Materiały źródłowe

• #1 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  Cluster headache is a primary headache disorder affecting up to 0.1% of the population. […] Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. […] The pathophysiology of cluster headache is complex and the underlying mechanisms are not fully elucidated. Cluster headache is a neurovascular rather than a vascular headache, with vascular cerebral changes being driven by the effects of trigeminal-autonomic reflex activation. […] The trigeminovascular pathway consists of neurons innervating the cerebral vessels and dura mater through cell bodies in the trigeminal ganglion.

• #2 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  Cluster headaches are the most common of the primary headache type known as trigeminal autonomic cephalgia. […] They have earned consideration as one of if not the most severe types of headache, and so, despite their rarity, recognition and treatment are vital. […] The exact etiology of cluster headaches is not clear. There have been several theories suggested and tested. […] There is a known association between the trigeminovascular system, the parasympathetic nerve fibers involved in the trigeminal autonomic reflex, and the hypothalamus. However, how these structures interact to cause these headaches is not certain. […] There is a definitive link between vasodilation and a pain attack. Activation of the trigeminovascular system causes perivascular afferent nerves to cause vasodilation.

• #3 Frontiers | Cluster headache: an update on clinical features, epidemiology, pathophysiology, diagnosis, and treatment

  https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1373528/full

  Cluster headache (CH) is one of the worst primary headaches that remain underdiagnosed and inappropriately treated. […] This paper aims to review CH’s recent clinical and pathophysiological findings, diagnosis, and treatment. […] It is a polygenetic and multifactorial entity that involves dysfunction of the trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamic networks. […] The pathophysiology of CH still needs to be understood. The current understanding is based on preclinical, clinical, and imaging studies in patients with the disease. […] The neuroanatomical and functional systems involved in the pathophysiology of CH can be divided into three principal components: (1) the trigeminovascular system, (2) the trigeminal-autonomic reflex (sphenopalatine ganglion stimulation), and (3) the hypothalamic system.

• #4 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  Cluster headaches are the most common of the primary headache type known as trigeminal autonomic cephalgia. […] They have earned consideration as one of if not the most severe types of headache, and so, despite their rarity, recognition and treatment are vital. […] The exact etiology of cluster headaches is not clear. There have been several theories suggested and tested. […] There is a known association between the trigeminovascular system, the parasympathetic nerve fibers involved in the trigeminal autonomic reflex, and the hypothalamus. However, how these structures interact to cause these headaches is not certain. […] There is a definitive link between vasodilation and a pain attack. Activation of the trigeminovascular system causes perivascular afferent nerves to cause vasodilation.

• #5 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  Cluster headache is a primary headache disorder affecting up to 0.1% of the population. […] Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. […] The pathophysiology of cluster headache is complex and the underlying mechanisms are not fully elucidated. Cluster headache is a neurovascular rather than a vascular headache, with vascular cerebral changes being driven by the effects of trigeminal-autonomic reflex activation. […] The trigeminovascular pathway consists of neurons innervating the cerebral vessels and dura mater through cell bodies in the trigeminal ganglion.

• #6 Frontiers | Cluster headache: an update on clinical features, epidemiology, pathophysiology, diagnosis, and treatment

  https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1373528/full

  Cluster headache (CH) is one of the worst primary headaches that remain underdiagnosed and inappropriately treated. […] This paper aims to review CH’s recent clinical and pathophysiological findings, diagnosis, and treatment. […] It is a polygenetic and multifactorial entity that involves dysfunction of the trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamic networks. […] The pathophysiology of CH still needs to be understood. The current understanding is based on preclinical, clinical, and imaging studies in patients with the disease. […] The neuroanatomical and functional systems involved in the pathophysiology of CH can be divided into three principal components: (1) the trigeminovascular system, (2) the trigeminal-autonomic reflex (sphenopalatine ganglion stimulation), and (3) the hypothalamic system.

• #7 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  Cluster headache is a primary headache disorder affecting up to 0.1% of the population. […] Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. […] The pathophysiology of cluster headache is complex and the underlying mechanisms are not fully elucidated. Cluster headache is a neurovascular rather than a vascular headache, with vascular cerebral changes being driven by the effects of trigeminal-autonomic reflex activation. […] The trigeminovascular pathway consists of neurons innervating the cerebral vessels and dura mater through cell bodies in the trigeminal ganglion.

• #8 Frontiers | Cluster headache: an update on clinical features, epidemiology, pathophysiology, diagnosis, and treatment

  https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1373528/full

  The interaction of these three components is responsible for the characteristic clinical presentation of CH. […] The trigeminovascular system is formed by neurons innervating the dura mater and meningeal vessels, whose neuronal body is in the trigeminal ganglion. […] CH attacks involve activation of parasympathetic outflow, which causes typical trigeminal-autonomic symptoms such as lacrimation, conjunctival injection, and nasal congestion. […] The hypothalamus also plays a role in the nociceptive process of the trigeminovascular system and receives projections from the trigeminal nerve via the trigeminal-hypothalamic tract. […] The mechanistic relevance of the hypothalamus in CH is supported by circannual patterns, attack phenotypes, and accompanying neuroendocrine hormonal alterations, as well as by several neuroimaging studies that revealed an activation of the posterior hypothalamic region during attacks of CH. […] The trigeminovascular system and the trigeminal-autonomic reflex not only modulate each other but also can potentiate each other through the release of vasoactive neuropeptides.

• #9 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In the pathophysiology of migraine and CH, both the peripheral nervous system and central nervous system are involved. Three key structures interact and subsequently involve cortical areas as well: the trigeminovascular system, parasympathetic nerve fibers (trigeminal autonomic reflex) and the hypothalamus. […] In migraine and CH, pain is likely due to activation of the trigeminovascular system. Nociceptive nerve fibers originate from the trigeminal ganglion (TG) and reach intracranial structures such as the dural, arachnoid and pial blood vessels, cerebral arteries and extracranial structures. From TG the nociceptive signals project to neurons in the trigeminal cervical complex (TCC), including the trigeminal nucleus caudalis (TNC), and the dorsal horn of the upper cervical spinal cord (C1-C2). These projections from the TCC terminate on neurons of the trigeminal brainstem nuclear complex and transmit all somatosensory information via further projections: to thalamic neurons (via a trigemino-thalamic tract), to hypothalamic nuclei (via a trigemino-hypothalamic tract), to basal ganglia nuclei and to brainstem nuclei including the locus coeruleus (LC) and periaqueductal gray (PAG). Subsequently, these structures reach several cortical areas involved in processing aspects of the nociceptive signals.

• #10 Evidence-based treatments for cluster headache | TCRM

  https://www.dovepress.com/evidence-based-treatments-for-cluster-headache-peer-reviewed-fulltext-article-TCRM

  Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. […] We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition. […] Although CH is clinically well defined, the exact cause and pathophysiology of this disorder remain nebulous. The three fundamental aspects of the condition are the distribution of pain in the first division of the trigeminal nerve, the autonomic features, and the cyclical pattern of the attacks. Any pathophysiological model, to be valid, should incorporate these three features. The trigeminal innervation of the cranial circulation contains a number of neuropeptides, including calcitonin gene-related peptide (CGRP), substance P, and vasoactive intestinal peptide. Stimulation of the trigeminal ganglion leads to the release of CGRP and substance P into the cranial circulation.

• #11 Evidence-based treatments for cluster headache | TCRM

  https://www.dovepress.com/evidence-based-treatments-for-cluster-headache-peer-reviewed-fulltext-article-TCRM

  Elevated plasma levels of CGRP in the external jugular vein have been found during CH attacks. […] This finding may indicate a hyperactive state of the trigeminal system during the bout. […] From the autonomic symptoms of CHs, it can be deduced that ipsilateral sympathetic dysfunction (ptosis, miosis, and facial sweating) and parasympathetic activation occur (rhinorrhea, lacrimation, and nasal congestion). […] However, the episodic and circadian pattern cannot be explained by a vascular phenomenon alone, as they suggest dysfunction of a central pacemaker, namely, the hypothalamus. […] Testosterone levels have been found to be lower in patients with CH during the attack, providing initial evidence for the involvement of the hypothalamus. […] This was supported by evidence of reduced stimulation by thyrotropin-releasing hormone and observations of disordered circadian rhythm for cortisol, luteinizing hormone, growth hormone, and prolactin.

