster headache patients in remission. A monoaminergic dysfunction at the hypothalamic level is hypothesized.
Article
The trigeminal ganglion was activated, in humans by thermocoagulation as part of the treatment of trigeminal neuralgia and in cats by electrical stimulation, and blood samples were taken from the external jugular vein for estimates of plasma levels of substance P and calcitonin gene-related peptide (CGRP). In those patients who were noted at the time of coagulation to have flushed there were marked elevations of the local (cranial) levels of both peptides. However, in the nonflushing patients no changes in the peptide levels were observed. Parallel experiments in the cat revealed that the levels of substance P-like and CGRP-like immunoreactivity were increased during electrical stimulation of the trigeminal ganglion. The observation of elevation of substance P-like and CGRP-like immunoreactivity after activation of the nociceptive afferent system of the head provides new insights into a putative role of peptides in the pathophysiology of migraine and cluster headache, and suggests new areas of possible therapeutic intervention.
Article
Regional cerebral blood flow was determined using the tracer [14C]iodoantipyrine and regional brain dissection, and regional cerebral glucose utilization was determined using the 2-deoxyglucose method in the alpha-chloralose-anesthetized cat to evaluate the effect of electrical stimulation of the facial nerve. The nerve was sectioned intracranially to isolate it from the brain stem and the distal portion stimulated before entry into the internal auditory meatus. Stimulation led to a global increase in cortical (frontal, parietal, temporal, occipital, and cingulate cortex) and white matter blood flow. This effect was predominantly ipsilateral to the side stimulated, although significant effects were also noted on the contralateral side. The latter were confined to the more anterior cortical structures. In contrast, there were no significant changes in regional metabolic activity as assessed by the rate of glucose utilization. This study provides direct evidence for a neurogenic vasodilator effect of activation of the facial-greater superficial petrosal pathway that is independent of regional brain metabolic activity.
Article
Pooled antisera to vasoactive intestinal polypeptide were used to block neurogenic extracranial vasodilatation elicited from either brainstem (locus coeruleus) or pterygopalatine ganglion stimulation in the cat. Vasodilatation was not inhibited by sham immune sera, or by antisera to bradykinin or substance P. The efferent pathway for vasodilatation from the locus coeruleus traverses the facial nerve (greater superficial petrosal branch) and the pterygopalatine and otic ganglia. Its blockade demonstrates a novel action of a peptide transmitter in the expression of a central neurogenic response.
Article
The diurnal rhythmicity of serum prolactin (PRL) and the PRL and thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) were studied in 31 cluster headache patients (4 chronic cases) and 14 healthy controls. Sixteen of the patients were studied both during clinical remission and headache periods. In males the nocturnal PRL peak was blunted during remissions as compared with that in cluster periods and that in control individuals. The 24-h mean PRL levels were lower during remission and cluster periods than in the controls. There were no significant differences in the PRL levels between female patients and controls. Headache attacks were often associated with increases of serum PRL levels. The PRL response to TRH was lower in the female patients but not in the male patients as compared with controls. The maximum testosterone levels were lower during cluster periods than during clinical remission but not when compared with controls. Serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, estradiol, T3, T4, and TSH did not differ between patients and controls. The results suggest an altered regulation of PRL secretion not only during active cluster periods but also during symptom-free intervals. The possible influence of sleep, estradiol, testosterone, medication, pain, and serotoninergic and dopaminergic mechanisms are discussed.
Article
The trigeminal sensory innervation of the major cerebral vessels is thought to carry the nociceptive information during a migraine headache, and this pain is usually referred to the forehead area. Using retrograde tracing techniques, we have described the distribution of sensory trigeminal cells that innervate the middle cerebral artery (MCA) and the forehead. Nearest-neighbor analysis of the ophthalmic division of the trigeminal ganglion revealed that cells innervating the forehead tend to be clumped around individual cells that innervate the MCA. An average of less than 1 cell per animal was found to project divergent collaterals to both areas. The close association of ganglion cell bodies innervating the cerebral vasculature and those innervating forehead areas may underlie the convergence of their central processes onto common brain-stem trigeminal nucleus cells, and thus the referral of headache pain. In contrast to the lack of ganglion cells with axonal collaterals to the cerebral vasculature and forehead, a significant population of cells that innervate the MCA also have collateral projections to other cerebral arterial branches (branches of the middle meningeal artery), as well as the surrounding dura. Thus, the innervation targets of individual trigeminal cells are very widespread intracranially (including arteries and dura), but separate cells in the ophthalmic division innervate extracranial targets.