• #12 What is a Cluster Headache? | Northwest Functional Neurology

  https://www.northwestfunctionalneurology.com/blog/what-is-a-cluster-headache

  While the jury is still out on the definitive mechanism of cluster headaches, the pathophysiology appears to involve abnormal activation of the trigeminovascular complex, a collection of brainstem neurons and associated blood vessels. […] In cluster headaches there is abnormal activation of the V1 distribution of the trigeminal nerve, the area responsible for pain around and behind the eyes. The cause of this trigeminovascular complex activation is poorly understood. […] Unique to cluster headaches is activation of the trigeminal-autonomic pathway, which leads to activation of the parasympathetic autonomic nervous system. This results in symptoms such as eyes watering, sinus congestion, and facial sweating. […] Pain inputs from the head, face, upper cervical spine, meninges, and blood vessels in the brain are conducted into the brainstem through the trigeminal nerve. The trigeminovascular pathway consists of neurons innervating the cerebral blood vessels and meninges, which have their cell bodies in the trigeminal ganglion.

• #13 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In the pathophysiology of migraine and CH, both the peripheral nervous system and central nervous system are involved. Three key structures interact and subsequently involve cortical areas as well: the trigeminovascular system, parasympathetic nerve fibers (trigeminal autonomic reflex) and the hypothalamus. […] In migraine and CH, pain is likely due to activation of the trigeminovascular system. Nociceptive nerve fibers originate from the trigeminal ganglion (TG) and reach intracranial structures such as the dural, arachnoid and pial blood vessels, cerebral arteries and extracranial structures. From TG the nociceptive signals project to neurons in the trigeminal cervical complex (TCC), including the trigeminal nucleus caudalis (TNC), and the dorsal horn of the upper cervical spinal cord (C1-C2). These projections from the TCC terminate on neurons of the trigeminal brainstem nuclear complex and transmit all somatosensory information via further projections: to thalamic neurons (via a trigemino-thalamic tract), to hypothalamic nuclei (via a trigemino-hypothalamic tract), to basal ganglia nuclei and to brainstem nuclei including the locus coeruleus (LC) and periaqueductal gray (PAG). Subsequently, these structures reach several cortical areas involved in processing aspects of the nociceptive signals.

• #14 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  The associated cranial autonomic symptoms characteristic of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway through parasympathetic outflow from the superior salivatory nucleus, the cranial facial nerve, through the sphenopalatine ganglion, resulting in vasodilatation and parasympathetic activation. […] These clinical features of cluster headache suggest a central mechanism, in particular, the hypothalamus. […] The role of the hypothalamus in cluster headache was further supported by the therapeutic effect of targeting the posterior hypothalamic gray through deep brain stimulation in cluster headache patients. […] The pathogenesis involving the trigeminal-autonomic reflex, the trigeminovascular pathway, and hypothalamus provides an explanation for the clinical phenotype.

• #15 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  The hypothalamus has a definite association with cluster headaches. The attacks have a circadian periodicity, happen most often at night, have a relapsing-remitting course, and have seasonal variation, all of which imply the involvement of the hypothalamus, the biological clock. […] The parasympathetic nerve fibers are part of the trigeminal autonomic reflex. Stimulation of trigeminal afferents projecting to nociceptive pathways like sphenopalatine ganglion and trigeminal ganglion may cause pain and autonomic symptoms, including conjunctival injection or lacrimation, rhinorrhea, and facial vasodilation; as a result of central disinhibition and neuropeptide release. […] As stated above, there is no single clear source of cluster headaches. There is a circadian periodicity, leading to investigation of the hypothalamus, which ultimately shows abnormalities in morphology studies.

• #16 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The first is the hypothalamus, which may be the location where cluster attacks originate. Not only is the hypothalamus the site of the circadian pacemaker in the suprachiasmatic nucleus, but imaging data shows preferential activation of the posterior hypothalamus at the onset of a cluster headache. Anatomical and functional changes of the hypothalamus have also been seen in cluster headache patients, as have alterations in hypothalamic and pituitary molecules such as orexin, melatonin, and luteinizing hormone. […] The second system involved in cluster headache is the autonomic system, specifically the superior salivatory nucleus and the sphenopalatine ganglion, which includes molecules such as vasoactive intestinal peptide that have been shown to be altered in cluster headache. Stimulation of the sphenopalatine ganglion can trigger or abort a cluster headache attack, depending on the setting.

• #17 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  Activation of the cranial SuS-parasympathetic pathway is believed to directly contribute to cranial autonomic symptoms found in cluster headache and up to 50% in migraine patients. Indeed, activation of this pathway induces a dilation of intracranial vessels and a cascade of events that results in plasma protein extravasation, neuropeptide release from dural vascular terminals of post-SPG neurons, local dural release of inflammatory mediators with perivascular alteration and activation and sensitization of the trigeminovascular system. The SuS also has a bidirectional connection with the hypothalamus, as well as with the limbic and cortical areas. […] The hypothalamus is involved in numerous physiological functions including controlling circadian rhythm. Furthermore, it has several connections involved in pain modulation in migraine as well as in cluster headache. The hypothalamus also partakes in autonomic and endocrine regulation. Preclinical data show that specific hypothalamic nuclei, such as the paraventricular and lateral hypothalamus, reach the TNC and SuS neurons through descending projections, thus influencing and triggering somatosensory and autonomic neurovascular mechanisms. The premonitory symptoms of headaches are considered the clinical side of an underlying hypothalamic dysregulation. Many neuro-endocrinological data support the hypothesis of hypothalamic-pituitary-adrenal axis failure in these primary headache disorders.

• #18 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  The hypothalamus has a definite association with cluster headaches. The attacks have a circadian periodicity, happen most often at night, have a relapsing-remitting course, and have seasonal variation, all of which imply the involvement of the hypothalamus, the biological clock. […] The parasympathetic nerve fibers are part of the trigeminal autonomic reflex. Stimulation of trigeminal afferents projecting to nociceptive pathways like sphenopalatine ganglion and trigeminal ganglion may cause pain and autonomic symptoms, including conjunctival injection or lacrimation, rhinorrhea, and facial vasodilation; as a result of central disinhibition and neuropeptide release. […] As stated above, there is no single clear source of cluster headaches. There is a circadian periodicity, leading to investigation of the hypothalamus, which ultimately shows abnormalities in morphology studies.

• #19 Cluster headache | Tidsskrift for Den norske legeforening

  https://tidsskriftet.no/en/2015/08/cluster-headache

  Cluster headache is a relatively rare type of headache, but nevertheless the most common of the so-called trigeminal autonomic cephalagias. The mechanisms that underlie cluster headache attacks are only partially known. A small area of the anterior hypothalamus determines rhythmic diurnal fluctuations in a number of physiological functions. This part of the brain was believed early on to be responsible for generating cluster headache attacks, on the basis of their striking regularity. In the late 1990s, positron emission tomography (PET) revealed marked activation of the posterior hypothalamus during nitroglycerin-induced attacks. The pain associated with cluster headache is mediated by the first branch of the fifth cranial nerve (trigeminal nerve). Increased levels of both calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are detected during both spontaneous and nitroglycerin-induced cluster headache attacks. It is assumed that strong activation of the trigeminal nucleus (pain signals) reflexively activates these fibres. In addition to symptoms that indicate increased parasympathetic activation during cluster headache attacks, many patients also show symptoms of sympathetic failure on the headache-affected side, in the form of a Horner-like syndrome. The most widely accepted theory is that this is the result of compression or stretching of the oculosympathetic fibres, which are in the adventitia of the internal carotid artery, due to parasympathetic vasodilation. […] The pathophysiology is unclear, but much suggests a central role for the hypothalamus.

• #20 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  The associated cranial autonomic symptoms characteristic of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway through parasympathetic outflow from the superior salivatory nucleus, the cranial facial nerve, through the sphenopalatine ganglion, resulting in vasodilatation and parasympathetic activation. […] These clinical features of cluster headache suggest a central mechanism, in particular, the hypothalamus. […] The role of the hypothalamus in cluster headache was further supported by the therapeutic effect of targeting the posterior hypothalamic gray through deep brain stimulation in cluster headache patients. […] The pathogenesis involving the trigeminal-autonomic reflex, the trigeminovascular pathway, and hypothalamus provides an explanation for the clinical phenotype.

• #21 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  The hypothalamus has a definite association with cluster headaches. The attacks have a circadian periodicity, happen most often at night, have a relapsing-remitting course, and have seasonal variation, all of which imply the involvement of the hypothalamus, the biological clock. […] The parasympathetic nerve fibers are part of the trigeminal autonomic reflex. Stimulation of trigeminal afferents projecting to nociceptive pathways like sphenopalatine ganglion and trigeminal ganglion may cause pain and autonomic symptoms, including conjunctival injection or lacrimation, rhinorrhea, and facial vasodilation; as a result of central disinhibition and neuropeptide release. […] As stated above, there is no single clear source of cluster headaches. There is a circadian periodicity, leading to investigation of the hypothalamus, which ultimately shows abnormalities in morphology studies.

• #22 Cluster Headache: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1142459-overview

  Cluster headache (CH), also known as histamine headache, is a primary neurovascular headache disorder, the pathophysiology and etiology of which are not well understood. […] The underlying pathophysiology of cluster headache (CH) is incompletely understood. […] The periodicity of the attacks suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms), with central disinhibition of the nociceptive and autonomic pathwaysspecifically, the trigeminal nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified the posterior hypothalamic gray matter as the key area for the basic defect in CH. […] Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance spectroscopy. […] Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. […] Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be precipitated with small amounts of histamine.

• #23 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The first is the hypothalamus, which may be the location where cluster attacks originate. Not only is the hypothalamus the site of the circadian pacemaker in the suprachiasmatic nucleus, but imaging data shows preferential activation of the posterior hypothalamus at the onset of a cluster headache. Anatomical and functional changes of the hypothalamus have also been seen in cluster headache patients, as have alterations in hypothalamic and pituitary molecules such as orexin, melatonin, and luteinizing hormone. […] The second system involved in cluster headache is the autonomic system, specifically the superior salivatory nucleus and the sphenopalatine ganglion, which includes molecules such as vasoactive intestinal peptide that have been shown to be altered in cluster headache. Stimulation of the sphenopalatine ganglion can trigger or abort a cluster headache attack, depending on the setting.

• #24 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In CH, activation in the hypothalamic grey matter ipsilateral to the side of a headache during attacks is seen with PET and fMRI. Also, altered functional connectivity of the hypothalamus and anterior thalamus were described. A voxel-based morphometry (VBM) study revealed concomitant grey matter volume increase of this hypothalamic region, but other VBM studies did not substantiate these results. Interestingly, a recent work hypothesized that the anterior hypothalamus might contribute to the circadian rhythm of CH attacks, whereas the posterior part might generate the restlessness experienced by CH patients during the attack. […] The efficacy of anti CGRP monoclonal antibodies and greater occipital nerve (GON) blockade in both migraine and CH indicates that the activation of the trigeminovascular system (with consequent release of CGRP) and the TCC is a key mechanism involved in the pathogenesis of both migraine and CH. Furthermore, the good response to oral corticosteroids as a transitional treatment may indicate that they may reduce the neurogenic inflammation induced by the activation of the trigeminovascular system in both diseases. The efficacy of melatonin in the prophylactic therapy for both migraine and CH points towards a pathogenetic role for the hypothalamus and the circadian rhythm regulation system in both migraine and CH. The pharmacological effect of verapamil is probably due to the interactions with muscarinic, serotoninergic and dopaminergic receptors, the inhibition of presynaptic adrenergic receptors (with a consequent increase in noradrenaline release) and the modulation of pain pathways. Its efficacy in both migraine and CH could be due to the modulation of brainstem circuitries, the rebalancing of autonomic system and the restoration of the pain control system.

• #25 Cluster headache – Wikipedia

  https://en.wikipedia.org/wiki/Cluster_headache

  The specific causes and pathogenesis of cluster headaches are not fully understood. […] Some experts consider the posterior hypothalamus to be important in the pathogenesis of cluster headaches. This is supported by a relatively high success ratio of deep-brain stimulation therapy on the posterior hypothalamic grey matter. […] A review suggests that the suprachiasmatic nucleus of the hypothalamus, which is the major biological clock in the human body, may be involved in cluster headaches, because cluster headaches occur with diurnal and seasonal rhythmicity. […] Positron emission tomography (PET) scans indicate the brain areas which are activated during attack only, compared to pain free periods. These pictures show brain areas that are active during pain in yellow/orange color (called „pain matrix”). The area in the center (in all three views) is activated only during cluster headaches. The bottom row voxel-based morphometry shows structural brain differences between individuals with and without CH; only a portion of the hypothalamus is different.

• #26 Cluster headache – Wikipedia

  https://en.wikipedia.org/wiki/Cluster_headache

  The specific causes and pathogenesis of cluster headaches are not fully understood. […] Some experts consider the posterior hypothalamus to be important in the pathogenesis of cluster headaches. This is supported by a relatively high success ratio of deep-brain stimulation therapy on the posterior hypothalamic grey matter. […] A review suggests that the suprachiasmatic nucleus of the hypothalamus, which is the major biological clock in the human body, may be involved in cluster headaches, because cluster headaches occur with diurnal and seasonal rhythmicity. […] Positron emission tomography (PET) scans indicate the brain areas which are activated during attack only, compared to pain free periods. These pictures show brain areas that are active during pain in yellow/orange color (called „pain matrix”). The area in the center (in all three views) is activated only during cluster headaches. The bottom row voxel-based morphometry shows structural brain differences between individuals with and without CH; only a portion of the hypothalamus is different.

• #27 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  Activation of the cranial SuS-parasympathetic pathway is believed to directly contribute to cranial autonomic symptoms found in cluster headache and up to 50% in migraine patients. Indeed, activation of this pathway induces a dilation of intracranial vessels and a cascade of events that results in plasma protein extravasation, neuropeptide release from dural vascular terminals of post-SPG neurons, local dural release of inflammatory mediators with perivascular alteration and activation and sensitization of the trigeminovascular system. The SuS also has a bidirectional connection with the hypothalamus, as well as with the limbic and cortical areas. […] The hypothalamus is involved in numerous physiological functions including controlling circadian rhythm. Furthermore, it has several connections involved in pain modulation in migraine as well as in cluster headache. The hypothalamus also partakes in autonomic and endocrine regulation. Preclinical data show that specific hypothalamic nuclei, such as the paraventricular and lateral hypothalamus, reach the TNC and SuS neurons through descending projections, thus influencing and triggering somatosensory and autonomic neurovascular mechanisms. The premonitory symptoms of headaches are considered the clinical side of an underlying hypothalamic dysregulation. Many neuro-endocrinological data support the hypothesis of hypothalamic-pituitary-adrenal axis failure in these primary headache disorders.

• #28 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  The associated cranial autonomic symptoms characteristic of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway through parasympathetic outflow from the superior salivatory nucleus, the cranial facial nerve, through the sphenopalatine ganglion, resulting in vasodilatation and parasympathetic activation. […] These clinical features of cluster headache suggest a central mechanism, in particular, the hypothalamus. […] The role of the hypothalamus in cluster headache was further supported by the therapeutic effect of targeting the posterior hypothalamic gray through deep brain stimulation in cluster headache patients. […] The pathogenesis involving the trigeminal-autonomic reflex, the trigeminovascular pathway, and hypothalamus provides an explanation for the clinical phenotype.