Article
The trigeminal ganglion of 9 anesthetized paralysed artificially ventilated Macaca nemestrina monkeys was electrically stimulated with frequencies varying from 0.2 to 200 Hz. This stimulation led to a frequency-dependent decrease in external carotid resistance but no significant change in internal carotid resistance was recorded. The response is probably mediated as previously described in the cat, i.e. predominantly through the greater superficial petrosal branch of the facial nerve and a small proportion through antidromic activation of the trigeminal system. Elucidation of the physiological and pharmacological mechanisms underlying such a response may aid in a better understanding of the pathophysiology of vascular headache.
Article
SYNOPSIS Ray and Wolff in a landmark study of human patients under local anesthesia, concluded that the brain was not sensitive to pain; however, at the time of their study, the anatomy and physiology of pain transmission and modulation were largely unknown and their stimulating electrodes were not implanted in the brainstem or thalamic cells or projections now known to be important to pain perception. We now report 15 patients, previously headache-free, who underwent electrode implantation in the periaqueductal gray between 1977 and 1982 who immediately at implantation or in the few days subsequent to implantation reported severe continuous head pain usually with florid “migrainous” feature that persisted for 2 months to 10 years. Ten of these patients were treated with reserpine and all were dramatically responsive to it, but 8 patients rapidly became tolerant. Seven patients who were treated with dihydroergotamine rapidly became headache-free; 2 of the 7 became tolerant quickly. One patient developed the “cough headache” syndrome after implantation, was responsive to indomethacin, the syndrome abating in 6 months. These data suggest that perturbation of brain may generate head pain.
Article
The authors report their experience in the treatment of trigeminal neuralgia with controlled increments of radiofrequency heating from an electrode placed in the Gasserian ganglion or its posterior rootlets. Touch is preserved in some or all of a trigeminal zone rendered analgesic. The electrode tip is introduced through the foramen ovale and placed among the desired rootlets with the help of a combination of radiographs and the conscious patient's response to electrical stimulation with a square wave signal and gentle electrical heating. The degree of heat is measured by a thermister at the electrode tip. The patient's cooperation is maintained by the use of the neurolept anesthetic Innovar and the production of brief unconsciousness for the painful parts of the operation by methohexital (Brevital). Of 274 patients with facial pain so treated, 214 had trigeminal neuralgia; 91% of the latter group experienced relief of pain and 125 followed for 2.5 to 6 years had a recurrence rate of 22%. In a total of 353 procedures, there has been no mortality and no neurological morbidity outside the trigeminal nerve. Only six of the patients with trigeminal neuralgia have complained significantly of postoperative paresthesias. The most serious undesired result has been the production of an anesthetic cornea in 28 patients, one of whom lost the sight of one eye due to corneal scarring. Correlating findings in these patients with those in studies by other authors, it is concluded that the preservation of some touch is due to resistance to heating by the heavily myelinated A beta fibers.
Article
The locus coeruleus was stimulated in 62 cats in order to investigate the effect on cephalic blood flow and cephalic vascular resistance. Flow was measured by electromagnetic flow probes applied to the common carotid artery. Stimulation over a range of frequencies (0.2-200 s-1) produced a frequency-dependent fall in carotid vascular resistance, greater on the ipsilateral side. This response was not affected by either cervical sympathectomy or spinal cord section. The response was blocked by bilateral section of the facial nerve but was not abolished by classical cholinergic, histaminergic or adrenergic blocking agents. Stimulation of the locus coeruleus also resulted in a pressor response through spinal mechanisms in which coeruleo-hypothalamic projections were not involved. A post-stimulation constriction in the carotid vasculature followed the dilator response and was attributed to release of catecholamines from the adrenal medulla.
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Out of 858 epileptic patients, 24 had painful seizures. Three distinct groups emerged: (1) those with unilateral pain in the face. arm, leg or trunk (Unilateral Group)—10 cases; (2) a Cephalic Group with pain restricted to the head—11 cases; and (3) an Abdominal Group with central abdominal pain—3 cases. Unilateral pain consistently implicated ictal involvement of the contralateral rolandic region at the time of pain. In most cases it was probably due to involvement of the primary somatosensory cortex (SI). Cephalic pain did not localize the site of seizure origin. In most cases it probably arose by a vascular mechanism. Abdominal ictal pain reflected temporal lobe epileptic activity in our cases. The mechanism of its production is uncertain, but it is unlikely to be due to a peripheral (for example gastrointestinal) mechanism.