• #29

  https://link.springer.com/article/10.1007/s40263-019-00696-2

  How this hypothalamic activation contributes to the generation of cluster headache attacks remains unclear, but the hypothalamus is currently regarded as the attack generator. […] Attention has recently shifted to structural and functional connectivity studies revealing changes in the pain matrix. […] Alterations in non-traditional pain-processing networks, including the hypothalamic-cerebellar network and occipital networks have also been reported. […] The hypothalamus is involved in cluster headache pathogenesis.

• #30 Evidence-based treatments for cluster headache | TCRM

  https://www.dovepress.com/evidence-based-treatments-for-cluster-headache-peer-reviewed-fulltext-article-TCRM

  Elevated plasma levels of CGRP in the external jugular vein have been found during CH attacks. […] This finding may indicate a hyperactive state of the trigeminal system during the bout. […] From the autonomic symptoms of CHs, it can be deduced that ipsilateral sympathetic dysfunction (ptosis, miosis, and facial sweating) and parasympathetic activation occur (rhinorrhea, lacrimation, and nasal congestion). […] However, the episodic and circadian pattern cannot be explained by a vascular phenomenon alone, as they suggest dysfunction of a central pacemaker, namely, the hypothalamus. […] Testosterone levels have been found to be lower in patients with CH during the attack, providing initial evidence for the involvement of the hypothalamus. […] This was supported by evidence of reduced stimulation by thyrotropin-releasing hormone and observations of disordered circadian rhythm for cortisol, luteinizing hormone, growth hormone, and prolactin.

• #31 Current Understanding on Pain Mechanism in Migraine and Cluster Headache

  https://brieflands.com/articles/aapm-17559.html

  The central sensitization hypothesis suggests an altered processing sensory signal in the brainstem, where the neurons of trigemino-cervical (TCC) system become hyperexcitable. […] In CH, activation of the trigeminovascular system triggers autonomic manifestations through the trigeminal-autonomic reflex. […] Neurogenic inflammation refers to a neurally mediated inflammatory response in meningeal tissue characterised by vasodilatation, leakage of plasma protein from blood vessels and mast cell degranulation. […] Elevated concentrations of CGRP, SP and VIP have been found in plasma samples during migraine attacks and also in attacks of CH. […] Studies conducted by Kudrow et al. were the first to implicate the hypothalamus in the pathogenesis of CH with the demonstration of lower levels of testosterone during a bout.

• #32 Evidence-based treatments for cluster headache | TCRM

  https://www.dovepress.com/evidence-based-treatments-for-cluster-headache-peer-reviewed-fulltext-article-TCRM

  Melatonin is suspected to be involved in CH genesis, mainly because it is a sensitive marker of endogenous rhythms, which are disrupted in CH. […] A suppressed nocturnal peak in melatonin is seen during the active phase of a CH, providing further evidence for a role of the hypothalamus gray matter in the pathophysiology of CHs. […] May et al, in a landmark study, confirmed a highly specific activation of the hypothalamic gray matter using positron emission tomography images in nitroglycerine-induced and spontaneous CHs, providing indisputable evidence for its role in CH. […] The term neurovascular headache, with reference to migraine, CH, and related disorders, is therefore a more appropriate term.

• #33 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In CH, activation in the hypothalamic grey matter ipsilateral to the side of a headache during attacks is seen with PET and fMRI. Also, altered functional connectivity of the hypothalamus and anterior thalamus were described. A voxel-based morphometry (VBM) study revealed concomitant grey matter volume increase of this hypothalamic region, but other VBM studies did not substantiate these results. Interestingly, a recent work hypothesized that the anterior hypothalamus might contribute to the circadian rhythm of CH attacks, whereas the posterior part might generate the restlessness experienced by CH patients during the attack. […] The efficacy of anti CGRP monoclonal antibodies and greater occipital nerve (GON) blockade in both migraine and CH indicates that the activation of the trigeminovascular system (with consequent release of CGRP) and the TCC is a key mechanism involved in the pathogenesis of both migraine and CH. Furthermore, the good response to oral corticosteroids as a transitional treatment may indicate that they may reduce the neurogenic inflammation induced by the activation of the trigeminovascular system in both diseases. The efficacy of melatonin in the prophylactic therapy for both migraine and CH points towards a pathogenetic role for the hypothalamus and the circadian rhythm regulation system in both migraine and CH. The pharmacological effect of verapamil is probably due to the interactions with muscarinic, serotoninergic and dopaminergic receptors, the inhibition of presynaptic adrenergic receptors (with a consequent increase in noradrenaline release) and the modulation of pain pathways. Its efficacy in both migraine and CH could be due to the modulation of brainstem circuitries, the rebalancing of autonomic system and the restoration of the pain control system.

• #34 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The first is the hypothalamus, which may be the location where cluster attacks originate. Not only is the hypothalamus the site of the circadian pacemaker in the suprachiasmatic nucleus, but imaging data shows preferential activation of the posterior hypothalamus at the onset of a cluster headache. Anatomical and functional changes of the hypothalamus have also been seen in cluster headache patients, as have alterations in hypothalamic and pituitary molecules such as orexin, melatonin, and luteinizing hormone. […] The second system involved in cluster headache is the autonomic system, specifically the superior salivatory nucleus and the sphenopalatine ganglion, which includes molecules such as vasoactive intestinal peptide that have been shown to be altered in cluster headache. Stimulation of the sphenopalatine ganglion can trigger or abort a cluster headache attack, depending on the setting.

• #35 Current Understanding on Pain Mechanism in Migraine and Cluster Headache

  https://brieflands.com/articles/aapm-17559

  In CH, activation of the trigeminovascular system triggers autonomic manifestations through the trigeminal-autonomic reflex. […] Neurogenic inflammation refers to a neurally mediated inflammatory response in meningeal tissue characterised by vasodilatation, leakage of plasma protein from blood vessels and mast cell degranulation. […] The release of neuropeptides has been proposed as a pain mechanism in migraine and other primary headaches. […] Elevated concentrations of CGRP, SP and VIP have been found in plasma samples during migraine attacks and also in attacks of CH. […] Studies conducted by Kudrow et al. were the first to implicate the hypothalamus in the pathogenesis of CH with the demonstration of lower levels of testosterone during a bout. […] Neuroimaging further supports the role of the hypothalamus in CH. PET imaging studies in nitroglycerine-provocation or spontaneous CH have found activation in the posterior hypothalamic gray matter. […] The authors concluded that the hypometabolism in and out of a bout in the PACC, a structure involved in the central descending opiatergic pain control system, may predispose to CH and to its recurrence.

• #36

  https://journals.lww.com/co-neurology/abstract/1994/06000/the_pathogenesis_of_cluster_headache.17.aspx

  Cluster headache is described here as having three distinct and contiguous clinical phases. Evidence of the pathophysiological changes associated with each phase is reviewed. The first phase, the cluster period, is characterized by chronobiological aberrations and impaired sympathetic nervous system activity. […] These changes may result in impaired autoregulatory chemoreceptor activity and susceptibility to attack provocation. An hypothesis that attempts to explain the second phase, cluster attack induction, is reviewed. Evidence for this model suggests that as a result of chemoreceptor dysfunction, a sustained hypoxemic event, as may result from altitude hypoxia, sleep apnea, or vasodilators, could provoke the cluster attack. […] Attack symptoms and signs, which constitute the third phase of cluster headache, are likely the result of parasympathetic and trigeminal nerve stimulation. Specifically, cluster headache pain is likely the consequence of neurovascular inflammation, as hypothesized in the trigeminovascular theory.

• #37 Current Understanding on Pain Mechanism in Migraine and Cluster Headache

  https://brieflands.com/articles/aapm-17559

  In CH, activation of the trigeminovascular system triggers autonomic manifestations through the trigeminal-autonomic reflex. […] Neurogenic inflammation refers to a neurally mediated inflammatory response in meningeal tissue characterised by vasodilatation, leakage of plasma protein from blood vessels and mast cell degranulation. […] The release of neuropeptides has been proposed as a pain mechanism in migraine and other primary headaches. […] Elevated concentrations of CGRP, SP and VIP have been found in plasma samples during migraine attacks and also in attacks of CH. […] Studies conducted by Kudrow et al. were the first to implicate the hypothalamus in the pathogenesis of CH with the demonstration of lower levels of testosterone during a bout. […] Neuroimaging further supports the role of the hypothalamus in CH. PET imaging studies in nitroglycerine-provocation or spontaneous CH have found activation in the posterior hypothalamic gray matter. […] The authors concluded that the hypometabolism in and out of a bout in the PACC, a structure involved in the central descending opiatergic pain control system, may predispose to CH and to its recurrence.

• #38 Approved in Migraine, CGRP Antagonists Also Promising in Cluster Headache – Neurology Advisor

  https://www.neurologyadvisor.com/features/approved-in-migraine-cgrp-antagonists-also-promising-in-cluster-headache/

  Cluster headache has been called the most severe pain condition occurring in people, with associated pain described as tearing, stabbing, and burning. […] The central denominator in both diseases may be the trigeminovascular pathway, alteration in hypothalamic activity, and functional changes in hypothalamic-brainstem connectivity, noted the review authors. […] Accumulating evidence, including a recent placebo-controlled provocation study led by Dr Vollesen, suggests that CGRP is also involved in cluster headache. […] [CGRP] may exert its cluster headache-inducing abilities in 3 distinctive ways, the investigators wrote. First, this may happen via vascular effects of CGRP, likely involving neurogenic inflammation. Second, CGRP receptor components are also found in the human trigeminal ganglion, which has been suggested as the possible site of action for the CGRP receptor antagonists in migraine treatment. Third, neurons in sphenopalatine ganglion express CGRP and its receptor components. Efferent outflow from sphenopalatine ganglia is suggested as initiating mechanism of cluster headache attacks, and on-demand sphenopalatine ganglia stimulation is an effective novel therapy for individuals with cluster headache with dual effects, acute pain relief, and attack prevention.

• #39 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In CH, activation in the hypothalamic grey matter ipsilateral to the side of a headache during attacks is seen with PET and fMRI. Also, altered functional connectivity of the hypothalamus and anterior thalamus were described. A voxel-based morphometry (VBM) study revealed concomitant grey matter volume increase of this hypothalamic region, but other VBM studies did not substantiate these results. Interestingly, a recent work hypothesized that the anterior hypothalamus might contribute to the circadian rhythm of CH attacks, whereas the posterior part might generate the restlessness experienced by CH patients during the attack. […] The efficacy of anti CGRP monoclonal antibodies and greater occipital nerve (GON) blockade in both migraine and CH indicates that the activation of the trigeminovascular system (with consequent release of CGRP) and the TCC is a key mechanism involved in the pathogenesis of both migraine and CH. Furthermore, the good response to oral corticosteroids as a transitional treatment may indicate that they may reduce the neurogenic inflammation induced by the activation of the trigeminovascular system in both diseases. The efficacy of melatonin in the prophylactic therapy for both migraine and CH points towards a pathogenetic role for the hypothalamus and the circadian rhythm regulation system in both migraine and CH. The pharmacological effect of verapamil is probably due to the interactions with muscarinic, serotoninergic and dopaminergic receptors, the inhibition of presynaptic adrenergic receptors (with a consequent increase in noradrenaline release) and the modulation of pain pathways. Its efficacy in both migraine and CH could be due to the modulation of brainstem circuitries, the rebalancing of autonomic system and the restoration of the pain control system.

• #40 Cluster headache: pathogenesis, diagnosis, and – ProQuest

  https://www.proquest.com/docview/199041951/5F003E9D95DB473CPQ/3

  Cluster headache is a stereotyped primary pain syndrome characterised by strictly unilateral severe pain, localised in or around the eye and accompanied by ipsilateral autonomic features. […] The syndrome is characterised by the circadian rhythmicity of the short-lived attacks, and the regular recurrence of headache bouts, which are interspersed by periods of complete remission in most individuals. […] Consequently, the vascular theory has been superseded by recognition that neurovascular factors are more important. […] The increased familial risk suggests that cluster headache has a genetic component in some families. […] Neuroimaging has broadened our pathophysiological view and has led to successful treatment by deep brain stimulation of the hypothalamus.

• #41 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The cause of cluster headaches is poorly understood. About five to 10 percent of cluster headache patients have a family history of cluster headache, suggesting a genetic link. Presumably, cluster headache has multiple susceptibility genes. One of those genes may be the orexin/hypocretin receptor 2 (HCRTR2) which is implicated in sleep, narcolepsy, and hypothalamic functioning. Mutations in HCRTR2 were associated with cluster headache in two independent studies, but not in a third. Cluster headache patients are much more likely to use tobacco than the general population, and the rate of patent foramen ovale is higher, but a causative relationship with these factors has not been established. […] Cluster headaches have been associated with hypothalamic and pituitary tumors, meningiomas (anywhere from the cavernous sinus to the upper cervical spine), carotid artery dissections, vascular malformations, and sleep apnea. These associations, and the clinical features of cluster headache, suggest that there are three brain systems involved.

• #42 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The cause of cluster headaches is poorly understood. About five to 10 percent of cluster headache patients have a family history of cluster headache, suggesting a genetic link. Presumably, cluster headache has multiple susceptibility genes. One of those genes may be the orexin/hypocretin receptor 2 (HCRTR2) which is implicated in sleep, narcolepsy, and hypothalamic functioning. Mutations in HCRTR2 were associated with cluster headache in two independent studies, but not in a third. Cluster headache patients are much more likely to use tobacco than the general population, and the rate of patent foramen ovale is higher, but a causative relationship with these factors has not been established. […] Cluster headaches have been associated with hypothalamic and pituitary tumors, meningiomas (anywhere from the cavernous sinus to the upper cervical spine), carotid artery dissections, vascular malformations, and sleep apnea. These associations, and the clinical features of cluster headache, suggest that there are three brain systems involved.

• #43 Cluster Headache | AAFP

  https://www.aafp.org/pubs/afp/issues/2013/0715/p122.html

  Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face. […] The pathophysiology of cluster headache is not fully understood, but may include a genetic component. […] The pathophysiology of cluster headache is not fully understood. Current theories implicate mechanisms such as vascular dilation, trigeminal nerve stimulation, and circadian effects. Histamine release, an increase in mast cells, genetic factors, and autonomic nervous system activation may also contribute. […] Acute cluster headache has been shown to involve activation of the posterior hypothalamic gray matter, and is inherited as an autosomal dominant condition in about 5% of patients. […] One study showed an association between cluster headache and the HCRTR2 gene. […] Disturbed circadian rhythms have been suggested as a possible contributor because headaches often begin during sleep.

• #44 Lesson: Pharmacologic Management of Cluster Headache

  https://journalce.powerpak.com/ce/pharmacologic-management-of-cluster-headache

  Genetic risk factors may also play a role in the pathophysiology of cluster headache. The G1246A polymorphism of the hypocretin 2 receptor, or orexin receptor type 2, is associated with a higher incidence of cluster headache. Hypocretin (or orexin) is a neuropeptide located in the lateral and posterior hypothalamus that is involved in the sleep-wake cycle and energy homeostasis. The degree of involvement of hypocretin neuropeptides in cluster headache is not known, and further research is needed to understand their interplay in cluster headache.

• #45 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers. […] Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. […] Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine. […] Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase-activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.

• #46 Cluster Headache and Migraine Shared and Unique Insights: Neurophysiological Implications, Neuroimaging, and Biomarkers: A Comprehensive Review

  https://www.mdpi.com/2077-0383/14/7/2160

  Pathophysiological characteristics of these two conditions include both peripheral and central mechanisms. […] However, it is now known that any nociceptive input triggers activations of central structures related to pain processing, which, along with the convergence of trigeminal and cervical nociceptive afferents in the caudal portion of the spinal trigeminal nucleus, explains that pain in CH and in MH is more attributed to central rather than peripheral changes. […] Thus, it is understandable that, on one hand, vasodilation may represent one of the possible triggers, but on the other hand, it should not be considered the cause of the disease, but rather an epiphenomenon. […] In general, both parasympathetic peripheral mechanisms and changes related to the trigeminovascular system play a secondary role in the pathophysiology of CH and MH, with central mechanisms now considered the primary factors in the pathophysiology of the diseases.

• #47 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  Various neuroimaging studies implicate the brainstem in the pathophysiology of migraine and CH. In migraine, abnormalities are seen in both ascending and descending nociceptive pathways during ictal and inter-ictal phases. Positron emission tomography (PET) imaging studies showed increased dorsal pons activation in migraine patients during the ictal phase. Functional magnetic resonance imaging (fMRI) studies reported increased functional connectivity between the cortical and subcortical regions involved in nociceptive processing and the PAG, having connections coming from the thalamus, hypothalamus, and autonomic nervous system. […] A dysfunction of pain control systems in both headaches and a role of the brainstem in their pathogenesis is also supported by neurophysiological studies. In migraine, loss of habituation, lower cortical pre-activation and abnormal sensitization was seen. In CH, altered pain perception and decreased pain thresholds was found.

• #48 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers. […] Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. […] Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine. […] Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase-activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.

• #49 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers. […] Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. […] Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine. […] Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase-activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.

• #50 Cluster Headache – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544241/

  There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers. […] Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. […] Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine. […] Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase-activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.

• #51 Cluster Headache Pathophysiology—A Disorder of Network Excitability?

  https://www.mdpi.com/2514-183X/5/2/16

  Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. […] Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. […] In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. […] Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). […] In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures.

• #52 Cluster Headache Pathophysiology—A Disorder of Network Excitability?

  https://www.mdpi.com/2514-183X/5/2/16

  Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. […] Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. […] In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. […] Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). […] In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures.

• #53 Cluster Headache Pathophysiology—A Disorder of Network Excitability?

  https://www.mdpi.com/2514-183X/5/2/16

  Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. […] Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. […] In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. […] Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). […] In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures.

• #54 Cluster Headache Pathophysiology—A Disorder of Network Excitability?

  https://www.mdpi.com/2514-183X/5/2/16

  Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. […] Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. […] In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. […] Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). […] In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures.

• #55 Cluster Headache Pathophysiology—A Disorder of Network Excitability?

  https://www.mdpi.com/2514-183X/5/2/16

  Consequently, these studies suggest that the pathophysiology of CH attacks implicates networks processing Aδ-fibre input. […] The chronology of central sensitization in CH is unstudied; in particular, we do not know whether sensitization precedes the bout or is a consequence thereof. […] We hypothesize that when the summation of several influencing factors maximally reduced the pain threshold, even weak activation of nociceptors might lead to the perception of intense pain with excitatory influences strongly outweighing inhibiting factors. […] The pathophysiological cascade of CH attacks outlined above implies network overactivity and malfunctioning of homeostatic plasticity in analogy to epileptic seizures. […] The predicted network overactivity may explain the excruciating pain that accompanies the attacks.

• #56

  https://link.springer.com/article/10.1007/s40263-019-00696-2

  How this hypothalamic activation contributes to the generation of cluster headache attacks remains unclear, but the hypothalamus is currently regarded as the attack generator. […] Attention has recently shifted to structural and functional connectivity studies revealing changes in the pain matrix. […] Alterations in non-traditional pain-processing networks, including the hypothalamic-cerebellar network and occipital networks have also been reported. […] The hypothalamus is involved in cluster headache pathogenesis.

• #57 Cluster headache – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/11/cluster-headache

  Cluster headache is the most common trigeminal autonomic cephalalgia. This primary headache disorder is characterized by attacks of severe unilateral pain localized to the orbital, periorbital, and/or temporal areas that last from 15 to 180 minutes. It occurs from once every other day to 8 times per day. […] Pathophysiology is thought to result from hypothalamic activation with secondary trigeminal and autonomic activation. Triggers for cluster attacks include alcohol, strong smells, sleep, circadian disruption, and weather changes.

• #58 Cluster headache – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/11/cluster-headache

  Cluster headache is the most common trigeminal autonomic cephalalgia. This primary headache disorder is characterized by attacks of severe unilateral pain localized to the orbital, periorbital, and/or temporal areas that last from 15 to 180 minutes. It occurs from once every other day to 8 times per day. […] Pathophysiology is thought to result from hypothalamic activation with secondary trigeminal and autonomic activation. Triggers for cluster attacks include alcohol, strong smells, sleep, circadian disruption, and weather changes.

• #59 Cluster headache – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/11/cluster-headache

  Cluster headache is the most common trigeminal autonomic cephalalgia. This primary headache disorder is characterized by attacks of severe unilateral pain localized to the orbital, periorbital, and/or temporal areas that last from 15 to 180 minutes. It occurs from once every other day to 8 times per day. […] Pathophysiology is thought to result from hypothalamic activation with secondary trigeminal and autonomic activation. Triggers for cluster attacks include alcohol, strong smells, sleep, circadian disruption, and weather changes.

• #60 Cluster headache – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/11/cluster-headache

  Cluster headache is the most common trigeminal autonomic cephalalgia. This primary headache disorder is characterized by attacks of severe unilateral pain localized to the orbital, periorbital, and/or temporal areas that last from 15 to 180 minutes. It occurs from once every other day to 8 times per day. […] Pathophysiology is thought to result from hypothalamic activation with secondary trigeminal and autonomic activation. Triggers for cluster attacks include alcohol, strong smells, sleep, circadian disruption, and weather changes.

• #61 Cluster headache – Symptoms, Causes, Images, and Treatment Options

  https://www.epocrates.com/online/diseases/11/cluster-headache

  Cluster headache is the most common trigeminal autonomic cephalalgia. This primary headache disorder is characterized by attacks of severe unilateral pain localized to the orbital, periorbital, and/or temporal areas that last from 15 to 180 minutes. It occurs from once every other day to 8 times per day. […] Pathophysiology is thought to result from hypothalamic activation with secondary trigeminal and autonomic activation. Triggers for cluster attacks include alcohol, strong smells, sleep, circadian disruption, and weather changes.

• #62

  https://journals.lww.com/co-neurology/abstract/1994/06000/the_pathogenesis_of_cluster_headache.17.aspx

  Cluster headache is described here as having three distinct and contiguous clinical phases. Evidence of the pathophysiological changes associated with each phase is reviewed. The first phase, the cluster period, is characterized by chronobiological aberrations and impaired sympathetic nervous system activity. […] These changes may result in impaired autoregulatory chemoreceptor activity and susceptibility to attack provocation. An hypothesis that attempts to explain the second phase, cluster attack induction, is reviewed. Evidence for this model suggests that as a result of chemoreceptor dysfunction, a sustained hypoxemic event, as may result from altitude hypoxia, sleep apnea, or vasodilators, could provoke the cluster attack. […] Attack symptoms and signs, which constitute the third phase of cluster headache, are likely the result of parasympathetic and trigeminal nerve stimulation. Specifically, cluster headache pain is likely the consequence of neurovascular inflammation, as hypothesized in the trigeminovascular theory.

• #63

  https://journals.lww.com/co-neurology/abstract/1994/06000/the_pathogenesis_of_cluster_headache.17.aspx

  Cluster headache is described here as having three distinct and contiguous clinical phases. Evidence of the pathophysiological changes associated with each phase is reviewed. The first phase, the cluster period, is characterized by chronobiological aberrations and impaired sympathetic nervous system activity. […] These changes may result in impaired autoregulatory chemoreceptor activity and susceptibility to attack provocation. An hypothesis that attempts to explain the second phase, cluster attack induction, is reviewed. Evidence for this model suggests that as a result of chemoreceptor dysfunction, a sustained hypoxemic event, as may result from altitude hypoxia, sleep apnea, or vasodilators, could provoke the cluster attack. […] Attack symptoms and signs, which constitute the third phase of cluster headache, are likely the result of parasympathetic and trigeminal nerve stimulation. Specifically, cluster headache pain is likely the consequence of neurovascular inflammation, as hypothesized in the trigeminovascular theory.

• #64 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The cause of cluster headaches is poorly understood. About five to 10 percent of cluster headache patients have a family history of cluster headache, suggesting a genetic link. Presumably, cluster headache has multiple susceptibility genes. One of those genes may be the orexin/hypocretin receptor 2 (HCRTR2) which is implicated in sleep, narcolepsy, and hypothalamic functioning. Mutations in HCRTR2 were associated with cluster headache in two independent studies, but not in a third. Cluster headache patients are much more likely to use tobacco than the general population, and the rate of patent foramen ovale is higher, but a causative relationship with these factors has not been established. […] Cluster headaches have been associated with hypothalamic and pituitary tumors, meningiomas (anywhere from the cavernous sinus to the upper cervical spine), carotid artery dissections, vascular malformations, and sleep apnea. These associations, and the clinical features of cluster headache, suggest that there are three brain systems involved.

• #65 Cluster Headache: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1142459-overview

  Cluster headache (CH), also known as histamine headache, is a primary neurovascular headache disorder, the pathophysiology and etiology of which are not well understood. […] The underlying pathophysiology of cluster headache (CH) is incompletely understood. […] The periodicity of the attacks suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms), with central disinhibition of the nociceptive and autonomic pathwaysspecifically, the trigeminal nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified the posterior hypothalamic gray matter as the key area for the basic defect in CH. […] Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance spectroscopy. […] Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. […] Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be precipitated with small amounts of histamine.

• #66 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The first is the hypothalamus, which may be the location where cluster attacks originate. Not only is the hypothalamus the site of the circadian pacemaker in the suprachiasmatic nucleus, but imaging data shows preferential activation of the posterior hypothalamus at the onset of a cluster headache. Anatomical and functional changes of the hypothalamus have also been seen in cluster headache patients, as have alterations in hypothalamic and pituitary molecules such as orexin, melatonin, and luteinizing hormone. […] The second system involved in cluster headache is the autonomic system, specifically the superior salivatory nucleus and the sphenopalatine ganglion, which includes molecules such as vasoactive intestinal peptide that have been shown to be altered in cluster headache. Stimulation of the sphenopalatine ganglion can trigger or abort a cluster headache attack, depending on the setting.

• #67 Migraine and cluster headache – the common link | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-018-0909-4

  In CH, activation in the hypothalamic grey matter ipsilateral to the side of a headache during attacks is seen with PET and fMRI. Also, altered functional connectivity of the hypothalamus and anterior thalamus were described. A voxel-based morphometry (VBM) study revealed concomitant grey matter volume increase of this hypothalamic region, but other VBM studies did not substantiate these results. Interestingly, a recent work hypothesized that the anterior hypothalamus might contribute to the circadian rhythm of CH attacks, whereas the posterior part might generate the restlessness experienced by CH patients during the attack. […] The efficacy of anti CGRP monoclonal antibodies and greater occipital nerve (GON) blockade in both migraine and CH indicates that the activation of the trigeminovascular system (with consequent release of CGRP) and the TCC is a key mechanism involved in the pathogenesis of both migraine and CH. Furthermore, the good response to oral corticosteroids as a transitional treatment may indicate that they may reduce the neurogenic inflammation induced by the activation of the trigeminovascular system in both diseases. The efficacy of melatonin in the prophylactic therapy for both migraine and CH points towards a pathogenetic role for the hypothalamus and the circadian rhythm regulation system in both migraine and CH. The pharmacological effect of verapamil is probably due to the interactions with muscarinic, serotoninergic and dopaminergic receptors, the inhibition of presynaptic adrenergic receptors (with a consequent increase in noradrenaline release) and the modulation of pain pathways. Its efficacy in both migraine and CH could be due to the modulation of brainstem circuitries, the rebalancing of autonomic system and the restoration of the pain control system.

• #68 Cluster Headache: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1142459-overview

  Cluster headache (CH), also known as histamine headache, is a primary neurovascular headache disorder, the pathophysiology and etiology of which are not well understood. […] The underlying pathophysiology of cluster headache (CH) is incompletely understood. […] The periodicity of the attacks suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms), with central disinhibition of the nociceptive and autonomic pathwaysspecifically, the trigeminal nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified the posterior hypothalamic gray matter as the key area for the basic defect in CH. […] Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance spectroscopy. […] Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. […] Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be precipitated with small amounts of histamine.

• #69 Frontiers | Cluster headache: an update on clinical features, epidemiology, pathophysiology, diagnosis, and treatment

  https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1373528/full

  The interaction of these three components is responsible for the characteristic clinical presentation of CH. […] The trigeminovascular system is formed by neurons innervating the dura mater and meningeal vessels, whose neuronal body is in the trigeminal ganglion. […] CH attacks involve activation of parasympathetic outflow, which causes typical trigeminal-autonomic symptoms such as lacrimation, conjunctival injection, and nasal congestion. […] The hypothalamus also plays a role in the nociceptive process of the trigeminovascular system and receives projections from the trigeminal nerve via the trigeminal-hypothalamic tract. […] The mechanistic relevance of the hypothalamus in CH is supported by circannual patterns, attack phenotypes, and accompanying neuroendocrine hormonal alterations, as well as by several neuroimaging studies that revealed an activation of the posterior hypothalamic region during attacks of CH. […] The trigeminovascular system and the trigeminal-autonomic reflex not only modulate each other but also can potentiate each other through the release of vasoactive neuropeptides.

• #70 Cluster headache | Tidsskrift for Den norske legeforening

  https://tidsskriftet.no/en/2015/08/cluster-headache

  Cluster headache is a relatively rare type of headache, but nevertheless the most common of the so-called trigeminal autonomic cephalagias. The mechanisms that underlie cluster headache attacks are only partially known. A small area of the anterior hypothalamus determines rhythmic diurnal fluctuations in a number of physiological functions. This part of the brain was believed early on to be responsible for generating cluster headache attacks, on the basis of their striking regularity. In the late 1990s, positron emission tomography (PET) revealed marked activation of the posterior hypothalamus during nitroglycerin-induced attacks. The pain associated with cluster headache is mediated by the first branch of the fifth cranial nerve (trigeminal nerve). Increased levels of both calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are detected during both spontaneous and nitroglycerin-induced cluster headache attacks. It is assumed that strong activation of the trigeminal nucleus (pain signals) reflexively activates these fibres. In addition to symptoms that indicate increased parasympathetic activation during cluster headache attacks, many patients also show symptoms of sympathetic failure on the headache-affected side, in the form of a Horner-like syndrome. The most widely accepted theory is that this is the result of compression or stretching of the oculosympathetic fibres, which are in the adventitia of the internal carotid artery, due to parasympathetic vasodilation. […] The pathophysiology is unclear, but much suggests a central role for the hypothalamus.

• #71 Approved in Migraine, CGRP Antagonists Also Promising in Cluster Headache – Neurology Advisor

  https://www.neurologyadvisor.com/features/approved-in-migraine-cgrp-antagonists-also-promising-in-cluster-headache/

  We demonstrated that CGRP provokes cluster headache attacks in patients with cluster headache exclusively during active phase in episodic cluster headache and in chronic cluster headache, concluded the review authors. We hypothesize that this difference hails from the hypothalamus modulating the provocability threshold of the system allowing a peripheral trigger to set off attacks. Our results also cautiously suggest efficacy of CGRP antagonism in the treatment of cluster headache and current phase 3 trials elucidating this will emerge in coming years.

• #72

  https://esmed.org/MRA/mra/article/view/3363

  Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. […] Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. […] As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. […] Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251-257. […] May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275-278. […] Wei DY, Goadsby PJ. Cluster headache pathophysiology – insights from current and emerging treatments. Nature reviews Neurology. 2021;17(5):308-324.

• #73 Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5909131/

  The associated cranial autonomic symptoms characteristic of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway through parasympathetic outflow from the superior salivatory nucleus, the cranial facial nerve, through the sphenopalatine ganglion, resulting in vasodilatation and parasympathetic activation. […] These clinical features of cluster headache suggest a central mechanism, in particular, the hypothalamus. […] The role of the hypothalamus in cluster headache was further supported by the therapeutic effect of targeting the posterior hypothalamic gray through deep brain stimulation in cluster headache patients. […] The pathogenesis involving the trigeminal-autonomic reflex, the trigeminovascular pathway, and hypothalamus provides an explanation for the clinical phenotype.

• #74 Cluster headaches | Neurosurgery Inselspital Bern

  https://neurochirurgie.insel.ch/en/diseases-specialities/functional-neurosurgery-and-pain-syndromes/pain-syndromes/cluster-headaches

  Cluster headaches are among the most severely experienced headaches. […] The headaches themselves are accompanied by vegetative symptoms such as watery eyes, runny nose or swelling of the eye. […] If cluster headaches occur chronically and respond inadequately to medication, a neuromodulatory procedure can be considered. […] Both occipital nerve stimulation (ONS) and deep brain stimulation (DBS) are possible effective treatment alternatives for cluster headaches. […] The imaging evaluation of the meta-analysis revealed interesting results. The thalamus and hypothalamus are known to be involved in pain processing. The trigeminal nerve, which also plays a role in the development of cluster headaches, emerges from the brain stem. […] The modulation of precisely these nerve fibers therefore appears to account for the effect of deep brain stimulation on headache suppression.

• #75 What is a Cluster Headache? | Northwest Functional Neurology

  https://www.northwestfunctionalneurology.com/blog/what-is-a-cluster-headache

  The cell bodies of the trigeminal ganglion contain several chemicals that cause blood vessels to dilate, including CGRP. This is elevated during cluster headache attacks as a result of trigeminovascular pathway activation. […] The autonomic symptoms seen of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway, resulting in dilatation of blood vessels and activation of the parasympathetic nervous system. […] Cluster headache bouts occur at the same time each year, particularly during the change in clocks to daylight savings in seasons. This is probably linked with photoperiodism, otherwise known as length of daylight, and involves brain structures including the hypothalamus and suprachiasmatic nucleus. […] There appears to be a mechanism involving poor utilization of oxygen within fibers from the parasympathetic system to blood vessels in the brain. Oxygen has been shown to affect these nerve fibers, and supplemental oxygen can decrease the firing of the trigeminal vascular and autonomic complexes. […] As we have seen, abnormal activation of the trigeminovascular system is believed to be one of the driving factors behind cluster headaches. […] The trigeminovascular system represents one possible common pathophysiological pathway and network in both migraines and cluster headaches.

• #76 Frontiers | Cluster headache: an update on clinical features, epidemiology, pathophysiology, diagnosis, and treatment

  https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2024.1373528/full

  The interaction of these three components is responsible for the characteristic clinical presentation of CH. […] The trigeminovascular system is formed by neurons innervating the dura mater and meningeal vessels, whose neuronal body is in the trigeminal ganglion. […] CH attacks involve activation of parasympathetic outflow, which causes typical trigeminal-autonomic symptoms such as lacrimation, conjunctival injection, and nasal congestion. […] The hypothalamus also plays a role in the nociceptive process of the trigeminovascular system and receives projections from the trigeminal nerve via the trigeminal-hypothalamic tract. […] The mechanistic relevance of the hypothalamus in CH is supported by circannual patterns, attack phenotypes, and accompanying neuroendocrine hormonal alterations, as well as by several neuroimaging studies that revealed an activation of the posterior hypothalamic region during attacks of CH. […] The trigeminovascular system and the trigeminal-autonomic reflex not only modulate each other but also can potentiate each other through the release of vasoactive neuropeptides.

• #77 Approved in Migraine, CGRP Antagonists Also Promising in Cluster Headache – Neurology Advisor

  https://www.neurologyadvisor.com/features/approved-in-migraine-cgrp-antagonists-also-promising-in-cluster-headache/

  We demonstrated that CGRP provokes cluster headache attacks in patients with cluster headache exclusively during active phase in episodic cluster headache and in chronic cluster headache, concluded the review authors. We hypothesize that this difference hails from the hypothalamus modulating the provocability threshold of the system allowing a peripheral trigger to set off attacks. Our results also cautiously suggest efficacy of CGRP antagonism in the treatment of cluster headache and current phase 3 trials elucidating this will emerge in coming years.

• #78 Lesson: Pharmacologic Management of Cluster Headache

  https://journalce.powerpak.com/ce/pharmacologic-management-of-cluster-headache

  The posterior hypothalamus is interconnected with the trigeminovascular system, the major set of neurons in the trigeminal nerve that innervate the cerebral blood vessels. Although the mechanism is not fully elucidated and conflicting theories exist for the generation of pain symptoms associated with cluster headache, it is proposed that a disruption between these systems leads to activation of the trigeminal-autonomic reflex, resulting in both the pain and the autonomic symptoms seen in cluster headache. […] Although a direct trigger for the pain in cluster headache has not been identified, the activation of the trigeminovascular system leads to the release of pronociceptive neuropeptides, including calcitonin gene-related peptide, neurokinin A, and substance P. Afferent pain pathways from the trigeminovascular system project to the trigeminocervical complex and then to the thalamus, relaying pain signals to cortical areas, which results in pain in an individual with cluster headache. Autonomic symptoms in cluster headache are produced through reflex activation of parasympathetic pathways from afferent trigeminovascular nociceptive input. These pathways may also be innervated and controlled by the posterior hypothalamus. When activated, the parasympathetic pathways innervate the cerebral blood vessels and meninges. This innervation causes further irritation and also results in autonomic symptoms (i.e., lacrimation, rhinorrhea).

• #79 Evidence-based treatments for cluster headache | TCRM

  https://www.dovepress.com/evidence-based-treatments-for-cluster-headache-peer-reviewed-fulltext-article-TCRM

  Melatonin is suspected to be involved in CH genesis, mainly because it is a sensitive marker of endogenous rhythms, which are disrupted in CH. […] A suppressed nocturnal peak in melatonin is seen during the active phase of a CH, providing further evidence for a role of the hypothalamus gray matter in the pathophysiology of CHs. […] May et al, in a landmark study, confirmed a highly specific activation of the hypothalamic gray matter using positron emission tomography images in nitroglycerine-induced and spontaneous CHs, providing indisputable evidence for its role in CH. […] The term neurovascular headache, with reference to migraine, CH, and related disorders, is therefore a more appropriate term.

• #80 Cluster Headache: History, Mechanisms, and Most Importantly, Treatment Options

  https://practicalneurology.com/diseases-diagnoses/headache-pain/cluster-headache-history-mechanisms-and-most-importantly-treatment-options/30363/

  The cause of cluster headaches is poorly understood. About five to 10 percent of cluster headache patients have a family history of cluster headache, suggesting a genetic link. Presumably, cluster headache has multiple susceptibility genes. One of those genes may be the orexin/hypocretin receptor 2 (HCRTR2) which is implicated in sleep, narcolepsy, and hypothalamic functioning. Mutations in HCRTR2 were associated with cluster headache in two independent studies, but not in a third. Cluster headache patients are much more likely to use tobacco than the general population, and the rate of patent foramen ovale is higher, but a causative relationship with these factors has not been established. […] Cluster headaches have been associated with hypothalamic and pituitary tumors, meningiomas (anywhere from the cavernous sinus to the upper cervical spine), carotid artery dissections, vascular malformations, and sleep apnea. These associations, and the clinical features of cluster headache, suggest that there are three brain systems involved.

• #81

  https://esmed.org/MRA/mra/article/view/3363

  Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. […] Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. […] As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. […] Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251-257. […] May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275-278. […] Wei DY, Goadsby PJ. Cluster headache pathophysiology – insights from current and emerging treatments. Nature reviews Neurology. 2021;17(5):308-324.

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